FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Lin, A Brook, J Grill, J Teng, E AF Lin, A. Brook, J. Grill, J. Teng, E. TI Participant-Informant Relationship Affects Quality of Life Ratings in Incipient and Clinical Alzheimer's Disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Lin, A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Brook, J.] Univ Calif Los Angeles, David Geffen Sch Med, Med, Los Angeles, CA 90095 USA. [Grill, J.] UCI, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA. [Teng, E.] Univ Calif Los Angeles, David Geffen Sch Med, Neurol, Los Angeles, CA 90095 USA. [Teng, E.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. FU National Institute on Aging [T35 AG026736, P50 AG16570]; Alzheimer's Disease Research Centers of California; Sidell-Kagan Foundation FX National Institute on Aging (T35 AG026736 [UCLA Medical Student Training in Aging Research Program], P50 AG16570 [UCLA Alzheimer's Disease Research Center]), Alzheimer's Disease Research Centers of California, and the Sidell-Kagan Foundation NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA B119 BP S130 EP S130 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800356 ER PT J AU Linden, J Stowers, KH Veeder, H Lee, S Sanchez-Reilly, S AF Linden, J. Stowers, K. H. Veeder, H. Lee, S. Sanchez-Reilly, S. TI Protecting our Vulnerable: Mistreatment in Palliative Care SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Linden, J.] Univ Hawaii Manoa, JABSOM, Honolulu, HI 96822 USA. [Stowers, K. H.; Sanchez-Reilly, S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Veeder, H.] VITAS Hosp, San Antonio, TX USA. [Lee, S.; Sanchez-Reilly, S.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA D153 BP S271 EP S271 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800755 ER PT J AU Lum, H Jones, J Sudore, R Schwartz, R Levy, C Kutner, JD AF Lum, H. Jones, J. Sudore, R. Schwartz, R. Levy, C. Kutner, J. D. TI A Group Visit Intervention Improves Advance Care Planning Readiness, Conversations, and Documentation SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Lum, H.; Schwartz, R.; Levy, C.; Kutner, J. D.] Univ Colorado, Sch Med, Aurora, CO USA. [Lum, H.; Schwartz, R.] VA Eastern Colorado GRECC, Denver, CO USA. [Jones, J.] Univ Colorado, Coll Nursing, Aurora, CO USA. [Sudore, R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Sudore, R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. FU Colorado Health Foundation; University of Colorado Hospital/University of Colorado Denver/University Physicians, Inc. Primary Care Strategic Initiative Fund FX The Colorado Health Foundation; University of Colorado Hospital/University of Colorado Denver/University Physicians, Inc. Primary Care Strategic Initiative Fund 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA B100 BP S122 EP S123 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800337 ER PT J AU Macip-Rodriguez, PM Dunn, K Bowers, E Hayes, BM Skarf, LM AF Macip-Rodriguez, P. M. Dunn, K. Bowers, E. Hayes, B. M. Skarf, L. M. TI VA SCAN-ECHO videoconferencing program: An Innovative tool to enhance primary care health providers' knowledge and delivery of palliative care nation-wide SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Macip-Rodriguez, P. M.] Massachusetts Gen Hosp, Med, Boston, MA 02114 USA. [Dunn, K.; Bowers, E.; Hayes, B. M.; Skarf, L. M.] VA Boston Hlth Care Syst, Palliat Care, Boston, MA USA. [Macip-Rodriguez, P. M.; Skarf, L. M.] Harvard Univ, Sch Med, 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA A79 BP S45 EP S45 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800123 ER PT J AU Mireles, C Murray, A Pagan-Ferrer, J Arevalo-Flechas, LC Ross, J AF Mireles, C. Murray, A. Pagan-Ferrer, J. Arevalo-Flechas, L. C. Ross, J. TI Determining the Efficacy of Clinical Novelas as a Teaching Tool for Fall Prevention in the Geriatric Population SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Mireles, C.; Murray, A.; Pagan-Ferrer, J.; Arevalo-Flechas, L. C.; Ross, J.] Univ Texas Hlth Sci Ctr San Antonio, Hlth Sci Ctr, San Antonio, TX 78229 USA. [Mireles, C.; Murray, A.; Pagan-Ferrer, J.; Arevalo-Flechas, L. C.; Ross, J.] South Texas Vet Hlth Care Syst, GRECC, San Antonio, TX USA. FU University of Texas System Patient Safety Medical Education Award FX Supported By: University of Texas System Patient Safety Medical Education Award 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C165 BP S207 EP S208 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800576 ER PT J AU Miura, L Onitsuka, J Srikantom, S Delmar, J Blehm, R AF Miura, L. Onitsuka, J. Srikantom, S. Delmar, J. Blehm, R. TI Preliminary Outcomes of a Fall Assessment Clinic SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Miura, L.; Onitsuka, J.; Srikantom, S.; Delmar, J.; Blehm, R.] Portland VA Med Ctr, Med, Portland, OR 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA A178 BP S80 EP S80 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800222 ER PT J AU Moreira, VI Arora, VM Hull, AM Matthiesen, MI Patel, JJ Louis, AJ Hariprasad, S Meltzer, DO Dale, W Press, VG AF Moreira, V. I. Arora, V. M. Hull, A. M. Matthiesen, M. I. Patel, J. J. Louis, A. J. Hariprasad, S. Meltzer, D. O. Dale, W. Press, V. G. TI Seeing Eye to Eye: Examining the Prevalence of Poor Vision Among Senior Inpatients with Diabetes Mellitus SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Moreira, V. I.; Arora, V. M.; Hull, A. M.; Patel, J. J.; Louis, A. J.; Hariprasad, S.; Meltzer, D. O.; Dale, W.; Press, V. G.] Univ Chicago Med, Med, Augusta, GA USA. [Matthiesen, M. I.] Massachusetts Gen Hosp, Pediat, Boston, MA 02114 USA. [Moreira, V. I.] Augusta Univ, Med Coll Georgia, Augusta, GA USA. FU NHLBI [K23 HL118151]; NIDDK [P30 DK092949]; University of Chicago BSD; NIH/NIDDK [DK020593] FX NHLBI K23 HL118151, NIDDK P30 DK092949, University of Chicago BSD & NIH/NIDDK DK020593 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA B89 BP S118 EP S119 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800326 ER PT J AU Nakano, C Chen, R Bell, C Robbins, J Ross, G Abbott, R Petrovitch, H Masaki, K AF Nakano, C. Chen, R. Bell, C. Robbins, J. Ross, G. Abbott, R. Petrovitch, H. Masaki, K. TI Dysphagia as a Predictor of All-Cause Mortality: The Honolulu-Asia Aging Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Nakano, C.; Bell, C.; Ross, G.; Abbott, R.; Petrovitch, H.; Masaki, K.] Univ Hawaii, Geriatr Med, Honolulu, HI 96822 USA. [Chen, R.; Masaki, K.] Kuakini Med Ctr, Honolulu, HI USA. [Ross, G.; Petrovitch, H.] Vet Affairs Pacific Islands Hlth Care Syst, Honolulu, HI USA. [Abbott, R.] Shiga Univ Med Sci, Ctr Epidemiol Res Asia, Otsu, Shiga 52021, Japan. [Robbins, J.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Robbins, J.] Univ Wisconsin, Madison, WI USA. FU John A. Hartford Foundation Center of Excellence in Geriatrics; Department of Geriatric Medicine, University of Hawaii; John A. Burns School of Medicine, University of Hawaii; Kuakini Medical Center; National Institutes of Health (NIH) from National Institute on Aging [N01-AG-4-2149, U01 AG019349, R01AG027060, R01AG038707]; National Institutes of Health (NIH) from National Heart, Lung, and Blood Institute [N01-HC-05102]; Hawaii Community Foundation [2004-0463]; Office for Research and Development, Department of Veterans Affairs FX Supported By: This study was supported by the John A. Hartford Foundation Center of Excellence in Geriatrics, Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii; the Kuakini Medical Center; the National Institutes of Health (NIH) (Contract N01-AG-4-2149, Grants U01 AG019349, R01AG027060, and R01AG038707 from the National Institute on Aging, and Contract N01-HC-05102 from the National Heart, Lung, and Blood Institute); Hawaii Community Foundation grant 2004-0463; and the Office for Research and Development, Department of Veterans Affairs. The views expressed in this abstract do not necessarily represent those of the federal government. The funding sources had no role in the analysis. 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA B63 BP S108 EP S108 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800300 ER PT J AU Niemiec, SS Halle, A Sarkisian, C AF Niemiec, S. Schepens Halle, A. Sarkisian, C. TI Knowledge and anxiety about aging and negative bias toward older adults in White and Asian occupational therapy students SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Niemiec, S. Schepens; Halle, A.] Univ So Calif, Div Occupat Sci & Occupat Therapy, Los Angeles, CA USA. [Sarkisian, C.] GRECC, VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Sarkisian, C.] Univ Calif Los Angeles, David Geffen Sch Med, Div Geriatr, Los Angeles, CA 90095 USA. FU NIH--NCMRR [K12 HD055929]; NINDS; Midcareer Award in Patient-Oriented Community-Academic Partnered Aging Research [1K24AG047899-01] FX Supported By: Dr. Schepens Niemiec is supported by K12 HD055929 NIH--NCMRR and NINDS. Dr. Sarkisian is supported by 1K24AG047899-01 Midcareer Award in Patient-Oriented Community-Academic Partnered Aging Research. 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C79 BP S177 EP S178 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800490 ER PT J AU Nirkhe, S Rhea, EM Banks, WA AF Nirkhe, S. Rhea, E. M. Banks, W. A. TI Effects of Intranasal Insulin on Brain Insulin Signaling in an Aged Mouse Model of Alzheimer's Disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Nirkhe, S.; Rhea, E. M.; Banks, W. A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Nirkhe, S.] Univ Washington, Sch Med, Seattle, WA USA. [Rhea, E. M.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Banks, W. A.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. FU Medical Student Training in Aging Research Program, National Institute on Aging FX Supported By: Medical Student Training in Aging Research Program, National Institute on Aging NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA D122 BP S260 EP S260 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800724 ER PT J AU Obal, L Tubbesing, SA Vega, A Nelson, S Toy, S Brazier, J Bai, J Dhanani, S AF Obal, L. Tubbesing, S. A. Vega, A. Nelson, S. Toy, S. Brazier, J. Bai, J. Dhanani, S. TI Using Geographic Information Systems to Improve Practitioner Travel Efficiency in Home Based Primary Care SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Brazier, J.] VA Greater Angeles Healthcare Syst, Adm Med, Los Angeles, CA USA. [Tubbesing, S. A.] Univ Calif Los Angeles, David Geffen Sch Med, Internal Med Geriatr, Los Angeles, CA 90095 USA. [Dhanani, S.] VA Southern Oregon Rehabil Ctr & Clin, White City, OR USA. [Bai, J.] Vet Emergency Management Evaluat Ctr, Los Angeles, CA USA. [Toy, S.] VA Greater Angeles Healthcare Syst, Geriatr & Rehabil Care, Los Angeles, CA USA. [Nelson, S.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Vega, A.] Univ Penn, NewCourtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Obal, L.; Tubbesing, S. A.] VA Greater Angeles Healthcare Syst, Geriatr & Extended Care, Los Angeles, CA USA. FU VA Office of Geriatrics and Extended Care FX Supported By: VA Office of Geriatrics and Extended Care 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C117 BP S191 EP S191 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800528 ER PT J AU Pang, L Volandes, A Paasche-Orlow, M AF Pang, L. Volandes, A. Paasche-Orlow, M. TI Use of video decision aid for goals of care discussion in Mandarin-speaking older adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Pang, L.] Mt Sinai, New York, NY USA. [Volandes, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Paasche-Orlow, M.] Boston Univ, Med Ctr, 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C186 BP S215 EP S215 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800597 ER PT J AU Pang, M Bartholomew, A Castle, S Lee, CC AF Pang, M. Bartholomew, A. Castle, S. Lee, C. C. TI Maintaining Diabetes Prevention Behaviors using a Social Cognitive Health Coaching Approach Within the Construct of GEROFIT SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Pang, M.; Bartholomew, A.; Castle, S.; Lee, C. C.] VA Greater Los Angeles, GRECC, Los Angeles, CA USA. [Castle, S.; Lee, C. C.] Univ Calif Los Angeles, David Geffen Sch Med, Internal Med Geriatr, Los Angeles, CA 90095 USA. FU VA Office of Geriatrics and Extended Care Transformative Non-Institutional Long Term Care Program; VHA Office of Rural Health FX Supported By: 1) VA Office of Geriatrics and Extended Care Transformative Non-Institutional Long Term Care Program; 2) VHA Office of Rural Health 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA D142 BP S267 EP S267 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800744 ER PT J AU Phibbs, C Intrator, O Kinosian, B Scott, W Dally, S Shay, K AF Phibbs, C. Intrator, O. Kinosian, B. Scott, W. Dally, S. Shay, K. TI Cost of Care for Veterans Receiving Primary Care in Patient Aligned Care Teams (PACT) vs. Geriatric PACT SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Phibbs, C.] Stanford Univ, Stanford, CA 94305 USA. [Phibbs, C.; Scott, W.; Dally, S.] VA Palo Alto Healthcare Syst, GECDAC & HERC, Palo Alto, CA USA. [Intrator, O.] Canandaigua VA Med Ctr, GECDAC, Canandaigua, NY USA. [Intrator, O.] Univ Rochester, Rochester, NY USA. [Kinosian, B.] Philadelphia VA Med Ctr, GECDAC, Philadelphia, PA USA. [Kinosian, B.] Univ Penn, Philadelphia, PA 19104 USA. [Shay, K.] Geriatr & Extended Care VA, Washington, DC USA. FU Veterans Affairs Office of Geriatrics and Extended Care Service FX Supported By: Veterans Affairs Office of Geriatrics and Extended Care Service 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA P17 BP S7 EP S7 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800018 ER PT J AU Ritchey, KC Olney, A Wojtowicz, M Howard, I Phelan, EA Matsumoto, AM AF Ritchey, K. C. Olney, A. Wojtowicz, M. Howard, I. Phelan, E. A. Matsumoto, A. M. TI The Relationship between Self-Report and Performance-Based Measures of Mobility in Persons with Osteoporosis SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Ritchey, K. C.; Wojtowicz, M.; Matsumoto, A. M.] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Ritchey, K. C.; Phelan, E. A.; Matsumoto, A. M.] Univ Washington, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Olney, A.; Howard, I.] VA Puget Sound Hlth Care Syst, RCS, Seattle, WA 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C170 BP S209 EP S209 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800581 ER PT J AU Rodriguez, JC Alessi, C Martin, JL Hays, R Dzierzewski, J Col, N Patterson, E Jouldjian, S Josephson, K Song, Y Fung, CH AF Rodriguez, J. C. Alessi, C. Martin, J. L. Hays, R. Dzierzewski, J. Col, N. Patterson, E. Jouldjian, S. Josephson, K. Song, Y. Fung, C. H. TI Association Between Pain And Difficulty Setting Up Positive Airway Pressure Devices Among Older Adults With Sleep-Disordered Breathing SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Rodriguez, J. C.; Alessi, C.; Martin, J. L.; Hays, R.; Dzierzewski, J.; Fung, C. H.] Univ Calif Los Angeles, Med, Los Angeles, CA USA. [Rodriguez, J. C.; Alessi, C.; Martin, J. L.; Dzierzewski, J.; Jouldjian, S.; Josephson, K.; Song, Y.; Fung, C. H.] Vet Affairs Greater Los Angeles, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Col, N.] Univ New England, Main, ME USA. [Patterson, E.] Ohio State Univ, Columbus, OH 43210 USA. FU National Institute On Aging of the National Institutes of Health [K23AG045937]; Beeson Career Development in Aging Research Award Program; NIA; AFAR; John A. Hartford Foundation; Atlantic Philanthropies FX Supported By: Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number K23AG045937 and The Beeson Career Development in Aging Research Award Program (supported by NIA, AFAR, The John A. Hartford Foundation, and The Atlantic Philanthropies). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA D59 BP S238 EP S238 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800662 ER PT J AU Rothbaum, R Mitchell, S Kiel, D Lee, Y Berry, S AF Rothbaum, R. Mitchell, S. Kiel, D. Lee, Y. Berry, S. TI Surgical repair of hip fracture in nursing home (NH) residents with advanced dementia modestly improves survival SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Rothbaum, R.; Mitchell, S.; Kiel, D.; Berry, S.] BIDMC, Boston, MA USA. [Lee, Y.] Brown Univ, Providence, RI 02912 USA. FU NIA [1 R01 AG045441] FX Supported By: 1 R01 AG045441 (NIA) 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C59 BP S170 EP S170 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800470 ER PT J AU Vandenberg, AE Vaughan, C Stevens, M Hastings, SN Powers, J Markland, AD Hwang, U Hung, W Echt, K AF Vandenberg, A. E. Vaughan, C. Stevens, M. Hastings, S. N. Powers, J. Markland, A. D. Hwang, U. Hung, W. Echt, K. TI Evaluating use of a clinical decision support tool to improve quality of geriatric prescribing in the ED SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Vandenberg, A. E.; Vaughan, C.; Stevens, M.; Echt, K.] Birmingham & Atlanta VAMC, GRECC, Atlanta, GA USA. [Vandenberg, A. E.; Vaughan, C.; Stevens, M.; Echt, K.] Emory Univ, Med, Atlanta, GA 30322 USA. [Hastings, S. N.] Durham VAMC, GRECC, Durham, NC USA. [Hastings, S. N.] Duke Univ, Med, Durham, NC USA. [Powers, J.] Tennessee Valley VAMC, GRECC, Nashville, TN USA. [Powers, J.] Vanderbilt Univ, Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Markland, A. D.] Birmingham & Atlanta VAMC, GRECC, Birmingham, AL USA. [Markland, A. D.] Univ Alabama Birmingham, Med, Birmingham, AL USA. [Hwang, U.; Hung, W.] James J Peters VAMC, GRECC, Bronx, NY USA. FU VA Office of Geriatrics and Extended Care; VA office of Rural Health; John A. Hartford Foundation; Emory University Department of Medicine FX Supported By: Funding provided by the VA Office of Geriatrics and Extended Care, VA office of Rural Health, John A. Hartford Foundation, and Emory University Department of Medicine 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA C109 BP S188 EP S188 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800520 ER PT J AU Wachterman, M Li, Z Lipsitz, S Lorenz, K Marcantonio, E Keating, N AF Wachterman, M. Li, Z. Lipsitz, S. Lorenz, K. Marcantonio, E. Keating, N. TI End-of-Life Experience of Older Adults Dying of End-Stage Renal Disease Versus Cancer SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Wachterman, M.] VA Boston Healthcare Syst, Boston, MA USA. [Wachterman, M.; Lipsitz, S.; Keating, N.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Li, Z.] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Lorenz, K.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Marcantonio, E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. FU National Palliative Care Research Center; National Institute on Aging; Department of Veterans Affairs FX Supported By: National Palliative Care Research Center; National Institute on Aging; Department of Veterans Affairs. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA P34 BP S13 EP S14 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800034 ER PT J AU Zullo, AR Lee, Y Daiello, LA Mor, V Boscardin, W Steinman, M AF Zullo, A. R. Lee, Y. Daiello, L. A. Mor, V. Boscardin, W. Steinman, M. TI Effect of Beta Blocker Use on Daily Functioning, Rehospitalization, and Death After Myocardial Infarction Among Older Nursing Home Residents. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 19-21, 2016 CL Long Beach, CA SP Amer Geriatr Soc C1 [Zullo, A. R.; Lee, Y.; Daiello, L. A.; Mor, V.] Brown Univ, Hlth Serv Policy & Practice, North Kingstown, RI USA. [Boscardin, W.; Steinman, M.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Boscardin, W.; Steinman, M.] San Francisco VA Med Ctr, San Francisco, CA USA. FU NIH [5R01HL111032-03]; AHRQ [5K12HS022998-02] FX Supported By: NIH (5R01HL111032-03) and AHRQ (5K12HS022998-02) 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2016 VL 64 SU 1 SI SI MA P25 BP S10 EP S10 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK2SD UT WOS:000374763800025 ER PT J AU Gill, J Haydon, TG Rawdon, TG McFadden, AMJ Ha, HJ Shen, ZL Feng, Y Pang, J Swennes, AG Paster, BJ Dewhirst, FE Fox, JG Spence, RP AF Gill, John Haydon, Taryrn G. Rawdon, Thomas G. McFadden, Andrew M. J. Ha, Hye-Jeong Shen, Zeli Feng, Yan Pang, Jassia Swennes, Alton G. Paster, Bruce J. Dewhirst, Floyd E. Fox, James G. Spence, Richard P. TI Helicobacter bilis and Helicobacter trogontum: infectious causes of abortion in sheep SO JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION LA English DT Article DE Abortion; Helicobacter; flexispira; ovine; rappini; sheep; surveillance ID OVINE ABORTION; SP-NOV; BACTERIUM; INTESTINES; STRAINS; LIVERS; MICE; 16S AB The aim of our study was to determine the association of Helicobacter spp. that had flexispira morphology with ovine abortion, and to understand the importance of these organisms as a cause of ovine abortion in New Zealand. A retrospective diagnostic survey was carried out on laboratory submissions from ovine abortion outbreaks. A comparison was made of the proportion of laboratory submissions where Helicobacter spp. were detected from flocks that had no other agent identified (group A) with a group that had a known cause of abortion identified (group B). This latter group was considered to be a negative control, given the premise that Helicobacter spp. were not causing abortions and that Helicobacter spp. should be present at a lower rate in the group. Where no diagnosis had been made, aborted material was positive for Helicobacter spp. with flexispira morphology in 8 submissions (20%, 8/40) from 5 of the 31 survey farms (16%, 5/31). Helicobacter spp. were not detected in any of the 18 submissions from the 17 control farms (group B). Helicobacter spp. were confirmed by 16S ribosomal RNA sequencing of 3 of the Helicobacter spp. isolated by culture from the livers of aborted sheep fetuses, and 7 of the 8 where samples were positive in a Helicobacter PCR assay. The Helicobacter spp. were identified as Helicobacter trogontum (Flexispira taxon 5 genotype) and Helicobacter bilis (Flexispira taxon 8 genotype). The findings support Helicobacter spp. being a probable causative agent of ovine abortions in New Zealand. C1 [Gill, John] Gribbles Vet Pathol, Dunedin, New Zealand. [Haydon, Taryrn G.; Rawdon, Thomas G.; McFadden, Andrew M. J.; Ha, Hye-Jeong; Spence, Richard P.] Minist Primary Ind, Upper Hutt, New Zealand. [Shen, Zeli; Feng, Yan; Pang, Jassia; Swennes, Alton G.; Fox, James G.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Paster, Bruce J.; Dewhirst, Floyd E.] Forsyth Inst, Cambridge, MA USA. [Paster, Bruce J.; Dewhirst, Floyd E.] Harvard Univ, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave,16-825, Cambridge, MA 16825 USA. EM jgfox@mit.edu FU Ministry for Primary Industries, Investigation and Diagnostic Centre; Office of The Director of the National Institutes of Health [T32-OD010978, R01-OD011141]; National Institute of Environmental Health [P30-ES002109]; National Institute of Dental and Craniofacial Research [R37DE016937] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was internally funded by the Ministry for Primary Industries, Investigation and Diagnostic Centre, and supported by Office of The Director of the National Institutes of Health under award number T32-OD010978 (JGF) and R01-OD011141 (JGF), National Institute of Environmental Health Sciences under award P30-ES002109 (JGF), and The National Institute of Dental and Craniofacial Research under award R37DE016937 (FED). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 23 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1040-6387 EI 1943-4936 J9 J VET DIAGN INVEST JI J. Vet. Diagn. Invest. PD MAY PY 2016 VL 28 IS 3 BP 225 EP 234 DI 10.1177/1040638716638704 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA DL5YD UT WOS:000375712100007 PM 27016722 ER PT J AU Chapman, JR Delmonico, FL AF Chapman, Jeremy R. Delmonico, Francis L. TI Buyer beware transplantation SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID ORGAN-TRANSPLANTATION; TOURISM; TRAFFICKING AB Poor long-term outcomes of commercial transplantation of transplant tourists reinforce the need to prevent this form of human trafficking. The development of an International Convention by the Council of Europe is highlighted and the implications for physicians of the criminalizing of organ trafficking are considered. The causes of poor outcomes from transplant tourism are considered, with the actions needed to provide both equity and sufficiency of access to transplantation as critical deterrent measures. Copyright (C) 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved. C1 [Chapman, Jeremy R.] Westmead Hosp, Dept Med & Canc, Sydney, NSW 2145, Australia. [Delmonico, Francis L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. RP Chapman, JR (reprint author), Westmead Hosp, Dept Med & Canc, Sydney, NSW 2145, Australia. EM Jeremy.chapman@sydney.edu.au NR 9 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAY PY 2016 VL 89 IS 5 BP 983 EP 985 DI 10.1016/j.kint.2016.01.021 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DK2DG UT WOS:000374724200007 PM 27083275 ER PT J AU Schiff, D Hong, FX Alexander, B AF Schiff, David Hong, Fangxin Alexander, Brian TI Defining optimal initial therapy for primary CNS lymphoma SO LANCET HAEMATOLOGY LA English DT Editorial Material ID NERVOUS-SYSTEM LYMPHOMA; RADIOTHERAPY; CHEMOTHERAPY; METHOTREXATE; CONSOLIDATION; RITUXIMAB C1 [Schiff, David] Univ Virginia, Sch Med, Neurooncol Ctr, Hosp West,Jefferson Pk Ave, Charlottesville, VA 22908 USA. [Hong, Fangxin] Harvard Univ, TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Alexander, Brian] Harvard Univ, TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Radiat Oncol, Boston, MA 02115 USA. [Alexander, Brian] Harvard Univ, Sch Med, Boston, MA USA. RP Schiff, D (reprint author), Univ Virginia, Sch Med, Neurooncol Ctr, Hosp West,Jefferson Pk Ave, Charlottesville, VA 22908 USA. EM ds4jd@virginia.edu NR 10 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2352-3026 J9 LANCET HAEMATOL JI Lancet Haematol. PD MAY PY 2016 VL 3 IS 5 BP E206 EP E207 DI 10.1016/S2352-3026(16)30021-7 PG 2 WC Hematology SC Hematology GA DK7VC UT WOS:000375133300002 PM 27132691 ER PT J AU Laubach, J Garderet, L Mahindra, A Gahrton, G Caers, J Sezer, O Voorhees, P Leleu, X Johnsen, HE Streetly, M Jurczyszyn, A Ludwig, H Mellqvist, UH Chng, WJ Pilarski, L Einsele, H Hou, J Turesson, I Zamagni, E Chim, CS Mazumder, A Westin, J Lu, J Reiman, T Kristinsson, S Joshua, D Roussel, M O'Gorman, P Terpos, E McCarthy, P Dimopoulos, M Moreau, P Orlowski, RZ Miguel, JS Anderson, KC Palumbo, A Kumar, S Rajkumar, V Durie, B Richardson, PG AF Laubach, J. Garderet, L. Mahindra, A. Gahrton, G. Caers, J. Sezer, O. Voorhees, P. Leleu, X. Johnsen, H. E. Streetly, M. Jurczyszyn, A. Ludwig, H. Mellqvist, U-H Chng, W-J Pilarski, L. Einsele, H. Hou, J. Turesson, I. Zamagni, E. Chim, C. S. Mazumder, A. Westin, J. Lu, J. Reiman, T. Kristinsson, S. Joshua, D. Roussel, M. O'Gorman, P. Terpos, E. McCarthy, P. Dimopoulos, M. Moreau, P. Orlowski, R. Z. Miguel, J. S. Anderson, K. C. Palumbo, A. Kumar, S. Rajkumar, V. Durie, B. Richardson, P. G. TI Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group SO LEUKEMIA LA English DT Review ID STEM-CELL TRANSPLANTATION; LENALIDOMIDE PLUS DEXAMETHASONE; SINGLE-AGENT CARFILZOMIB; HIGH-DOSE CHEMOTHERAPY; BORTEZOMIB-THALIDOMIDE-DEXAMETHASONE; PEGYLATED LIPOSOMAL DOXORUBICIN; BONE-MARROW-TRANSPLANTATION; PREVIOUSLY TREATED PATIENTS; HIGH-RISK CYTOGENETICS; RANDOMIZED PHASE-III AB The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM. C1 [Laubach, J.; Anderson, K. C.; Richardson, P. G.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Garderet, L.] Hop St Antoine, F-75571 Paris, France. [Mahindra, A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gahrton, G.; Kristinsson, S.] Karolinska Univ Hosp Huddinge, Ctr Hematol, Karolinska Inst, Stockholm, Sweden. [Caers, J.] CHU Liege, Dept Hematol, Liege, Belgium. [Sezer, O.] Mem Hosp, Dept Hematol, Istanbul, Turkey. [Voorhees, P.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Leleu, X.] CHRU Lille, Hop Huriez, Malad Sang, F-59037 Lille, France. [Johnsen, H. E.] Aalborg Univ Hosp, Aalborg, Denmark. [Streetly, M.] Kings Coll Hosp London, London, England. [Jurczyszyn, A.] Jagiellonian Univ, Coll Med, Krakow, Poland. [Ludwig, H.] Wilhelminenspital Stadt Wien, Wilhelminen Canc Res Inst, Vienna, Austria. [Mellqvist, U-H] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Chng, W-J] Natl Univ Singapore, Canc Sci Inst, Singapore 117548, Singapore. [Pilarski, L.] Univ Alberta, Edmonton, AB, Canada. [Pilarski, L.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Einsele, H.] Univ Hosp Wurzburg, Div Hematol, Dept Internal Med 2, Wurzburg, Germany. [Hou, J.] Second Mil Med Univ, Changzheng Hosp, Myeloma & Lymphoma Ctr, Shanghai, Peoples R China. [Turesson, I.] Skano Univ Hosp, Malmo, Sweden. [Zamagni, E.] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Chim, C. S.] Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Mazumder, A.] NYU, Ctr Comprehens Canc, New York, NY USA. [Westin, J.] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Lu, J.] Peking Univ, Peoples Hosp, Beijing 100871, Peoples R China. [Reiman, T.] St Johns Hosp, St John, NB, Canada. [Reiman, T.] Dalhousie Univ, St John, NB, Canada. [Joshua, D.] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia. [Roussel, M.] Hop Purpan, Hematol Clin, Toulouse, France. [O'Gorman, P.] Dublin City Univ, Natl Inst Cellular Biotechnol, Dublin 9, Ireland. [Terpos, E.; Dimopoulos, M.] Univ Athens, Sch Med, Athens 11528, Greece. [McCarthy, P.] Roswell Pk Canc Inst, Blood & Marrow Transplant Program, Buffalo, NY 14263 USA. [Moreau, P.] Univ Hosp Hotel Dieu, Nantes, France. [Orlowski, R. Z.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Miguel, J. S.] Univ Navarra, Univ Navarra Clin, Ctr Invest Med Aplicada, E-31080 Pamplona, Spain. [Palumbo, A.] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Kumar, S.; Rajkumar, V.] Mayo Clin, Rochester, MN USA. [Durie, B.] Cedars Sinai Outpatient Canc Ctr, Los Angeles, CA USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM paul_richardson@dfci.harvard.edu RI richard, chrystelle/K-8595-2015 FU Amgen; Celgene; Janssen; Celgene Corporation; Millennium Pharmaceuticals: A Takeda Oncology Company; Novartis; Array Biopharma; Oncopeptides; Onyx Pharmaceuticals; GlaxoSmithKline; Acetylon Pharmaceuticals; Takeda; Amgen/Onyx; Janssen-Cilag; Onyx; NIH; Bristol-Myers Squibb; Millennium Pharmaceuticals; Merck; Millennium; Sanofi/Genzyme; Spectrum Pharmaceuticals FX JL reports grants from Novartis, grants from Celgene, grants from Onyx, grants from Millennium, outside the submitted work. LG reports personal fees from BMS, personal fees from Amgen, outside the submitted work. AM has received honorarium from Millennium Pharmaceuticals in the last 36 months for advisory board. GG reports grants and personal fees from Celgene, personal fees from Fujimoto Pharmaceutical Company, Japan, outside the submitted work. OS reports personal fees from Amgen, personal fees from Celgene and personal fees from Janssen. PV reports personal fees and other from Celgene Corporation, personal fees from Millennium Pharmaceuticals: A Takeda Oncology Company, personal fees from Novartis, other from Array Biopharma, grants and other from Oncopeptides, grants from Onyx Pharmaceuticals, grants and personal fees from GlaxoSmithKline, grants from Janssen and grants from Acetylon Pharmaceuticals. XL has received honorarium from Celgene, Millennium, Amgen, Janssen, Novartis, BMS, TEVA, LeoPHARMA and Pierre Fabre. MS has received Speakers Fees from Celgene and Janssen. HL reports grants from Takeda, grants and personal fees from Celgene, personal fees from Amgen/Onyx, personal fees from Janssen-Cilag. U-HM reports honoraria from Novartis, Mundipharma, Celgene, Amgen and Janssen and participated in advisory boards for Amgen and Celgene. WJC has received Honorarium from Celgene, Janssen, Millennium Takeda, Novartis and Onyx. EZ has received honoraria from Celgene and Janssen. CSC has received honorarium from Celgene and Janssen. TR has received honoraria from Celgene and Janssen. DJ has served on the advisory boards for Celgene, Onyx and Janssen; DJ has received payment for services from Celgene and Janssen. MR reports grants and personal fees from Celgene, grants from Janssen and grants from Onyx. POG has received honoraria from Celgene, Janssen and Takeda. ET has received honoraria and research grants from Amgen and Janssen-Cilag; ET has received honoraria from Celgene and Roche. PM has received compensation/honoraria for participation in scientific advisory boards for Celgene, Janssen, Sanofi, Karyopharm, The Binding Site and Bristol Myers Squibb. MD has received honoraria from Celgene, Janssen, Onyx, Takeda and Novartis. PM has served on the advisory board for Janssen, Celgene, Takeda, Novartis and Amgen. RO has been funded by the NIH, and has also received research grants from Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Janssen, Millennium Pharmaceuticals and Spectrum Pharmaceuticals. In addition, he has served on scientific advisory boards with compensation for Abbott Laboratories, Amgen, Inc., Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Forma Therapeutics, Incyte, Janssen, Millennium Pharmaceuticals, on scientific advisory boards without compensation for Acetylon Pharmaceuticals, Inc. KCA has served on Advisory boards for Celgene, Millennium, Sanofi Aventis, Gilead and Bristol-Myers Squibb. KA is also the scientific founder of Acetylon and Oncopep. AP has received honoraria from Janssen, Celgene, Amgen, Millennium/Takeda and BMS. SK's institution has received consulting fees from Merck, Millennium, Celgene, Sanofi/Genzyme and Onyx and grants from R01. SK has received payment for services from Sharp Healthcare. PGR has served on advisory boards for Celgene, Millennium, Johnson & Johnson, Novartis, Bristol-Myers Squibb and Onyx. JC, HEJ, AJ, LP, HE, JH, IT, AM, JW, JL, SK, VR and BD have nothing to disclose. NR 128 TC 12 Z9 12 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1005 EP 1017 DI 10.1038/leu.2015.356 PG 13 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800001 PM 26710887 ER PT J AU Chng, WJ Chung, TH Kumar, S Usmani, S Munshi, N Avet-Loiseau, H Goldschmidt, H Durie, B Sonneveld, P AF Chng, W. J. Chung, T-H Kumar, S. Usmani, S. Munshi, N. Avet-Loiseau, H. Goldschmidt, H. Durie, B. Sonneveld, P. CA Int Myeloma Working Grp TI Gene signature combinations improve prognostic stratification of multiple myeloma patients SO LEUKEMIA LA English DT Article ID INTERNATIONAL STAGING SYSTEM; TOTAL THERAPY 3; INTERGROUPE FRANCOPHONE; EXPRESSION SIGNATURE; BORTEZOMIB; PREDICTION; SURVIVAL; CLASSIFICATION; PATHOGENESIS; METAANALYSIS AB Multiple myeloma (MM) is a plasma cell neoplasm with significant molecular heterogeneity. Gene expression profiling (GEP) has contributed significantly to our understanding of the underlying biology and has led to several prognostic gene signatures. However, the best way to apply these GEP signatures in clinical practice is unclear. In this study, we investigated the integration of proven prognostic signatures for improved patient risk stratification. Three publicly available MM GEP data sets that encompass newly diagnosed as well as relapsed patients were analyzed using standardized estimation of nine prognostic MM signature indices and simulations of signature index combinations. Cox regression analysis was used to assess the performance of simulated combination indices. Taking the average of multiple GEP signature indices was a simple but highly effective way of integrating multiple GEP signatures. Furthermore, although adding more signatures in general improved performance substantially, we identified a core signature combination, EMC92+HZDCD, as the top-performing prognostic signature combination across all data sets. In this study, we provided a rationale for gene signature integration and a practical strategy to choose an optimal risk score estimation in the presence of multiple prognostic signatures. C1 [Chng, W. J.] Natl Univ Singapore, Canc Sci Inst, Singapore 117548, Singapore. [Chung, T-H] Natl Univ Hlth Syst, Natl Univ Canc Inst Singapore, Singapore, Singapore. [Kumar, S.] Mayo Clin, Dept Hematol, Rochester, MN USA. [Usmani, S.] Carolinas Healthcare Syst, Levine Canc Inst, Charlotte, NC USA. [Munshi, N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Avet-Loiseau, H.] Univ Toulouse, Unite Genom Myelome, Toulouse, France. [Goldschmidt, H.] Univ Heidelberg Hosp, Heidelberg, Germany. [Durie, B.] Cedars Sinai Samuel Oschin Canc Ctr, Los Angeles, CA USA. [Sonneveld, P.] Erasmus MC, Rotterdam, Netherlands. RP Chng, WJ (reprint author), Natl Univ Canc Inst, Canc Sci Inst Singapore, 1E Kent Ridge Rd,NUHS Tower Block, Singapore 119228, Singapore. EM mdccwj@nus.edu.sg NR 31 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1071 EP 1078 DI 10.1038/leu.2015.341 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800008 PM 26669975 ER PT J AU Moschetta, M Mishima, Y Kawano, Y Manier, S Paiva, B Palomera, L Aljawai, Y Calcinotto, A Unitt, C Sahin, I Sacco, A Glavey, S Shi, J Reagan, MR Prosper, F Bellone, M Chesi, M Bergsagel, LP Vacca, A Roccaro, AM Ghobrial, IM AF Moschetta, M. Mishima, Y. Kawano, Y. Manier, S. Paiva, B. Palomera, L. Aljawai, Y. Calcinotto, A. Unitt, C. Sahin, I. Sacco, A. Glavey, S. Shi, J. Reagan, M. R. Prosper, F. Bellone, M. Chesi, M. Bergsagel, L. P. Vacca, A. Roccaro, A. M. Ghobrial, I. M. TI Targeting vasculogenesis to prevent progression in multiple myeloma SO LEUKEMIA LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; BONE-MARROW ANGIOGENESIS; HEMATOLOGIC MALIGNANCIES; TUMOR PROGRESSION; MASS CYTOMETRY; MOUSE MODEL; ANTIANGIOGENESIS; VASCULARIZATION; MOBILIZATION; THALIDOMIDE AB The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions. C1 [Moschetta, M.; Mishima, Y.; Kawano, Y.; Manier, S.; Aljawai, Y.; Sahin, I.; Sacco, A.; Glavey, S.; Reagan, M. R.; Roccaro, A. M.; Ghobrial, I. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Moschetta, M.; Vacca, A.] Univ Bari, Sch Med, Bari, Italy. [Paiva, B.; Prosper, F.] Univ Navarra Clin, CIMA, Pamplona, Spain. [Palomera, L.] Hosp Clin Univ Lozano Blesa, Zaragoza, Spain. [Calcinotto, A.; Bellone, M.] IRCCS San Raffaele Sci Inst, Cellular Immunol Unit, Milan, Italy. [Unitt, C.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Shi, J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Reagan, M. R.] Maine Med Ctr Res Inst, Scarborough, ME USA. [Chesi, M.; Bergsagel, L. P.] Mayo Clin, Ctr Comprehens Canc, Scottsdale, AZ USA. [Roccaro, A. M.] Spedali Civili Brescia, Dept Hematol, CREA, Brescia, Italy. RP Roccaro, AM; Ghobrial, IM (reprint author), Dana Farber Canc Inst, Med Oncol, 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; Bellone, Matteo/0000-0002-2586-2569; Reagan, Michaela/0000-0003-2884-6481 FU NIH [R01 CA181683-01A1]; Leukemia and Lymphoma Society; Associazione Italiana per la Ricerca sul Cancro, AIRC 5 x 1000 Molecular Clinical Oncology Special Program, Milan, IT [9965]; AIRC/FIRC FX We wish to thank the Animal Research Facility (ARF) team of the Dana Farber Cancer Institute for the valuable technical support. We thank Dr Benezra R (Memorial Sloan-Kettering Institute, NY, USA) for providing us the ID1/ID3 transgenic mice. We thank Sonal Jhaveri (PGSAO, Dana Farber Cancer Institute) for editing the manuscript. We thank Eli Lilly & Co. for providing the DC101 antibody. This work was supported by NIH R01 CA181683-01A1 and the Leukemia and Lymphoma Society. This work was supported by Associazione Italiana per la Ricerca sul Cancro, AIRC 5 x 1000 Molecular Clinical Oncology Special Program, Milan, IT (grant no. 9965 to M Bellone and A Vacca). Arianna Calcinotto was awarded a fellowship from AIRC/FIRC and conducted this study in partial fulfillment of her PhD at San Raffaele University. NR 42 TC 4 Z9 4 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1103 EP 1115 DI 10.1038/leu.2016.3 PG 13 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800012 PM 26859080 ER PT J AU Argyropoulos, KV Vogel, R Ziegler, C Altan-Bonnet, G Velardi, E Calafiore, M Dogan, A Arcila, M Patel, M Knapp, K Mallek, C Hunter, ZR Treon, SP van den Brink, MRM Palomba, ML AF Argyropoulos, K. V. Vogel, R. Ziegler, C. Altan-Bonnet, G. Velardi, E. Calafiore, M. Dogan, A. Arcila, M. Patel, M. Knapp, K. Mallek, C. Hunter, Z. R. Treon, S. P. van den Brink, M. R. M. Palomba, M. L. TI Clonal B cells in Waldenstrom's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling SO LEUKEMIA LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; M MONOCLONAL GAMMOPATHY; NON-HODGKIN-LYMPHOMA; MYD88 L265P; TYROSINE KINASE; FOLLICULAR LYMPHOMA; TUMOR PROGRESSION; SOMATIC MUTATION; FLOW-CYTOMETRY AB Waldenstrom's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a 'high' and a 'healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups. C1 [Argyropoulos, K. V.; Velardi, E.; Calafiore, M.; van den Brink, M. R. M.] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. [Vogel, R.; Ziegler, C.; Altan-Bonnet, G.] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA. [Dogan, A.; Arcila, M.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Patel, M.; Knapp, K.; Mallek, C.] Mem Sloan Kettering Canc Ctr, Hematol Oncol Tissue Bank, New York, NY 10065 USA. [Hunter, Z. R.; Treon, S. P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [van den Brink, M. R. M.; Palomba, M. L.] Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, 1275 York Ave, New York, NY 10065 USA. RP Palomba, ML (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, 1275 York Ave, New York, NY 10065 USA. EM Palombam@mskcc.org OI VELARDI, ENRICO/0000-0001-8383-0453; Hunter, Zachary/0000-0002-1689-1691 FU Lymphoma Foundation; NIH fund [U54 CA148967]; SASS Medical Foundation Post-Doctoral Research Fellowship FX We would like to thank Dr Katya Manova, Dmitry Yarilin and Mesruh Turkekul from the Molecular Cytology Core Facility at Memorial Sloan Kettering Cancer Center for the help with immunohistochemistry studies. This work was supported by The Lymphoma Foundation and NIH U54 CA148967 fund. KVA is supported by a SASS Medical Foundation Post-Doctoral Research Fellowship. NR 47 TC 2 Z9 2 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1116 EP 1125 DI 10.1038/leu.2016.8 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800013 PM 26867669 ER PT J AU Driessen, EMC de Lorenzo, P Campbell, M Felice, M Ferster, A Hann, I Vora, A Hovi, L Escherich, G Li, CK Mann, G Leblanc, T Locatelli, F Biondi, A Rubnitz, J Schrappe, M Silverman, L Stary, J Suppiah, R Szczepanski, T Valsecchi, M Pieters, R AF Driessen, E. M. C. de Lorenzo, P. Campbell, M. Felice, M. Ferster, A. Hann, I. Vora, A. Hovi, L. Escherich, G. Li, C. K. Mann, G. Leblanc, T. Locatelli, F. Biondi, A. Rubnitz, J. Schrappe, M. Silverman, L. Stary, J. Suppiah, R. Szczepanski, T. Valsecchi, M. Pieters, R. TI Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol SO LEUKEMIA LA English DT Letter ID STEM-CELL TRANSPLANTATION; MLL GENE REARRANGEMENTS; CHILDRENS ONCOLOGY GROUP; CHEMOTHERAPY; INHIBITOR; SURVIVAL; IMPACT C1 [Driessen, E. M. C.; Pieters, R.] Erasmus MC Sophia Childrens Hosp, Pediat Oncol Hematol, Rotterdam, Netherlands. [de Lorenzo, P.; Valsecchi, M.] Univ Milano Bicocca, Dept Clin Med & Prevent, Interfant Trial Data Ctr 99, Monza, Italy. [Campbell, M.] Univ Chile, Roberto del Rio Hosp, Chilean Natl Pediat Oncol Grp, PINDA, Santiago, Chile. [Felice, M.] Hosp Pediat Prof Dr Juan P Garrahan, Dept Pediat Hematol Oncol, Buenos Aires, DF, Argentina. [Ferster, A.] Hop Univ Enfants Reine Fabiola ULB, Dept Hematooncol, Brussels, Belgium. [Hann, I.] Great Ormond St Hosp Sick Children, UK Childrens Canc Study Grp, London, England. [Vora, A.] Sheffield Childrens Hosp, Dept Paediat Haematol, Sheffield, S Yorkshire, England. [Hovi, L.] Univ Helsinki, Nord Soc Paediat Haematol & Oncol, Helsinki, Finland. [Escherich, G.] Univ Med Ctr Hamburg Eppendorf, Clin Pediat Hematol & Oncol, Hamburg, Germany. [Li, C. K.] Prince Wales Hosp, Hong Kong Paediat Haematol & Oncol Study Grp, Hong Kong, Hong Kong, Peoples R China. [Mann, G.] Med Univ Sch, St Anna Childrens Canc Res Inst, A-1090 Vienna, Austria. [Mann, G.] Med Univ Sch, St Anna Childrens Hosp, Dept Pediat, A-1090 Vienna, Austria. [Leblanc, T.] Hop Robert Debre, Dept Pediat Hematol, Ft He FRALLE Grp, F-75019 Paris, France. [Locatelli, F.; Biondi, A.] Italy Bambino Gesu Childrens Hosp, Assoc Italiana Ematol Oncol Pediat, Rome, Italy. [Rubnitz, J.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Schrappe, M.] Berlin Frankfurt Munster Study Grp, Hannover, Germany. [Silverman, L.] Dana Farber Canc Inst, ALL Consortium, Boston, MA 02115 USA. [Stary, J.] Czech Pediat Haematol, Prague, Czech Republic. [Suppiah, R.] Australian & New Zealand Childrens Haematol & Onc, North Adelaide, Australia. [Szczepanski, T.] Med Univ Silesia, Polish Pediat Leukemia & Lymphoma Study Grp, Katowice, Poland. [Szczepanski, T.] Med Univ Silesia, Dept Pediat Hematol & Oncol, Katowice, Poland. [Pieters, R.] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Pieters, R.] Dutch Childhood Oncol Grp, The Hague, Netherlands. RP Pieters, R (reprint author), Erasmus MC Sophia Childrens Hosp, Pediat Oncol Hematol, Rotterdam, Netherlands.; Pieters, R (reprint author), Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.; Pieters, R (reprint author), Dutch Childhood Oncol Grp, The Hague, Netherlands. EM r.pieters@prinsesmaximacentrum.nl NR 15 TC 3 Z9 4 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1184 EP 1187 DI 10.1038/leu.2015.246 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800021 PM 26369984 ER PT J AU Arreba-Tutusaus, P Mack, TS Bullinger, L Schnoder, TM Polanetzki, A Weinert, S Ballaschk, A Wang, Z Deshpande, AJ Armstrong, SA Dohner, K Fischer, T Heidel, FH AF Arreba-Tutusaus, P. Mack, T. S. Bullinger, L. Schnoeder, T. M. Polanetzki, A. Weinert, S. Ballaschk, A. Wang, Z. Deshpande, A. J. Armstrong, S. A. Doehner, K. Fischer, T. Heidel, F. H. TI Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo SO LEUKEMIA LA English DT Letter ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; KINASE INHIBITOR; MUTATIONS; EXPRESSION; IMATINIB; PKC412; GENE; SIZE C1 [Arreba-Tutusaus, P.; Mack, T. S.; Schnoeder, T. M.; Polanetzki, A.; Ballaschk, A.; Fischer, T.; Heidel, F. H.] Univ Magdeburg, Ctr Internal Med, Dept Hematol & Oncol, D-39106 Magdeburg, Saxony Anhalt, Germany. [Bullinger, L.; Doehner, K.] Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Baden Wurttembe, Germany. [Bullinger, L.; Wang, Z.; Deshpande, A. J.; Armstrong, S. A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bullinger, L.; Wang, Z.; Deshpande, A. J.; Armstrong, S. A.] Harvard Univ, Sch Med, Boston, MA USA. [Weinert, S.] Univ Magdeburg, Ctr Internal Med, Dept Cardiol & Angiol, D-39106 Magdeburg, Saxony Anhalt, Germany. [Deshpande, A. J.] Sanford Burnham Med Res Inst, Tumor Initiat & Maintenance, La Jolla, CA USA. [Armstrong, S. A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY USA. [Armstrong, S. A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY USA. RP Heidel, FH (reprint author), Univ Magdeburg, Ctr Internal Med, Dept Hematol & Oncol, D-39106 Magdeburg, Saxony Anhalt, Germany. EM florian.heidel@med.ovgu.de FU NCI NIH HHS [P01 CA066996, P30 CA008748] NR 16 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1220 EP 1225 DI 10.1038/leu.2015.292 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800032 PM 26487272 ER PT J AU Ye, HH Ma, D Jiang, Y Cauley, SF Du, YP Wald, LL Griswold, MA Setsompop, K AF Ye, Huihui Ma, Dan Jiang, Yun Cauley, Stephen F. Du, Yiping Wald, Lawrence L. Griswold, Mark A. Setsompop, Kawin TI Accelerating magnetic resonance fingerprinting (MRF) using t-blipped simultaneous multislice (SMS) acquisition SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MR fingerprinting (MRF); simultaneous multislice (SMS); t-blipped SMS-MRF ID RECONSTRUCTION; GRAPPA; EXCITATION; IMAGES; GROG; FMRI AB PurposeWe incorporate simultaneous multislice (SMS) acquisition into MR fingerprinting (MRF) to accelerate the MRF acquisition. MethodsThe t-Blipped SMS-MRF method is achieved by adding a G(z) blip before each data acquisition window and balancing it with a G(z) blip of opposing polarity at the end of each TR. Thus the signal from different simultaneously excited slices are encoded with different phases without disturbing the signal evolution. Furthermore, by varying the G(z) blip area and/or polarity as a function of repetition time, the slices' differential phase can also be made to vary as a function of time. For reconstruction of t-Blipped SMS-MRF data, we demonstrate a combined slice-direction SENSE and modified dictionary matching method. ResultsIn Monte Carlo simulation, the parameter mapping from multiband factor (MB)=2 t-Blipped SMS-MRF shows good accuracy and precision when compared with results from reference conventional MRF data with concordance correlation coefficients (CCC) of 0.96 for T-1 estimates and 0.90 for T-2 estimates. For in vivo experiments, T-1 and T-2 maps from MB=2 t-Blipped SMS-MRF have a high agreement with ones from conventional MRF. ConclusionThe MB=2 t-Blipped SMS-MRF acquisition/reconstruction method has been demonstrated and validated to provide more rapid parameter mapping in the MRF framework. Magn Reson Med 75:2078-2085, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Ye, Huihui; Du, Yiping] Zhejiang Univ, Minist China, Collaborat Innovat Ctr Brain Sci, Hangzhou 310003, Zhejiang, Peoples R China. [Ye, Huihui; Du, Yiping] Zhejiang Univ, Minist China, Key Lab Biomed Engn Educ, Hangzhou 310003, Zhejiang, Peoples R China. [Ye, Huihui; Cauley, Stephen F.; Wald, Lawrence L.; Setsompop, Kawin] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Ma, Dan; Jiang, Yun; Griswold, Mark A.] Case Western Reserve Univ, Dept Biomed Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Cauley, Stephen F.; Wald, Lawrence L.; Setsompop, Kawin] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wald, Lawrence L.] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Griswold, Mark A.] Case Western Reserve Univ, Dept Radiol, Cleveland, OH 44106 USA. [Griswold, Mark A.] Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Setsompop, K (reprint author), 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM kawin@nmr.mgh.harvard.edu RI Wald, Lawrence/D-4151-2009 FU NIH NIBIB [R01EB017219, R00EB012107, R01EB017337, P41EB015896]; National Key Basic Research Program of China [2013CB329501]; National Natural Science Foundation of China [81371518] FX Grant sponsor: NIH NIBIB; Grant numbers: R01EB017219, R00EB012107, R01EB017337, P41EB015896; Grant sponsor: the National Key Basic Research Program of China; Grant number: 2013CB329501; Grant sponsor: the National Natural Science Foundation of China; Grant number: 81371518. NR 23 TC 2 Z9 2 U1 5 U2 10 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 MAY PY 2016 VL 75 IS 5 BP 2078 EP 2085 DI 10.1002/mrm.25799 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DJ8WX UT WOS:000374495600025 PM 26059430 ER PT J AU Kyle, RA Steensma, DP Shampo, MA AF Kyle, Robert A. Steensma, David P. Shampo, Marc A. TI Barry James Marshall-Discovery of Helicobacter pylori as a Cause of Peptic Ulcer SO MAYO CLINIC PROCEEDINGS LA English DT Biographical-Item C1 [Kyle, Robert A.; Shampo, Marc A.] Mayo Clin, Rochester, MN USA. [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kyle, RA (reprint author), Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 5 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD MAY PY 2016 VL 91 IS 5 BP E67 EP E68 DI 10.1016/j.mayocp.2016.01.025 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DL8FU UT WOS:000375877200002 PM 27150219 ER PT J AU Friedman, CP Donaldson, KM Vantsevich, AV AF Friedman, Charles P. Donaldson, Katherine M. Vantsevich, Anna V. TI Educating medical students in the era of ubiquitous information SO MEDICAL TEACHER LA English DT Article ID HEALTH-CARE; TECHNOLOGY; ERROR AB Health care around the world is going digital. This inexorable trend will result in: (1) routine documentation of care in digital form and emerging national infrastructures for sharing data that allow progress toward a learning health system; and (2) a biomedical knowledge cloud that is fully integrated into practice environments and accessible to both providers and consumers of healthcare. Concurrently, medical students will be complete digital natives who have literally grown up with the Internet and will enter practice early in the next decade when the projected changes in practice approach maturity. This essay describes three competencies linked to this evolving information environment(1) knowing what you do and don't know, (2) ability to ask a good question, and (3) skills in evaluating and weighing evidenceand suggests educational approaches to promote student mastery of each competency. Shifting medical education to address these competencies will call into question many current methods but may be essential to fully prepare trainees for optimal practice in the future. C1 [Friedman, Charles P.] Univ Michigan, Sch Med, Dept Learning Hlth Sci, Ann Arbor, MI 48109 USA. [Friedman, Charles P.] Univ Michigan, Sch Informat, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Donaldson, Katherine M.] Univ Chicago, NORC, Hlth Sci, Bethesda, MD USA. [Vantsevich, Anna V.] Mental Hlth Serv, San Francisco VA Med Ctr, San Francisco, CA USA. RP Friedman, CP (reprint author), Univ Michigan, Sch Med, 209 Victor Vaughan Bldg,SPC 2054, Ann Arbor, MI 48109 USA. EM cpfried@umich.edu NR 29 TC 0 Z9 0 U1 6 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0142-159X EI 1466-187X J9 MED TEACH JI Med. Teach. PD MAY PY 2016 VL 38 IS 5 BP 504 EP 509 DI 10.3109/0142159X.2016.1150990 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DL7YD UT WOS:000375855400010 PM 27027546 ER PT J AU Malorni, L Giuliano, M Migliaccio, I Wang, T Creighton, CJ Lupien, M Fu, XY Hilsenbeck, SG Healy, N De Angelis, C Mazumdar, A Trivedi, MV Massarweh, S Gutierrez, C De Placido, S Jeselsohn, R Brown, M Brown, PH Osborne, CK Schiff, R AF Malorni, Luca Giuliano, Mario Migliaccio, Ilenia Wang, Tao Creighton, Chad J. Lupien, Mathieu Fu, Xiaoyong Hilsenbeck, Susan G. Healy, Nuala De Angelis, Carmine Mazumdar, Abhijit Trivedi, Meghana V. Massarweh, Suleiman Gutierrez, Carolina De Placido, Sabino Jeselsohn, Rinath Brown, Myles Brown, Powel H. Osborne, C. Kent Schiff, Rachel TI Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance SO MOLECULAR CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; ACTIVATED PROTEIN-KINASE; ESTROGEN-RECEPTOR-ALPHA; TAMOXIFEN RESISTANCE; ELEVATED LEVELS; DNA-BINDING; CROSS-TALK; ER-ALPHA; GROWTH; ANTIESTROGEN AB The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo. AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program. Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance. C1 [Malorni, Luca; Giuliano, Mario; Wang, Tao; Creighton, Chad J.; Fu, Xiaoyong; Hilsenbeck, Susan G.; De Angelis, Carmine; Trivedi, Meghana V.; Gutierrez, Carolina; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Malorni, Luca; Giuliano, Mario; Wang, Tao; Creighton, Chad J.; Fu, Xiaoyong; Hilsenbeck, Susan G.; De Angelis, Carmine; Trivedi, Meghana V.; Gutierrez, Carolina; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA. [Malorni, Luca; Giuliano, Mario; Creighton, Chad J.; Fu, Xiaoyong; Hilsenbeck, Susan G.; De Angelis, Carmine; Trivedi, Meghana V.; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Malorni, Luca; Migliaccio, Ilenia] Hosp Prato, Sandro Pitigliani Med Oncol Unit, Via Suor Niccolina 20, I-59100 Prato, Italy. [Malorni, Luca; Migliaccio, Ilenia] Hosp Prato, Translat Res Unit, Dept Oncol, Prato, Italy. [Giuliano, Mario; De Angelis, Carmine; De Placido, Sabino] Univ Naples Federico II, Div Oncol, Dept Clin Med & Surg, Naples, Italy. [Lupien, Mathieu] Univ Toronto, Univ Hlth Network, Ontario Inst Canc Res, Ontario Canc Inst,Princess Margaret Canc Ctr, Toronto, ON, Canada. [Lupien, Mathieu] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Healy, Nuala] St James Hosp, Dept Radiol, Dublin 8, Ireland. [Mazumdar, Abhijit; Brown, Powel H.] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Trivedi, Meghana V.] Univ Houston, Coll Pharm, Dept Clin Sci & Adm, Houston, TX 77030 USA. [Massarweh, Suleiman] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Massarweh, Suleiman] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA. [Gutierrez, Carolina] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Jeselsohn, Rinath; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jeselsohn, Rinath; Brown, Myles] Harvard Univ, Sch Med, Boston, MA USA. [Jeselsohn, Rinath; Brown, Myles] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Malorni, L (reprint author), Hosp Prato, Sandro Pitigliani Med Oncol Unit, Via Suor Niccolina 20, I-59100 Prato, Italy.; Schiff, R (reprint author), Baylor Coll Med, 1 Baylor Plaza,Alkek Buld N1230, Houston, TX 77030 USA. EM lmalorni@uslcentro.toscana.it; rschiff@bcm.edu FU American Italian Cancer Foundation; Susan G. Komen for the cure grants; Promise grant [PG12221410]; Stand Up 2 Cancer Dream Team Translational Research Grant [SU2C-AACR-DT0409]; NIH [P50 CA058183, CA186784-01]; Cancer Center Grant [P30CA125123]; EIF/Lee Jeans Breast Cancer Research Program; Breast Cancer Research Foundation; Cancer Prevention Research Institute of Texas [CPRIT RP140102]; Baylor College of Medicine Comprehensive Cancer Training Program FX This study was partly supported by the American Italian Cancer Foundation, Susan G. Komen for the cure grants (to L. Malorni and R. Schiff) and Promise grant PG12221410 (to C.K. Osborne and R. Schiff), a Stand Up 2 Cancer Dream Team Translational Research Grant (grant Number SU2C-AACR-DT0409), NIH SPORE grants P50 CA058183 and CA186784-01, and Cancer Center Grant P30CA125123, the EIF/Lee Jeans Breast Cancer Research Program, Breast Cancer Research Foundation, Cancer Prevention Research Institute of Texas (CPRIT RP140102), and Baylor College of Medicine Comprehensive Cancer Training Program (to M. Giuliano and C. De Angelis). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. NR 36 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD MAY PY 2016 VL 14 IS 5 BP 470 EP 481 DI 10.1158/1541-7786.MCR-15-0423 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7XE UT WOS:000375852900006 PM 26965145 ER PT J AU Tsai, SQ Topkar, VV Joung, JK Aryee, MJ AF Tsai, Shengdar Q. Topkar, Ved V. Joung, J. Keith Aryee, Martin J. TI Open-source guideseq software for analysis of GUIDE-seq data SO NATURE BIOTECHNOLOGY LA English DT Letter C1 [Tsai, Shengdar Q.; Topkar, Ved V.; Joung, J. Keith; Aryee, Martin J.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Tsai, Shengdar Q.; Topkar, Ved V.; Joung, J. Keith; Aryee, Martin J.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Tsai, Shengdar Q.; Topkar, Ved V.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Tsai, Shengdar Q.; Joung, J. Keith; Aryee, Martin J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Aryee, Martin J.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Joung, JK; Aryee, MJ (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.; Joung, JK; Aryee, MJ (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.; Joung, JK (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA.; Joung, JK; Aryee, MJ (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA.; Aryee, MJ (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM jjoung@mgh.harvard.edu; aryee.martin@mgh.harvard.edu OI Aryee, Martin/0000-0002-6848-1344 NR 0 TC 2 Z9 2 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAY PY 2016 VL 34 IS 5 BP 483 EP 483 DI 10.1038/nbt.3534 PG 1 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DL6FL UT WOS:000375735000024 PM 27153277 ER PT J AU MacArthur, D AF MacArthur, Daniel TI Superheroes of disease resistance SO NATURE BIOTECHNOLOGY LA English DT Editorial Material C1 [MacArthur, Daniel] Massachusetts Gen Hosp, Boston, MA 02114 USA. [MacArthur, Daniel] Broad Inst MIT & Harvard, Cambridge, MA USA. RP MacArthur, D (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; MacArthur, D (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA. EM macarthur@atgu.mgh.harvard.edu NR 5 TC 2 Z9 2 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAY PY 2016 VL 34 IS 5 BP 512 EP 513 DI 10.1038/nbt.3555 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DL6FL UT WOS:000375735000028 PM 27065009 ER PT J AU Kim, JW Botvinnik, OB Abudayyeh, O Birger, C Rosenbluh, J Shrestha, Y Abazeed, ME Hammerman, PS DiCara, D Konieczkowski, DJ Johannessen, CM Liberzon, A Alizad-Rahvar, AR Alexe, G Aguirre, A Ghandi, M Greulich, H Vazquez, F Weir, BA Van Allen, EM Tsherniak, A Shao, DD Zack, TI Noble, M Getz, G Beroukhim, R Garraway, LA Ardakani, M Romualdi, C Sales, G Barbie, DA Boehm, JS Hahn, WC Mesirov, JP Tamayo, P AF Kim, Jong Wook Botvinnik, Olga B. Abudayyeh, Omar Birger, Chet Rosenbluh, Joseph Shrestha, Yashaswi Abazeed, Mohamed E. Hammerman, Peter S. DiCara, Daniel Konieczkowski, David J. Johannessen, Cory M. Liberzon, Arthur Alizad-Rahvar, Amir Reza Alexe, Gabriela Aguirre, Andrew Ghandi, Mahmoud Greulich, Heidi Vazquez, Francisca Weir, Barbara A. Van Allen, Eliezer M. Tsherniak, Aviad Shao, Diane D. Zack, Travis I. Noble, Michael Getz, Gad Beroukhim, Rameen Garraway, Levi A. Ardakani, Masoud Romualdi, Chiara Sales, Gabriele Barbie, David A. Boehm, Jesse S. Hahn, William C. Mesirov, Jill P. Tamayo, Pablo TI Characterizing genomic alterations in cancer by complementary functional associations SO NATURE BIOTECHNOLOGY LA English DT Article ID BETA-CATENIN; MUTUAL INFORMATION; NETWORK ANALYSIS; GENES; REVEALS; MODULES; CELLS; NRF2; VULNERABILITIES; TUMORIGENESIS AB Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of beta-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes. C1 [Kim, Jong Wook; Botvinnik, Olga B.; Abudayyeh, Omar; Birger, Chet; Rosenbluh, Joseph; Shrestha, Yashaswi; Abazeed, Mohamed E.; Hammerman, Peter S.; DiCara, Daniel; Konieczkowski, David J.; Johannessen, Cory M.; Liberzon, Arthur; Alexe, Gabriela; Aguirre, Andrew; Ghandi, Mahmoud; Greulich, Heidi; Vazquez, Francisca; Weir, Barbara A.; Van Allen, Eliezer M.; Tsherniak, Aviad; Shao, Diane D.; Zack, Travis I.; Noble, Michael; Getz, Gad; Beroukhim, Rameen; Garraway, Levi A.; Barbie, David A.; Boehm, Jesse S.; Hahn, William C.; Mesirov, Jill P.; Tamayo, Pablo] Eli & Edythe Broad Inst Harvard & Massachusetts I, Cambridge, MA USA. [Kim, Jong Wook; Abudayyeh, Omar; Rosenbluh, Joseph; Shrestha, Yashaswi; Konieczkowski, David J.; Johannessen, Cory M.; Aguirre, Andrew; Greulich, Heidi; Vazquez, Francisca; Van Allen, Eliezer M.; Shao, Diane D.; Beroukhim, Rameen; Garraway, Levi A.; Barbie, David A.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Botvinnik, Olga B.] Univ Calif San Diego, Bioinformat & Syst Biol Program, La Jolla, CA 92093 USA. [Botvinnik, Olga B.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Botvinnik, Olga B.] Univ Calif San Diego, Stem Cell Program, La Jolla, CA 92093 USA. [Botvinnik, Olga B.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Abudayyeh, Omar; Hammerman, Peter S.] Harvard Univ, Sch Med, Boston, MA USA. [Abazeed, Mohamed E.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Hammerman, Peter S.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Alizad-Rahvar, Amir Reza; Ardakani, Masoud] Univ Alberta, Dept Elect & Comp Engn, Edmonton, AB, Canada. [Alexe, Gabriela] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Alexe, Gabriela] Boston Childrens Hosp, Boston, MA USA. [Alexe, Gabriela] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Greulich, Heidi; Beroukhim, Rameen; Garraway, Levi A.; Hahn, William C.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Zack, Travis I.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zack, Travis I.; Beroukhim, Rameen] Harvard Univ, Program Biophys, Boston, MA 02115 USA. [Romualdi, Chiara; Sales, Gabriele] Univ Padua, Dept Biol, Padua, Italy. [Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Mesirov, Jill P.; Tamayo, Pablo] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Mesirov, Jill P.; Tamayo, Pablo] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Tamayo, P (reprint author), Eli & Edythe Broad Inst Harvard & Massachusetts I, Cambridge, MA USA.; Tamayo, P (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.; Tamayo, P (reprint author), Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. EM ptamayo@ucsd.edu RI Romualdi, Chiara/K-1132-2016; OI Romualdi, Chiara/0000-0003-4792-9047; Ghandi, Mahmoud/0000-0003-1897-2265 FU US National Institutes of Health [R01 CA154480, R01 CA121941, U01 CA176058, R01 CA109467, U01 CA184898-02] FX This project was supported in part by US National Institutes of Health grants R01 CA154480, R01 CA121941, U01 CA176058, R01 CA109467 and U01 CA184898-02. NR 45 TC 2 Z9 2 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAY PY 2016 VL 34 IS 5 BP 539 EP 546 DI 10.1038/nbt.3527 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DL6FL UT WOS:000375735000035 PM 27088724 ER PT J AU Hu, JZ Meyers, RM Dong, JC Panchakshari, RA Alt, FW Frock, RL AF Hu, Jiazhi Meyers, Robin M. Dong, Junchao Panchakshari, Rohit A. Alt, Frederick W. Frock, Richard L. TI Detecting DNA double-stranded breaks in mammalian genomes by linear amplification-mediated high-throughput genome-wide translocation sequencing SO NATURE PROTOCOLS LA English DT Article ID CHROMOSOMAL TRANSLOCATIONS; READ ALIGNMENT; B-CELLS; RECOMBINATION; CRISPR-CAS9; PCR; INSTABILITY; REVEALS; SYSTEM; REARRANGEMENTS AB Unbiased, high-throughput assays for detecting and quantifying DNANA double-stranded breaks (DSBs) across the genome in mammalian cells will facilitate basic studies of the mechanisms that generate and repair endogenous DSBs. They will also enable more applied studies, such as those to evaluate the on-and off-target activities of engineered nucleases. Here we describe a linear amplification-mediated high-throughput genome-wide sequencing (LALAM-HTGTSTS) method for the detection of genome-wide 'prey' DSBs via their translocation in cultured mammalian cells to a fixed 'bait' DSB. Bait-prey junctions are cloned directly from isolated genomic DNANA using LALAM-PCRPCRPCR and unidirectionally ligated to bridge adapters; subsequent PCRPCRPCR steps amplify the single-stranded DNANA junction library in preparation for Illumina Miseq paired-end sequencing. A custom bioinformatics pipeline identifies prey sequences that contribute to junctions and maps them across the genome. LALAM-HTGTSTS differs from related approaches because it detects a wide range of broken end structures with nucleotide-level resolution. Familiarity with nucleic acid methods and next-generation sequencing analysis is necessary for library generation and data interpretation. LALAM-HTGTSTS assays are sensitive, reproducible, relatively inexpensive, scalable and straightforward to implement with a turnaround time of <1 week. C1 [Hu, Jiazhi; Meyers, Robin M.; Dong, Junchao; Panchakshari, Rohit A.; Alt, Frederick W.; Frock, Richard L.] Harvard Univ, Sch Med, Dept Genet, Program Cellular & Mol Med,Boston Childrens Hosp, Boston, MA USA. [Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Alt, FW; Frock, RL (reprint author), Harvard Univ, Sch Med, Dept Genet, Program Cellular & Mol Med,Boston Childrens Hosp, Boston, MA USA.; Alt, FW (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; richard.frock@childrens.harvard.edu OI Frock, Richard/0000-0001-6963-4931 FU National Institutes of Health [R01AI020047, R01AI077595]; National Institutes of Health National Research Service Award [T32AI007512]; Robertson Foundation/Cancer Research Institute Irvington Fellowship FX We thank members of the Alt laboratory for discussions about improving LAM-HTGTS, and we thank Z. Herbert from the Molecular Biology Core Facilities at Dana-Farber Cancer Institute for discussions on transitioning HTGTS to Illumina Miseq. This work is supported by National Institutes of Health Grant nos. R01AI020047 and R01AI077595 to F.W.A. R.L.F. was supported by the National Institutes of Health National Research Service Award no. T32AI007512. J.H. is supported by a Robertson Foundation/Cancer Research Institute Irvington Fellowship. F.W.A. is an investigator of the Howard Hughes Medical Institute. NR 46 TC 7 Z9 7 U1 6 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD MAY PY 2016 VL 11 IS 5 BP 853 EP 871 DI 10.1038/nprot.2016.043 PG 19 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DJ8ES UT WOS:000374445900002 PM 27031497 ER PT J AU Pastor, BM Mostoslavsky, R AF Pastor, Barbara Martinez Mostoslavsky, Raul TI SIRT6: a new guardian of mitosis SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID HISTONE DEACETYLASE SIRT6; HETEROCHROMATIN; DNA; CHROMATIN; STRESS; METHYLTRANSFERASES; TRANSCRIPTION; REPEATS; CELLS AB The sirtuin family protein SIRT6 is a stress-responsive NAD-dependent histone deacetylase with key roles in glucose homeostasis, DNA repair and cellular lifespan. SIRT6 is now shown to mediate deacetylation of histone H3 Lys18 specifically at pericentric chromatin, thus maintaining transcriptional silencing of satellite repeats in a manner independent of HP1 and trimethylated H3 Lys9, thereby assuring correct segregation of chromosomes. C1 [Pastor, Barbara Martinez; Mostoslavsky, Raul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Mostoslavsky, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. EM rmostoslavsky@mgh.harvard.edu NR 25 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAY PY 2016 VL 23 IS 5 BP 360 EP 362 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DL4UK UT WOS:000375633100002 PM 27142319 ER PT J AU Lu, A Li, Y Schmidt, FI Yin, Q Chen, SB Fu, TM Tong, AB Ploegh, HL Mao, YD Wu, H AF Lu, Alvin Li, Yang Schmidt, Florian I. Yin, Qian Chen, Shuobing Fu, Tian-Min Tong, Alexander B. Ploegh, Hidde L. Mao, Youdong Wu, Hao TI Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID CARD-ONLY PROTEINS; INTERLEUKIN-1-BETA GENERATION; INFLAMMASOME ACTIVATION; SIGNAL-TRANSDUCTION; IMMUNE-RESPONSE; CYTOCHALASIN-D; KAPPA-B; ACTIN; COMPLEX; CAPZ AB Inflammasomes are cytosolic caspase-1-activation complexes that sense intrinsic and extrinsic danger signals, and trigger inflammatory responses and pyroptotic cell death. Homotypic interactions among Pyrin domains and caspase recruitment domains (CARDs) in inflammasome-complex components mediate oligomerization into filamentous assemblies. Several cytosolic proteins consisting of only interaction domains exert inhibitory effects on inflammasome assembly. In this study, we determined the structure of the human caspase-1 CARD domain (caspase-1(CARD)) filament by cryo-electron microscopy and investigated the biophysical properties of two caspase-1-like CARD-only proteins: human inhibitor of CARD (INCA or CARD17) and ICEBERG (CARD18). Our results reveal that INCA caps caspase-1 filaments, thereby exerting potent inhibition with low-nanomolar K-i on caspase-1(CARD) polymerization in vitro and inflammasome activation in cells. Whereas caspase-1(CARD) uses six complementary surfaces of three types for filament assembly, INCA is defective in two of the six interfaces and thus terminates the caspase-1 filament. C1 [Lu, Alvin; Li, Yang; Yin, Qian; Fu, Tian-Min; Tong, Alexander B.; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Lu, Alvin; Li, Yang; Yin, Qian; Fu, Tian-Min; Tong, Alexander B.; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Schmidt, Florian I.; Ploegh, Hidde L.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Chen, Shuobing; Mao, Youdong] Peking Univ, Acad Adv Interdisciplinary Studies,Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Ctr Quantitat Biol,PekingTsinghua Joint Ctr Life, Beijing 100871, Peoples R China. [Chen, Shuobing; Mao, Youdong] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02115 USA. [Ploegh, Hidde L.] MIT, Dept Biol, Cambridge, MA USA. [Mao, Youdong] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Yin, Qian] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. RP Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Wu, H (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. EM wu@crystal.harvard.edu RI Schmidt, Florian/H-7372-2012; OI Schmidt, Florian/0000-0002-9979-9769; Lu, Alvin/0000-0003-2353-848X FU US National Institutes of Health (NIH) [DP1-HD-087988, DP1-GM-106409, R00: 4R00AI108793-02]; Advanced Postdoc. Mobility Fellowship from the Swiss National Science Foundation; NIH grant, Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID) [AI100645]; US National Science Foundation (NSF) [ECS-0335765] FX The work was supported by US National Institutes of Health (NIH) grants to H.W. (Pioneer Award DP1-HD-087988), to H.L.P. (Pioneer Award DP1-GM-106409), and to Q.Y. (R00: 4R00AI108793-02). F.I.S. was supported by an Advanced Postdoc. Mobility Fellowship from the Swiss National Science Foundation. The cryo-EM facility was funded through the NIH grant AI100645, Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID). The experiments were performed in part at the Center for Nanoscale Systems at Harvard University, a member of the National Nanotechnology Infrastructure Network (NNIN), which is supported by the US National Science Foundation (NSF) under award no. ECS-0335765. We thank E. Egelman for generous guidance in methods of helical reconstruction. NR 44 TC 3 Z9 4 U1 6 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAY PY 2016 VL 23 IS 5 BP 416 EP 425 DI 10.1038/nsmb.3199 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DL4UK UT WOS:000375633100013 PM 27043298 ER PT J AU Itoh, K Maki, T Shindo, A Egawa, N Liang, AC Itoh, N Lo, EH Lok, J Arai, K AF Itoh, Kanako Maki, Takakuni Shindo, Akihiro Egawa, Naohiro Liang, Anna C. Itoh, Naoki Lo, Eng H. Lok, Josephine Arai, Ken TI Magnesium sulfate protects oligodendrocyte lineage cells in a rat cell-culture model of hypoxic-ischemic injury SO NEUROSCIENCE RESEARCH LA English DT Article DE Oligodendrocyte; Magnesium sulfate; White matter; Hypoxic-ischemic injury ID CONTROLLED-TRIAL; PRECURSOR CELLS; ACUTE STROKE; IN-VITRO; PROMOTE; BRAIN AB Hypoxic-ischemic (HI) brain injury in newborns results in serious damage. Magnesium sulfate has been clinically used as a cyto-protective agent against HI brain injury in newborns in some countries, including Japan. However, it is not clear how magnesium exerts this effect and how it acts on the individual types of cells within the newborn brain. In this study, we exposed cultured rat oligodendrocyte precursor cells to magnesium sulfate during the period when they differentiate into oligodendrocytes, and showed that magnesium-exposed oligodendrocytes exhibited more resistance to HI injury. Our data may support the use of magnesium sulfate in the clinical setting. (C) 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 [Itoh, Kanako; Maki, Takakuni; Shindo, Akihiro; Egawa, Naohiro; Liang, Anna C.; Itoh, Naoki; Lo, Eng H.; Lok, Josephine; Arai, Ken] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA USA. [Itoh, Kanako; Maki, Takakuni; Shindo, Akihiro; Egawa, Naohiro; Liang, Anna C.; Itoh, Naoki; Lo, Eng H.; Lok, Josephine; Arai, Ken] Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA USA. [Itoh, Kanako; Maki, Takakuni; Shindo, Akihiro; Egawa, Naohiro; Liang, Anna C.; Itoh, Naoki; Lo, Eng H.; Lok, Josephine; Arai, Ken] Harvard Univ, Sch Med, Charlestown, MA USA. [Itoh, Kanako; Lok, Josephine] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Itoh, Kanako; Lok, Josephine] Harvard Univ, Sch Med, Boston, MA USA. RP Arai, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA USA.; Arai, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA USA.; Arai, K (reprint author), Harvard Univ, Sch Med, Charlestown, MA USA. EM karai@partners.org FU NINDS NIH HHS [P01 NS055104, R01 NS065089] NR 18 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 EI 1872-8111 J9 NEUROSCI RES JI Neurosci. Res. PD MAY PY 2016 VL 106 BP 66 EP 69 DI 10.1016/j.neures.2015.12.004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA DL8FX UT WOS:000375877600009 PM 26699082 ER PT J AU Salameh, N Sarracanie, M Armstrong, BD Rosen, MS Comment, A AF Salameh, Najat Sarracanie, Mathieu Armstrong, Brandon D. Rosen, Matthew S. Comment, Arnaud TI Overhauser-enhanced magnetic resonance elastography SO NMR IN BIOMEDICINE LA English DT Article DE MR Elastography (MRE); Electron Spin Resonance (ESR); ultra-low magnetic field; Overhauler MRI; iron overload; magnetic susceptibility ID MR ELASTOGRAPHY; LIVER FIBROSIS; HEPATIC-FIBROSIS; IN-VIVO; NONINVASIVE ASSESSMENT; BREAST-LESIONS; IRON OVERLOAD; MULTIFREQUENCY; RATIO AB Magnetic resonance elastography (MRE) is a powerful technique to assess the mechanical properties of living tissue. However, it suffers from reduced sensitivity in regions with short T-2 and T-2* such as in tissue with high concentrations of paramagnetic iron, or in regions surrounding implanted devices. In this work, we exploit the longer T-2* attainable at ultra-low magnetic fields in combination with Overhauser dynamic nuclear polarization (DNP) to enable rapid MRE at 0.0065T. A 3D balanced steady-state free precession based MRE sequence with undersampling and fractional encoding was implemented on a 0.0065T MRI scanner. A custom-built RF coil for DNP and a programmable vibration system for elastography were developed. Displacement fields and stiffness maps were reconstructed from data recorded in a polyvinyl alcohol gel phantom loaded with stable nitroxide radicals. A DNP enhancement of 25 was achieved during the MRE sequence, allowing the acquisition of 3D Overhauser-enhanced MRE (OMRE) images with (1.5x2.7x9) mm(3) resolution over eight temporal steps and 11 slices in 6minutes. In conclusion, OMRE at ultra-low magnetic field can be used to detect mechanical waves over short acquisition times. This new modality shows promise to broaden the scope of conventional MRE applications, and may extend the utility of low-cost, portable MRI systems to detect elasticity changes in patients with implanted devices or iron overload. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Salameh, Najat; Sarracanie, Mathieu; Armstrong, Brandon D.; Rosen, Matthew S.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Salameh, Najat; Sarracanie, Mathieu; Rosen, Matthew S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Salameh, Najat; Sarracanie, Mathieu; Armstrong, Brandon D.; Rosen, Matthew S.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Salameh, Najat; Comment, Arnaud] Ecole Polytech Fed Lausanne, Inst Phys Biol Syst, Lausanne, Switzerland. RP Salameh, N (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM najat.salameh@gmail.com RI Comment, Arnaud/G-5693-2011 OI Comment, Arnaud/0000-0002-8484-3448 FU Swiss National Science Foundation [P300P2_147768, PP00P2_133562]; Department of Defense, Defense Medical Research and Development Program, Applied Research and Advanced Technology Development [W81XWH-11-2-0076 (DM09094)] FX This work was supported by the Swiss National Science Foundation (P300P2_147768 and PP00P2_133562), and by the Department of Defense, Defense Medical Research and Development Program, Applied Research and Advanced Technology Development Award W81XWH-11-2-0076 (DM09094). NR 43 TC 0 Z9 0 U1 8 U2 13 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 MAY PY 2016 VL 29 IS 5 BP 607 EP 613 DI 10.1002/nbm.3499 PG 7 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DJ8XA UT WOS:000374495900008 PM 26915977 ER PT J AU Wu, Y Kim, J Chan, ST Zhou, IY Guo, Y Igarashi, T Zheng, HR Guo, G Sun, PZ AF Wu, Yin Kim, Jinsuh Chan, Suk-Tak Zhou, Iris Yuwen Guo, Yingkun Igarashi, Takahiro Zheng, Hairong Guo, Gang Sun, Phillip Zhe TI Comparison of image sensitivity between conventional tensor-based and fast diffusion kurtosis imaging protocols in a rodent model of acute ischemic stroke SO NMR IN BIOMEDICINE LA English DT Article DE acute stroke; contrast-to-noise ratio; diffusion kurtosis imaging; mean diffusion; mean kurtosis ID NON-GAUSSIAN DIFFUSION; MILD COGNITIVE IMPAIRMENT; TRAUMATIC BRAIN-INJURY; ALZHEIMERS-DISEASE; MICROSTRUCTURAL ALTERATIONS; WATER DIFFUSION; TISSUE; MRI; TIME; PH AB Diffusion kurtosis imaging (DKI) can offer a useful complementary tool to routine diffusion MRI for improved stratification of heterogeneous tissue damage in acute ischemic stroke. However, its relatively long imaging time has hampered its clinical application in the emergency setting. A recently proposed fast DKI approach substantially shortens the imaging time, which may help to overcome the scan time limitation. However, to date, the sensitivity of the fast DKI protocol for the imaging of acute stroke has not been fully described. In this study, we performed routine and fast DKI scans in a rodent model of acute stroke, and compared the sensitivity of diffusivity and kurtosis indices (i.e. axial, radial and mean) in depicting acute ischemic lesions. In addition, we analyzed the contrast-to-noise ratio (CNR) between the ipsilateral ischemic and contralateral normal regions using both conventional and fast DKI methods. We found that the mean kurtosis shows a relative change of 47.1 +/- 7.3% between the ischemic and contralateral normal regions, being the most sensitive parameter in revealing acute ischemic injury. The two DKI methods yielded highly correlated diffusivity and kurtosis measures and lesion volumes (R(2)0.90, p<0.01). Importantly, the fast DKI method exhibited significantly higher CNR of mean kurtosis (1.6 +/- 0.2) compared with the routine tensor protocol (1.3 +/- 0.2, p<0.05), with its CNR per unit time (CNR efficiency) approximately doubled when the scan time was taken into account. In conclusion, the fast DKI method provides excellent sensitivity and efficiency to image acute ischemic tissue damage, which is essential for image-guided and individualized stroke treatment. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Wu, Yin; Chan, Suk-Tak; Zhou, Iris Yuwen; Guo, Yingkun; Igarashi, Takahiro; Sun, Phillip Zhe] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Wu, Yin; Chan, Suk-Tak; Zhou, Iris Yuwen; Guo, Yingkun; Igarashi, Takahiro; Sun, Phillip Zhe] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Wu, Yin; Zheng, Hairong] Chinese Acad Sci, Shenzhen Inst Adv Technol, Paul C Lauterbur Res Ctr Biomed Imaging, Shenzhen Key Lab MRI, Shenzhen, Guangdong, Peoples R China. [Kim, Jinsuh; Sun, Phillip Zhe] Univ Illinois, Dept Radiol, Chicago, IL USA. [Guo, Gang] Xiamen 2nd Hosp, Dept Radiol, Xiamen, Fujian, Peoples R China. RP Sun, PZ (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Sun, PZ (reprint author), Harvard Univ, Sch Med, Charlestown, MA 02129 USA. EM pzhesun@mgh.harvard.edu RI Zhou, Iris Yuwen/A-2089-2017 OI Zhou, Iris Yuwen/0000-0002-4351-7398 FU National Basic Research Program of China [2015CB755500]; National Natural Science Foundation of China (NSFC) [81571668, 81471721]; Shenzhen Science and Technology Program [JCYJ20140610151856743]; National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [1R21NS085574, 1R01NS083654] FX This study received funding from the National Basic Research Program of China (2015CB755500), National Natural Science Foundation of China (NSFC) (81571668 and 81471721), Shenzhen Science and Technology Program (JCYJ20140610151856743) and National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) (1R21NS085574 and 1R01NS083654). NR 52 TC 2 Z9 3 U1 1 U2 3 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 MAY PY 2016 VL 29 IS 5 BP 625 EP 630 DI 10.1002/nbm.3506 PG 6 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DJ8XA UT WOS:000374495900010 PM 26918411 ER PT J AU Duong, HA Le, KT Soulema, AL Yueh, RH Scheuner, MT Holick, MF Christensen, R Tajima, TL Leung, AM Mallya, SM AF Duong, Hannah A. Le, Karen T. Soulema, Albert L. Yueh, Ronald H. Scheuner, Maren T. Holick, Michael F. Christensen, Russell Tajima, Tracey L. Leung, Angela M. Mallya, Sanjay M. TI Gnathodiaphyseal dysplasia: report of a family with a novel mutation of the ANO5 gene SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID FIBROOSSEOUS LESIONS; BONE; OSTEONECROSIS; PROTEIN; JAW AB Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant disorder characterized by florid osseous dysplasia of the jaws, bone fragility, and diaphyseal cortical thickening and bowing of long bones. We present a family with previously undiagnosed GDD. The disorder was identified by the characteristic gnathic and skeletal manifestations in the father. Clinical and radiologic examination of the patient's son also revealed the characteristic features of GDD. Gene sequencing revealed a novel mutation (c. 1067 G>A, p. Cys356 Tyr) in the ANO5 gene, which is causative for GDD. This mutation was predicted to be detrimental by computational analyses and by structural modeling of the protein. The implications for recognition and management of this disease are discussed. C1 [Duong, Hannah A.; Mallya, Sanjay M.] Univ Calif Los Angeles, Sch Dent, Sect Oral & Maxillofacial Radiol, Los Angeles, CA 90024 USA. [Le, Karen T.; Leung, Angela M.] VA Greater Los Angeles Healthcare Syst, Div Endocrinol, Los Angeles, CA USA. [Le, Karen T.] Cedars Sinai Med Ctr, Div Endocrinol, Los Angeles, CA 90048 USA. [Soulema, Albert L.; Tajima, Tracey L.] VA Greater Los Angeles Healthcare Syst, Dept Dent, Los Angeles, CA USA. [Yueh, Ronald H.] VA Greater Los Angeles Healthcare Syst, Oral & Maxillofacial Surg, Dent Serv, Sepulveda Campus, Los Angeles, CA USA. [Scheuner, Maren T.] VA Greater Los Angeles Healthcare Syst, Div Med Genet, Los Angeles, CA USA. [Scheuner, Maren T.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Holick, Michael F.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Christensen, Russell] Univ Calif Los Angeles, Sch Dent, Sect Oral & Maxillofacial Pathol, Los Angeles, CA 90024 USA. [Leung, Angela M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol, Los Angeles, CA 90095 USA. RP Mallya, SM (reprint author), Univ Calif Los Angeles, Sch Dent, 53-068 CHS,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM Smallya@ucla.edu FU Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [K23 HD068552] FX AML was supported, in part, by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under award number K23 HD068552. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 21 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 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD MAY PY 2016 VL 121 IS 5 BP E123 EP E128 DI 10.1016/j.oooo.2016.01.014 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DL4LN UT WOS:000375608100005 PM 27068316 ER PT J AU Kempfle, J Kozin, ED Remenschneider, AK Eckhard, A Edge, A Lee, DJ AF Kempfle, Judith Kozin, Elliott D. Remenschneider, Aaron K. Eckhard, Andreas Edge, Albert Lee, Daniel J. TI Endoscopic Transcanal Retrocochlear Approach to the Internal Auditory Canal with Cochlear Preservation: Pilot Cadaveric Study SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE internal auditory canal; vestibular schwannoma; temporal bone; endoscopic ear surgery; lateral skull base surgical navigation; neurotology ID LATERAL SKULL BASE; ANATOMY; EAR AB Contemporary operative approaches to the internal auditory canal (IAC) require the creation of large surgical portals for visualization with associated morbidity, including hearing loss, vestibular dysfunction, facial nerve injury, and skull base defects that increase the risk of cerebrospinal fluid leak. Transcanal approaches to the IAC have been possible only via a transcochlear technique. To preserve cochlear function, we describe a novel endoscopic transcanal infracochlear approach to the IAC in cadaveric temporal bones. Navigation fiducials were secured on fresh cadaveric heads, and real-time computed tomography imaging was used for surgical guidance. With a combination of curved instruments and rigid angled endoscopy, a transcanal hypotympanotomy and subcochlear tunnel were created with superior extension to access the IAC. Postprocedure imaging and temporal bone dissection confirmed access to the IAC without injury to the cochlea or neighboring neurovascular structures. C1 [Kempfle, Judith; Kozin, Elliott D.; Remenschneider, Aaron K.; Eckhard, Andreas; Edge, Albert; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Kempfle, Judith; Kozin, Elliott D.; Remenschneider, Aaron K.; Eckhard, Andreas; Edge, Albert; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Kozin, Elliott D.; Remenschneider, Aaron K.; Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. RP Kozin, ED (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Elliott_Kozin@meei.harvard.edu FU Medtronic Surgical Technologies FX Medtronic Surgical Technologies research grant; sponsor was not involved in any capacity in the study beyond supplying funding for cadaveric specimens and surgical instruments. NR 6 TC 2 Z9 2 U1 0 U2 0 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 MAY PY 2016 VL 154 IS 5 BP 920 EP 923 DI 10.1177/0194599816630979 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DL4HB UT WOS:000375593800025 PM 26932951 ER PT J AU Yao, WC Sedaghat, AR Yadav, P Fay, A Metson, R AF Yao, William C. Sedaghat, Ahmad R. Yadav, Prashant Fay, Aaron Metson, Ralph TI Orbital Decompression in the Endoscopic Age: The Modified Inferomedial Orbital Strut SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT AAO-HNSF Annual Meeting and OTO EXPO CY SEP 27-30, 2015 CL Dallas, TX SP AAO, HNSF DE orbital decompression; Graves' disease; endoscopic orbital decompression; orbital strut; orbital sling; balanced decompression ID THYROID EYE DISEASE; GRAVES OPHTHALMOPATHY; DYSTHYROID OPHTHALMOPATHY; LATERAL WALL; FOLLOW-UP; ORBITOPATHY; DIPLOPIA; PRESERVATION; EXOPHTHALMOS; SURGERY AB Objective Postoperative diplopia occurs in up to 45% of patients following orbital decompression for exophthalmos associated with Graves' orbitopathy. We sought to describe outcomes of our balanced orbital decompression strategy that includes the preservation of a modified inferomedial orbital strut (mIOS). Study Design Case series with chart review. Setting Academic medical center. Subjects and Methods A total of 115 consecutive orbital decompressions were performed on 73 patients (42 bilateral) with Graves' orbitopathy. All patients underwent (1) a balanced decompression technique incorporating an endoscopic medial and external lateral decompression and (2) a mIOS technique with preservation of the anterior half of the inferomedial orbital strut. A periorbital periosteal (orbital) sling was utilized in patients (n = 54) without threatened vision loss, proptosis >28 mm, or periorbital disruption to prevent prolapse of the medial rectus muscle. Results Utilization of the mIOS technique with or without a sling did not adversely affect the reduction in proptosis (5.1 mm with sling vs 5.0 mm without sling; P = .85).The incidence of new-onset postoperative diplopia was 17% (n = 6). The sling was not associated with postoperative diplopia (odds ratio = 0.54, 95% confidence interval: 0.08-3.40, P = .51), while it was associated with resolution of preexisting diplopia (odds ratio = 6.67, 95% confidence interval: 1.06-42.06, P = .04). No intraoperative complications occurred, and no patients suffered a decrement in visual acuity. Conclusion Balanced orbital decompression utilizing a mIOS in patients with Graves' orbitopathy provides a safe and effective reduction in proptosis with a low rate of new-onset diplopia as compared with historical values. Utilization of an orbital sling may be beneficial in reducing postoperative diplopia in select patients. C1 [Yao, William C.] Univ Texas Houston, Sch Med, Dept Otorhinolaryngol, Houston, TX USA. [Sedaghat, Ahmad R.; Metson, Ralph] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Sedaghat, Ahmad R.; Metson, Ralph] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Yadav, Prashant; Fay, Aaron] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Yao, WC (reprint author), Univ Texas Houston, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, 6431 Fannin St,MSB 5-036, Houston, TX 77030 USA. EM William.C.Yao@uth.tmc.edu NR 31 TC 1 Z9 2 U1 2 U2 2 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 MAY PY 2016 VL 154 IS 5 BP 963 EP 969 DI 10.1177/0194599816630722 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DL4HB UT WOS:000375593800032 PM 26932949 ER PT J AU Pugmire, BS Gee, MS Kaplan, JL Hahn, PF Doody, DP Winter, HS Gervais, DA AF Pugmire, Brian S. Gee, Michael S. Kaplan, Jess L. Hahn, Peter F. Doody, Daniel P. Winter, Harland S. Gervais, Debra A. TI Role of percutaneous abscess drainage in the management of young patients with Crohn disease SO PEDIATRIC RADIOLOGY LA English DT Article DE Abscess; Children; Crohn disease; Gastrointestinal tract; Interventional radiology; Percutaneous drainage ID INFLAMMATORY-BOWEL-DISEASE; INTRAABDOMINAL ABSCESSES; PELVIC ABSCESSES; CHILDREN; TERM AB Intra-abdominal abscess is a common complication of Crohn disease in children. Prior studies, primarily in adults, have shown that percutaneous abscess drainage is a safe and effective treatment for this condition; however, the data regarding this procedure and indications in pediatric patients is limited. Our aim was to determine the success rate of percutaneous abscess drainage for abscesses related to Crohn disease in pediatric patients with a focus on treatment endpoints that are relevant in the era of biological medical therapy. We retrospectively reviewed 25 cases of patients ages a parts per thousand currency sign20 years with Crohn disease who underwent percutaneous abscess drainage. Technical success was defined as catheter placement within the abscess with reduction in abscess size on post-treatment imaging. Clinical success was defined as (1) no surgery within 1 year of drainage or (2) surgical resection following drainage with no residual abscess at surgery or on preoperative imaging. Multiple clinical parameters were analyzed for association with treatment success or failure. All cases were classified as technical successes. Nineteen cases were classified as clinical successes (76%), including 7 patients (28%) who required no surgery within 1 year of percutaneous drainage and 12 patients (48%) who had elective bowel resection within 1 year. There was a statistically significant association between resumption of immunosuppressive therapy within 8 weeks of drainage and both clinical success (P < 0.01) and avoidance of surgery after 1 year (P < 0.01). Percutaneous abscess drainage is an effective treatment for Crohn disease-related abscesses in pediatric patients. Early resumption of immunosuppressive therapy is statistically associated with both clinical success and avoidance of bowel resection, suggesting a role for percutaneous drainage in facilitating prompt initiation of medical therapy and preventing surgical bowel resection. C1 [Pugmire, Brian S.] Cincinnati Childrens Hosp Med Ctr, Dept Radiol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. [Gee, Michael S.] Massachusetts Gen Hosp Children, Dept Radiol, Boston, MA USA. [Gee, Michael S.; Hahn, Peter F.; Gervais, Debra A.] Massachusetts Gen Hosp, Div Abdominal Imaging, Boston, MA 02114 USA. [Kaplan, Jess L.; Winter, Harland S.] Massachusetts Gen Hosp Children, Dept Pediat, Boston, MA USA. [Doody, Daniel P.] Massachusetts Gen Hosp Children, Dept Surg, Boston, MA USA. RP Pugmire, BS (reprint author), Cincinnati Childrens Hosp Med Ctr, Dept Radiol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM Brian.Pugmire@cchmc.org NR 20 TC 0 Z9 0 U1 1 U2 1 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 MAY PY 2016 VL 46 IS 5 BP 653 EP 659 DI 10.1007/s00247-015-3533-3 PG 7 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA DJ9ZF UT WOS:000374571400009 PM 26833482 ER PT J AU Boronat, S Barber, I Pargaonkar, V Chang, J Thiele, EA AF Boronat, Susana Barber, Ignasi Pargaonkar, Vivek Chang, Joshua Thiele, Elizabeth A. TI Sclerotic bone lesions at abdominal magnetic resonance imaging in children with tuberous sclerosis complex SO PEDIATRIC RADIOLOGY LA English DT Article DE Bone; Children; Magnetic resonance imaging; Sclerotic bone lesions; Tuberous sclerosis complex ID CONSENSUS CONFERENCE; DIAGNOSTIC-CRITERIA; SPINE; LYMPHANGIOLEIOMYOMATOSIS; RECOMMENDATIONS; APPEARANCES AB Sclerotic bone lesions are often seen on chest CT in adults with tuberous sclerosis complex. To characterize bone lesions at abdominal MRI in children with tuberous sclerosis complex. This retrospective review included 70 children with tuberous sclerosis complex who had undergone abdominal MRI for renal imaging. An additional longitudinal study was performed in 50 children who had had two or more MRI scans. Abdominal CT (eight children) and radiographs (three children) were reviewed and compared with MRI. A total of 173 sclerotic bone lesions were detected in 51/70 children (73%; 95% confidence interval: 0.61-0.82) chiefly affecting vertebral pedicles. New lesions appeared in 20 children and growth of previous sclerotic bone lesions was documented in 14 children. Sclerotic bone lesions were more frequent in girls and in children with more extensive renal involvement. Sclerotic bone lesions are commonly detected by abdominal MRI in children with tuberous sclerosis complex. They usually affect posterior vertebral elements and their number and size increase with age. As current recommendations for tuberous sclerosis complex surveillance include renal MR performed in childhood, recognition of these lesions is useful. C1 [Boronat, Susana; Chang, Joshua; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. [Barber, Ignasi] Univ Autonoma Barcelona, Vall Hebron Hosp, Dept Pediat Radiol, E-08193 Barcelona, Spain. [Pargaonkar, Vivek] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Boronat, Susana] Univ Autonoma Barcelona, Vall Hebron Hosp, Dept Pediat Neurol, E-08193 Barcelona, Spain. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org NR 19 TC 1 Z9 1 U1 0 U2 2 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 MAY PY 2016 VL 46 IS 5 BP 689 EP 694 DI 10.1007/s00247-016-3549-3 PG 6 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA DJ9ZF UT WOS:000374571400014 PM 26965910 ER PT J AU Suri, P Pearson, AM Scherer, EA Zhao, WY Lurie, JD Morgan, TS Weinstein, JN AF Suri, Pradeep Pearson, Adam M. Scherer, Emily A. Zhao, Wenyan Lurie, Jon D. Morgan, Tamara S. Weinstein, James N. TI Recurrence of Pain After Usual Nonoperative Care for Symptomatic Lumbar Disk Herniation: Analysis of Data From the Spine Patient Outcomes Research Trial SO PM&R LA English DT Article ID LOW-BACK-PAIN; RISK-FACTORS; LONGITUDINAL ASSESSMENT; NONSURGICAL TREATMENT; GENERAL-POPULATION; SPORT; SCIATICA; COHORT; PREDICTORS; DISABILITY AB Objective: To determine risks and predictors of recurrent leg and low back pain (LBP) after unstructured, usual nonoperative care for subacute/chronic symptomatic lumbar disk herniation (LDH). Design: Secondary analysis of data from a concurrent randomized trial and observational cohort study. Setting: Thirteen outpatient spine practices. Participants: A total of 199 participants with resolution of leg pain and 142 participants with resolution of LBP from among 478 participants receiving usual nonoperative care for symptomatic LDH. Assessment of Risk Factors: Potential predictors of recurrence included time to initial symptom resolution, sociodemographics, clinical characteristics, work-related factors, imaging-detected herniation characteristics, and baseline pain bothersomeness. Main Outcome Measurements: Leg pain and LBP bothersomeness were assessed by the use of a 0-6 numerical scale at up to 4 years of follow-up. For individuals with initial resolution of leg pain, we defined recurrent leg pain as having leg pain, receiving lumbar epidural steroid injections, or undergoing lumbar surgery subsequent to initial leg pain resolution. We calculated cumulative risks of recurrence by using Kaplan-Meier survival plots and examined predictors of recurrence using Cox proportional hazards models. We used similar definitions for LBP recurrence. Results: One-and 3-year cumulative recurrence risks were 23% and 51% for leg pain, and 28% and 70% for LBP, respectively. Early leg pain resolution did not predict future leg pain recurrence. Complete leg pain resolution (adjusted hazard ratio [aHR] 0.47, 95% confidence interval [CI] 0.31-0.72) and posterolateral herniation location (aHR 0.61; 95% CI 0.39-0.97) predicted a lower risk of leg pain recurrence, and joint problems (aHR 1.89; 95% CI 1.16-3.05) and smoking (aHR 1.81; 95% CI 1.07-3.05) predicted a greater risk of leg pain recurrence. For participants with complete initial resolution of pain, recurrence risks at 1 and 3 years were 16% and 41% for leg pain and 24% and 59% for LBP, respectively. Conclusions: Recurrence of pain is common after unstructured, usual nonsurgical care for LDH. These risk estimates depend on the specific definitions applied, and the predictors identified require replication in future studies. C1 [Suri, Pradeep] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr ERIC, S-152 ERIC,1660 S Columbian Way, Seattle, WA USA. [Suri, Pradeep] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Pearson, Adam M.; Zhao, Wenyan] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Dept Orthopaed, Hanover, NH USA. [Scherer, Emily A.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Dept Med, Hanover, NH USA. [Lurie, Jon D.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Dept Med, Hanover, NH USA. [Morgan, Tamara S.; Weinstein, James N.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. RP Suri, P (reprint author), VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr ERIC, S-152 ERIC,1660 S Columbian Way, Seattle, WA USA.; Suri, P (reprint author), Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. EM pradeep.suri@va.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [U01-AR45444]; Office of Research on Women's Health; National Institutes of Health; National Institute of Occupational Safety and Health; Centers for Disease Control and Prevention; NIAMS [P60-AR048094, P60-AR062799]; VA Puget Sound Health Care System FX Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; U01-AR45444) and the Office of Research on Women's Health, the National Institutes of Health, and the National Institute of Occupational Safety and Health, the Centers for Disease Control and Prevention. The Multidisciplinary Clinical Research Center in Musculoskeletal Diseases is funded by NIAMS (P60-AR048094 and P60-AR062799). Dr. Suri's participation is this study was funded by VA Puget Sound Health Care System. The authors report no financial arrangements that may represent a possible conflict of interest with the work presented. NR 36 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 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD MAY PY 2016 VL 8 IS 5 BP 405 EP 414 DI 10.1016/j.pmrj.2015.10.016 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DL6LA UT WOS:000375749500002 PM 26548963 ER PT J AU Schneider, JC Ozsecen, MY Muraoka, NK Mancinelli, C Della Croce, U Ryan, CM Bonato, P AF Schneider, Jeffrey C. Ozsecen, Muzaffer Y. Muraoka, Nicholas K. Mancinelli, Chiara Della Croce, Ugo Ryan, Colleen M. Bonato, Paolo TI Feasibility of an Exoskeleton-Based Interactive Video Game System for Upper Extremity Burn Contractures SO PM&R LA English DT Article ID VIRTUAL-REALITY; CONTROLLED-TRIAL; PART II; REHABILITATION; INJURY; EFFICACY; PAIN; MOTION; HAND; THERAPY AB Background: Burn contractures are common and difficult to treat. Measuring continuous joint motion would inform the assessment of contracture interventions; however, it is not standard clinical practice. This study examines use of an interactive gaming system to measure continuous joint motion data. Objective: To assess the usability of an exoskeleton-based interactive gaming system in the rehabilitation of upper extremity burn contractures. Design: Feasibility study. Setting: Eight subjects with a history of burn injury and upper extremity contractures were recruited from the outpatient clinic of a regional inpatient rehabilitation facility. Methods: Subjects used an exoskeleton-based interactive gaming system to play 4 different video games. Continuous joint motion data were collected at the shoulder and elbow during game play. Main Outcome Measures: Visual analog scale for engagement, difficulty and comfort. Angular range of motion by subject, joint, and game. Results: The study population had an age of 43 +/- 16 (mean +/- standard deviation) years and total body surface area burned range of 10%-90%. Subjects reported satisfactory levels of enjoyment, comfort, and difficulty. Continuous joint motion data demonstrated variable characteristics by subject, plane of motion, and game. Conclusions: This study demonstrates the feasibility of use of an exoskeleton-based interactive gaming system in the burn population. Future studies are needed that examine the efficacy of tailoring interactive video games to the specific joint impairments of burn survivors. C1 [Schneider, Jeffrey C.; Ozsecen, Muzaffer Y.; Muraoka, Nicholas K.; Mancinelli, Chiara; Della Croce, Ugo; Bonato, Paolo] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, 300 First Ave, Boston, MA 02129 USA. [Della Croce, Ugo] Univ Sassari, Dipartimento Sci Polit Sci Comunicaz & Ingn, I-07100 Sassari, Italy. [Ryan, Colleen M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02129 USA. [Ryan, Colleen M.] Shriners Hosp Children, Boston, MA USA. RP Schneider, JC (reprint author), Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, 300 First Ave, Boston, MA 02129 USA. EM jcschneider@partners.org FU Harvard Catalyst, the Harvard Clinical and Translational Science Center; NIH [1 UL1 RR 025758-02]; Department of Education, NIDRR [H133A120034] FX grant, Harvard Catalyst, the Harvard Clinical and Translational Science Center; NIH grant #1 UL1 RR 025758-02; financial contributions from participating institutions; grant, Department of Education, NIDRR grant #H133A120034. NR 27 TC 0 Z9 0 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD MAY PY 2016 VL 8 IS 5 BP 445 EP 452 DI 10.1016/j.pmrj.2015.09.012 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DL6LA UT WOS:000375749500006 PM 26409198 ER PT J AU Goodman, KA Patton, CE Fisher, GA Hoffe, SE Haddock, MG Parikh, PJ Kim, J Baxter, NN Czito, BG Hong, TS Herman, JM Crane, CH Hoffman, KE AF Goodman, Karyn A. Patton, Caroline E. Fisher, George A. Hoffe, Sarah E. Haddock, Michael G. Parikh, Parag J. Kim, John Baxter, Nancy N. Czito, Brian G. Hong, Theodore S. Herman, Joseph M. Crane, Christopher H. Hoffman, Karen E. TI Appropriate customization of radiation therapy for stage II and III rectal cancer: Executive summary of an ASTRO Clinical Practice Statement using the RAND/UCLA Appropriateness Method SO PRACTICAL RADIATION ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; SHORT-COURSE RADIOTHERAPY; TOTAL MESORECTAL EXCISION; PREOPERATIVE RADIOTHERAPY; POSTOPERATIVE CHEMORADIOTHERAPY; NEOADJUVANT CHEMOTHERAPY; CHEMORADIATION THERAPY; SPHINCTER PRESERVATION; NONOPERATIVE TREATMENT; RANDOMIZED-TRIAL AB Purpose: To summarize results of a Clinical Practice Statement on radiation therapy for stage II-III rectal cancer, which addressed appropriate customization of (neo)adjuvant radiation therapy and use of non-surgical therapy for patients who are inoperable or refuse abdominoperineal resection. Methods and materials: The RAND/University of California, Los Angeles, Appropriateness Method was applied to combine current evidence with multidisciplinary expert opinion. A systematic literature review was conducted and used by the expert panel to rate appropriateness of radiation therapy options for different clinical scenarios. Treatments were categorized by median rating as Appropriate, May Be Appropriate, or Rarely Appropriate. Results: In the neoadjuvant setting, chemoradiation was rated Appropriate and the ratings indicated short-course radiation therapy, chemotherapy alone, and no neoadjuvant therapy are potential options in selected patients. However, neoadjuvant endorectal brachytherapy was rated Rarely Appropriate. For adjuvant therapy, chemoradiation (plus >= 4 months of chemotherapy) was rated Appropriate and chemotherapy alone May Be Appropriate for most scenarios. For medically inoperable patients, definitive external beam radiation therapy and chemotherapy alone were rated May Be Appropriate, whereas endorectal brachytherapy and chemoradiation plus endorectal brachytherapy were possible approaches for some scenarios. The last option, definitive chemoradiation, was rated Appropriate to May Be Appropriate based on performance status. Finally, for patients with low-lying tumors refusing abdominoperineal resection, definitive chemoradiation alone, chemoradiation plus endorectal brachytherapy, and chemoradiation plus external beam radiation therapy were all rated Appropriate. Conclusions: This Clinical Practice Statement demonstrated the central role of radiation therapy in stage II-III rectal cancer management and evaluated ways to better individualize its use in the neoadjuvant, adjuvant, and definitive settings. Ongoing trials may clarify areas of continuing uncertainty and allow further customization. (c) 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights C1 [Goodman, Karyn A.] Univ Colorado, Dept Radiat Oncol, Aurora, CO USA. [Patton, Caroline E.] Amer Soc Radiat Oncol, Fairfax, VA USA. [Fisher, George A.] Stanford Univ, Dept Med Oncol, Stanford, CA 94305 USA. [Hoffe, Sarah E.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Radiat Oncol, Tampa, FL 33682 USA. [Haddock, Michael G.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Parikh, Parag J.] Washington Univ, Dept Radiat Oncol, St Louis, MO USA. [Kim, John] Univ Toronto, Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Baxter, Nancy N.] Univ Toronto, St Michaels Hosp, Div Gen Surg, Toronto, ON, Canada. [Czito, Brian G.] Duke Univ, Dept Radiat Oncol, Durham, NC USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Herman, Joseph M.] Johns Hopkins Univ, Dept Radiat Oncol, Baltimore, MD USA. [Crane, Christopher H.; Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Goodman, KA (reprint author), Univ Colorado, Sch Med, Dept Radiat Oncol, 1665 Aurora Court,Suite 1032,Mail Stop F706, Aurora, CO 80045 USA. EM karyn.goodman@ucdenver.edu RI Baxter, Nancy/E-7020-2015 OI Baxter, Nancy/0000-0003-4793-4620 NR 37 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1879-8500 J9 PRACT RADIAT ONCOL JI Pract. Radiat. Oncol. PD MAY-JUN PY 2016 VL 6 IS 3 BP 166 EP 175 DI 10.1016/j.prro.2015.11.014 PG 10 WC Oncology SC Oncology GA DK1JN UT WOS:000374668400008 PM 26922700 ER PT J AU Braschi-Amirfarzan, M Keraliya, AR Krajewski, KM Tirumani, SH Shinagare, AB Hornick, JL Baldini, EH George, S Ramaiya, NH Jagannathan, JP AF Braschi-Amirfarzan, Marta Keraliya, Abhishek R. Krajewski, Katherine M. Tirumani, Sree Harsha Shinagare, Atul B. Hornick, Jason L. Baldini, Elizabeth H. George, Suzanne Ramaiya, Nikhil H. Jagannathan, Jyothi P. TI Role of Imaging in Management of Desmoid-type Fibromatosis: A Primer for Radiologists SO RADIOGRAPHICS LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; AGGRESSIVE FIBROMATOSIS; PROGNOSTIC-FACTORS; SINGLE INSTITUTION; RADIATION-THERAPY; CHEST-WALL; DEEP FIBROMATOSIS; SURGICAL SERIES; ABDOMINAL-WALL; FREE SURVIVAL AB Desmoid-type fibromatosis (DF) is a locally aggressive fibroblastic neoplasm that has variable clinical and biologic behaviors ranging from indolent tumors that can undergo spontaneous regression to aggressive tumors with a tendency toward local invasion and recurrence. The management of DF has evolved considerably in the last decade from aggressive first-line surgery and radiation therapy to systemic treatment (chemotherapy, hormonal therapy, and targeted therapy) and symptomatic local control (surgery and radiation therapy). Imaging plays an important role in each of these treatment settings. In surgical candidates, computed tomography (CT) and magnetic resonance (MR) imaging are the modalities of choice for assessing resectability and surgical planning. For evaluating recurrence, MR imaging is the modality of choice for extra-abdominal recurrence, whereas CT is the preferred modality for intra-abdominal recurrence. Signal intensity changes at MR imaging can be used to monitor the biologic behavior of certain DFs chosen for expectant management. Response to systemic treatment with anti-inflammatory agents, hormonal therapy (eg, tamoxifen), cytotoxic chemotherapy (eg, doxorubicin, vinblastine, methotrexate), and targeted therapy (eg, sorafenib), as well as to radiation therapy, can be assessed at CT by monitoring size and attenuation changes or at MR imaging by monitoring size, T2 signal intensity, and degree of enhancement. Several patterns of response can be seen at imaging. Imaging also helps in detecting complications associated with systemic therapy and radiation therapy. (C) RSNA, 2016 C1 [Braschi-Amirfarzan, Marta; Keraliya, Abhishek R.; Krajewski, Katherine M.; Tirumani, Sree Harsha; Shinagare, Atul B.; Ramaiya, Nikhil H.; Jagannathan, Jyothi P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. [Braschi-Amirfarzan, Marta; Keraliya, Abhishek R.; Krajewski, Katherine M.; Tirumani, Sree Harsha; Shinagare, Atul B.; Ramaiya, Nikhil H.; Jagannathan, Jyothi P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Hornick, Jason L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Hornick, Jason L.; Baldini, Elizabeth H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Baldini, Elizabeth H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. [George, Suzanne] Harvard Univ, Sch Med, Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Braschi-Amirfarzan, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA.; Braschi-Amirfarzan, M (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. EM mbraschi@partners.org NR 64 TC 1 Z9 1 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD MAY-JUN PY 2016 VL 36 IS 3 BP 767 EP 782 DI 10.1148/rg.2016150153 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DL7AS UT WOS:000375791800011 PM 27163593 ER PT J AU Hasegawa, K Camargo, CA AF Hasegawa, Kohei Camargo, Carlos A., Jr. TI Prevalence of blood eosinophilia in hospitalized patients with acute exacerbation of COPD SO RESPIROLOGY LA English DT Article DE chronic obstructive pulmonary disease; eosinophilia; hospitalization; mortality; readmission ID OBSTRUCTIVE PULMONARY-DISEASE; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND AB In this cohort of 3084 patients hospitalized for acute exacerbation of COPD (AECOPD), we found that 17% had blood eosinophilia (300 cells/L); the use of an alternative cut-off level (2%) demonstrated that 40% had elevated eosinophil count. Patients with eosinophilia had higher frequency of readmission for AECOPD during 1-year follow-up period. This is the first study to investigate the prevalence of eosinophilia among inpatients with AECOPDthe population with the highest morbidity and health-care utilization. C1 [Hasegawa, Kohei; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Hasegawa, K (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM khasegawa1@partners.org FU AHRQ HHS [R01 HS023305] NR 15 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD MAY PY 2016 VL 21 IS 4 BP 761 EP 764 DI 10.1111/resp.12724 PG 4 WC Respiratory System SC Respiratory System GA DK1QQ UT WOS:000374688900026 PM 26699685 ER PT J AU Glaser, J Reeves, ST Stoll, WD Epperson, TI Hilbert, M Madan, A George, MS Borckardt, JJ AF Glaser, John Reeves, Scott T. Stoll, William David Epperson, Thomas I. Hilbert, Megan Madan, Alok George, Mark S. Borckardt, Jeffrey J. TI Motor/Prefrontal Transcranial Direct Current Stimulation (tDCS) Following Lumbar Surgery Reduces Postoperative Analgesia Use SO SPINE LA English DT Article DE back pain; brain stimulation; lumbar surgery; motor cortex; opioid use; pain; prefrontal cortex; transcranial direct current stimulation ID MOTOR CORTEX STIMULATION; CHRONIC NEUROPATHIC PAIN; SPINAL-CORD-INJURY; PREFRONTAL CORTEX; FIBROMYALGIA; RTMS; ELECTROACUPUNCTURE; REPLACEMENT; PERCEPTION; BRAIN AB Design. Randomized, controlled pilot trial. Objective. The present study is the first randomized, double-blind, sham-controlled pilot clinical trial of transcranial direct current stimulation (tDCS) for pain and patient-controlled analgesia (PCA) opioid usage among patients receiving spine surgery. Summary of Background Data. Lumbar spinal surgeries are common, and while pain is often a complaint that precedes surgical intervention, the procedures themselves are associated with considerable postoperative pain lasting days to weeks. Adequate postoperative pain control is an important factor in determining recovery and new analgesic strategies are needed that can be used adjunctively to existing strategies potentially to reduce reliance on opioid analgesia. Several novel brain stimulation technologies including tDCS are beginning to demonstrate promise as treatments for a variety of pain conditions. Methods. Twenty-seven patients undergoing lumbar spine procedures at Medical University of South Carolina were randomly assigned to receive four 20-minute sessions of real or sham tDCS during their postsurgical hospital stay. Patient-administered hydromorphone usage was tracked along with numeric rating scale pain ratings. Results. The effect of tDCS on the slope of the cumulative PCA curve was significant (P < 0.001) and tDCS was associated with a 23% reduction in PCA usage. In the real tDCS group a 31% reduction was observed in pain-at-its-least ratings from admission to discharge (P = 0.027), but no other changes in numeric rating scale pain ratings were significant in either group. Conclusion. The present pilot trial is the first study to demonstrate an opioid sparing effect of tDCS after spine surgical procedures. Although this was a small pilot trial in a heterogeneous sample of spinal surgery patients, a moderate effect-size was observed for tDCS, suggesting that future work in this area is warranted. C1 [Glaser, John] Med Univ S Carolina, Dept Orthoped Surg, Charleston, SC 29425 USA. [Reeves, Scott T.; Stoll, William David; Epperson, Thomas I.; Hilbert, Megan; Borckardt, Jeffrey J.] Med Univ S Carolina, Dept Anesthesia & Perioperat Med, Charleston, SC 29425 USA. [Madan, Alok] Menninger Clin, Houston, TX USA. [Madan, Alok] Baylor Coll Med, Houston, TX 77030 USA. [George, Mark S.; Borckardt, Jeffrey J.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. [George, Mark S.; Borckardt, Jeffrey J.] Ralph H Johnson VAMC, Charleston, SC USA. RP Borckardt, JJ (reprint author), Inst Psychiat MSC 861, 507 North,67 President St, Charleston, SC 29425 USA. EM borckard@musc.edu FU National Association for Spine Surgery (NASS) FX National Association for Spine Surgery (NASS) grant funds were received in support of this work. NR 30 TC 2 Z9 2 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD MAY PY 2016 VL 41 IS 10 BP 835 EP 839 DI 10.1097/BRS.0000000000001525 PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DL4RZ UT WOS:000375626200013 PM 26909844 ER PT J AU Sullivan, JM Havrda, MC Kettenbach, AN Paolella, BR Zhang, ZH Gerber, SA Israel, MA AF Sullivan, Jaclyn M. Havrda, Matthew C. Kettenbach, Arminja N. Paolella, Brenton R. Zhang, Zhonghua Gerber, Scott A. Israel, Mark A. TI Phosphorylation Regulates Id2 Degradation and Mediates the Proliferation of Neural Precursor Cells SO STEM CELLS LA English DT Article DE Neural stem cell; Glioma; Transcription factors; Cancer stem cells; Cellular proliferation; Neoplastic stem cell biology; Tissue-specific stem cells; Progenitor cells ID LOOP-HELIX PROTEINS; PROGENITOR CELLS; MULTISITE PHOSPHORYLATION; RETINOBLASTOMA PROTEIN; LYMPHOCYTE DEVELOPMENT; TRANSCRIPTION FACTORS; MALIGNANT GLIOMAS; HUMAN FIBROBLASTS; SELF-RENEWAL; STEM-CELLS AB Inhibitor of DNA binding proteins (Id1-Id4) function to inhibit differentiation and promote proliferation of many different cell types. Among the Id family members, Id2 has been most extensively studied in the central nervous system (CNS). Id2 contributes to cultured neural precursor cell (NPC) proliferation as well as to the proliferation of CNS tumors such as glioblastoma that are likely to arise from NPC-like cells. We identified three phosphorylation sites near the N-terminus of Id2 in NPCs. To interrogate the importance of Id2 phosphorylation, Id2(-/-) NPCs were modified to express wild type (WT) Id2 or an Id2 mutant protein that could not be phosphorylated at the identified sites. We observed that NPCs expressing this mutant lacking phosphorylation near the N-terminus had higher steady-state levels of Id2 when compared to NPCs expressing WT Id2. This elevated level was the result of a longer half-life and reduced proteasome-mediated degradation. Moreover, NPCs expressing constitutively de-phosphorylated Id2 proliferated more rapidly than NPCs expressing WT Id2, a finding consistent with the well-characterized function of Id2 in driving proliferation. Observing that phosphorylation of Id2 modulates the degradation of this important cell-cycle regulator, we sought to identify a phosphatase that would stabilize Id2 enhancing its activity in NPCs and extended our analysis to include human glioblastoma-derived stem cells (GSCs). We found that expression of the phosphatase PP2A altered Id2 levels. Our findings suggest that inhibition of PP2A may be a novel strategy to regulate the proliferation of normal NPCs and malignant GSCs by decreasing Id2 levels. C1 [Sullivan, Jaclyn M.; Havrda, Matthew C.; Kettenbach, Arminja N.; Paolella, Brenton R.; Zhang, Zhonghua; Gerber, Scott A.; Israel, Mark A.] Norris Cotton Canc Ctr, Pharmacol & Toxicol, One Med Ctr Dr, Lebanon, NH 03756 USA. [Sullivan, Jaclyn M.] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH USA. [Havrda, Matthew C.; Zhang, Zhonghua; Israel, Mark A.] Geisel Sch Med Dartmouth, Dept Pediat, Hanover, NH USA. [Kettenbach, Arminja N.; Gerber, Scott A.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA. [Paolella, Brenton R.; Gerber, Scott A.; Israel, Mark A.] Geisel Sch Med Dartmouth, Dept Genet, Hanover, NH USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sullivan, JM (reprint author), One Med Ctr Dr,Rubin 751, Lebanon, NH 03756 USA. EM Jaclyn.M.Sullivan.GR@dartmouth.edu FU Jordan and Kyra Memorial Foundation; Theodora B. Betz Foundation; Albert J. Ryan Foundation FX The authors would like to thank staff of the Molecular Biology Core and the Immune Monitoring and Flow Cytometry Resource at the Norris Cotton Cancer Center. We also thank Tabatha Richardson and Jay Weier for their helpful review during the writing of this manuscript. This work was supported by the Jordan and Kyra Memorial Foundation (M.A.I), The Theodora B. Betz Foundation (M.A.I), and the Albert J. Ryan Foundation (J.M.S). NR 65 TC 2 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD MAY PY 2016 VL 34 IS 5 BP 1321 EP 1331 DI 10.1002/stem.2291 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DL8MU UT WOS:000375896900017 PM 26756672 ER PT J AU Hasegawa, K Brenner, BE Nowak, RM Trent, SA Herrera, V Gabriel, S Bittner, JC Camargo, CA AF Hasegawa, Kohei Brenner, Barry E. Nowak, Richard M. Trent, Stacy A. Herrera, Vivian Gabriel, Susan Bittner, Jane C. Camargo, Carlos A., Jr. TI Association of Guideline-concordant Acute Asthma Care in the Emergency Department With Shorter Hospital Length of Stay: A Multicenter Observational Study SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID CHILDREN; EXACERBATION AB Objectives: The objectives were to determine whether guideline-concordant emergency department (ED) management of acute asthma is associated with a shorter hospital length of stay (LOS) among patients hospitalized for asthma. Methods: A multicenter chart review study of patients aged 2-54 years who were hospitalized for acute asthma at one of the 25 U.S. hospitals during 2012-2013. Based on level A recommendations from national asthma guidelines, we derived four process measures of ED treatment before hospitalization: inhaled b-agonists, inhaled anticholinergic agents, systemic corticosteroids, and lack of methylxanthines. The outcome measure was hospital LOS. Results: Among 854 ED patients subsequently hospitalized for acute asthma, 532 patients (62%) received care perfectly concordant with the four process measures in the ED. Overall, the median hospital LOS was 2 days (interquartile range = 1-3 days). In the multivariable negative binomial model, patients who received perfectly concordant ED asthma care had a significantly shorter hospital LOS (17%, 95% confidence interval [CI] = -27% to -5%, p = 0.006), compared to other patients. In the mediation analysis, the direct effect of guideline-concordant ED asthma care on hospital LOS was similar to that of primary analysis (-16%, 95% CI = -27% to -5%, p = 0.005). By contrast, the indirect effect mediated by quality of inpatient asthma care was not significant, indicating that the effect of ED asthma care on hospital LOS was mediated through pathways other than quality of inpatient care. Conclusion: In this multicenter observational study, patients who received perfectly concordant asthma care in the ED had a shorter hospital LOS. Our findings encourage further adoption of guidelinerecommended emergency asthma care to improve patient outcomes. (C) 2016 by the Society for Academic Emergency Medicine C1 [Hasegawa, Kohei; Bittner, Jane C.; Camargo, Carlos A., Jr.] Harvard Univ, Dept Emergency Med, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Brenner, Barry E.] Univ Hosp, Case Med Ctr, Dept Emergency Med, Cleveland, OH USA. [Nowak, Richard M.] Henry Ford Hosp, Dept Emergency Med, Detroit, MI 48202 USA. [Trent, Stacy A.] Denver Hlth Med Ctr, Dept Emergency Med, Denver, CO USA. [Herrera, Vivian; Gabriel, Susan] Novartis Pharmaceut, E Hanover, NJ USA. RP Hasegawa, K (reprint author), Harvard Univ, Dept Emergency Med, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. EM khasegawa1@partners.org FU Novartis Pharmaceuticals Corporation, East Hanover, NJ; Teva FX The study was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ (CAC, principal investigator). The sponsor had no role in the conduct of the study nor collection, management, or analysis of the data.; Dr. Hasegawa has received research support from Teva. Dr. Camargo has provided asthma-related consultation for GlaxoSmithKline, Novartis, and Teva. The other authors have no potential conflicts to disclose. NR 21 TC 1 Z9 1 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD MAY PY 2016 VL 23 IS 5 BP 616 EP 622 DI 10.1111/acem.12920 PG 7 WC Emergency Medicine SC Emergency Medicine GA DL2TT UT WOS:000375488800011 PM 26833429 ER PT J AU Van Cleave, J Okumura, MJ Swigonski, N O'Connor, KG Mann, M Lail, JL AF Van Cleave, Jeanne Okumura, Megumi J. Swigonski, Nancy O'Connor, Karen G. Mann, Marie Lail, Jennifer L. TI Medical Homes for Children With Special Health Care Needs: Primary Care or Subspecialty Service? SO ACADEMIC PEDIATRICS LA English DT Article DE children with special health care needs; medical home; primary care; subspecialty care ID PEDIATRIC PRIMARY-CARE; GENERAL PEDIATRICIANS; MANAGEMENT; TRANSFORMATION; INNOVATIONS; PROGRAMS; LESSONS; COMPLEX; PAYMENT; YOUTH AB OBJECTIVE: To examine primary care pediatricians' (PCPs) beliefs about whether the family-centered medical home (FCMH) should be in primary or subspecialty care for children with different degrees of complexity; and to examine practice characteristics associated with these beliefs. METHODS: Data from the American Academy of Pediatrics Periodic Survey (PS 79) conducted in 2012 were analyzed. Outcomes were agreement/strong agreement that 1) primary care should be the FCMH locus for most children with special health care needs (CSHCN) and 2) subspecialty care is the best FCMH locus for children with rare or complex conditions. In multivariate models, we tested associations between outcomes and practice barriers (eg, work culture, time, cost) and facilitators (eg, having a care coordinator) to FCMH implementation. RESULTS: Among 572 PCPs, 65% agreed/strongly agreed primary care is the best FCMH setting for most CSHCN, and 43% agreed/strongly agreed subspecialty care is the best setting for children with complexity. Cost and time as barriers to FCMH implementation were oppositely associated with the belief that primary care was best for most CSHCN (cost: adjusted odds ratio [AOR] 2.31, 1.36-3.90; time: AOR 0.48, 0.29-0.81). Lack of skills to communicate and coordinate care was associated with the belief that specialty care was the best FCMH for children with complexity (AOR 1.99, 1.05-3.79). CONCLUSIONS: A substantial minority endorsed specialty care as the best FCMH locus for children with medical complexity. Several barriers were associated with believing primary care to be the best FCMH for most CSHCN. Addressing medical complexity in FCMH implementation may enhance perceived value by pediatricians. C1 [Van Cleave, Jeanne] MassGen Hosp Children, Div Gen Acad Pediat, Boston, MA USA. [Van Cleave, Jeanne] Harvard Univ, Sch Med, Boston, MA USA. [Okumura, Megumi J.] Univ Calif San Francisco, Sch Med, Dept Pediat & Internal Med, San Francisco, CA USA. [Swigonski, Nancy] Indiana Univ, Childrens Hlth Serv Res, Indianapolis, IN 46204 USA. [O'Connor, Karen G.] Amer Acad Pediat, Dept Res, Elk Grove Village, IL USA. [Mann, Marie] US Dept Hlth & Human Serv, HRSA Maternal & Child Hlth Bur, Rockville, MD USA. [Lail, Jennifer L.] Cincinnati Childrens Hosp Med Ctr, James M Anderson Ctr Hlth Syst Excellence, Cincinnati, OH 45229 USA. RP Van Cleave, J (reprint author), 125 Nashua St 860, Boston, MA 02114 USA. EM jvancleave@partners.org FU AAP; National Institute of Mental Health [K23MH083885]; National Center for Medical Home Implementation, Medical Home Capacity Building for CSHCN Cooperative Agreement; Health Resources and Services Administration, Maternal and Child Health Bureau [U43MC09134] FX Presented in part at the Pediatric Academic Societies annual meeting, May 6,2014, Vancouver, BC, Canada. The survey was supported by the AAP and the National Center for Medical Home Implementation, Medical Home Capacity Building for CSHCN Cooperative Agreement, Health Resources and Services Administration, Maternal and Child Health Bureau (grant U43MC09134). Part of JVC's effort was supported by the National Institute of Mental Health (grant K23MH083885). NR 31 TC 2 Z9 2 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 EI 1876-2867 J9 ACAD PEDIATR JI Acad. Pediatr. PD MAY-JUN PY 2016 VL 16 IS 4 BP 366 EP 372 PG 7 WC Pediatrics SC Pediatrics GA DL1DQ UT WOS:000375372800008 PM 26523634 ER PT J AU Padole, A Khawaja, RDA Otrakji, A Zhang, D Liu, B Xu, XG Kalra, MK AF Padole, Atul Khawaja, Ranish Deedar Ali Otrakji, Alexi Zhang, Da Liu, Bob Xu, X. George Kalra, Mannudeep K. TI Comparison of Measured and Estimated CT Organ Doses for Modulated and Fixed Tube Current: A Human Cadaver Study SO ACADEMIC RADIOLOGY LA English DT Article DE CT radiation organ doses; measured vs estimated organ doses; AEC and fixed mAs; human cadaver dosimetry ID MULTISLICE COMPUTED-TOMOGRAPHY; AUTOMATIC EXPOSURE CONTROL; MONTE-CARLO SIMULATIONS; VALIDATION; PATIENT; FEASIBILITY; DOSIMETRY; SOFTWARE; ABDOMEN; PELVIS AB Rationale and Objectives: The aim of this study was to compare the directly measured and the estimated computed tomography (CT) organ doses obtained from commercial radiation dose-tracking (RDT) software for CT performed with modulated tube current or automatic exposure control (AEC) technique and fixed tube current (mAs). Materials and Methods: With the institutional review board (IRB) approval, the ionization chambers were surgically implanted in a human cadaver (88 years old, male, 68 kg) in six locations such as liver, stomach, colon, left kidney, small intestine, and urinary bladder. The cadaver was scanned with routine abdomen pelvis protocol on a 128-slice, dual-source multidetector computed tomography (MDCT) scanner using both AEC and fixed mAs. The effective and quality reference mAs of 100, 200, and 300 were used for AEC and fixed mAs, respectively. Scanning was repeated three times for each setting, and measured and estimated organ doses (from RDT software) were recorded (N = 3*3*2 = 18). Results: Mean CTDIvol for AEC and fixed mAs were 4, 8, 13 mGy and 7, 14, 21 mGy, respectively. The most estimated organ doses were significantly greater (P < 0.01) than the measured organ doses for both AEC and fixed mAs. At AEC, the mean estimated organ doses (for six organs) were 14.7 mGy compared to mean measured organ doses of 12.3 mGy. Similarly, at fixed mAs, the mean estimated organ doses (for six organs) were 24 mGy compared to measured organ doses of 22.3 mGy. The differences among the measured and estimated organ doses were higher for AEC technique compared to the fixed mAs for most organs (P < 0.01). Conclusions: The most CT organ doses estimated from RDT software are greater compared to directly measured organ doses, particularly when AEC technique is used for CT scanning. C1 [Padole, Atul; Khawaja, Ranish Deedar Ali; Otrakji, Alexi; Zhang, Da; Liu, Bob; Kalra, Mannudeep K.] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. [Xu, X. George] Rensselaer Polytech Inst, Dept Mech Aerosp & Nucl Engn, Troy, NY USA. RP Padole, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM apadole@mgh.harvard.edu OI Padole, Atul/0000-0002-3917-4871 FU National Institute of Biomedical Imaging and Bioengineering [R01EB015478] FX The research is sponsored in part by the National Institute of Biomedical Imaging and Bioengineering (R01EB015478). NR 30 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD MAY PY 2016 VL 23 IS 5 BP 634 EP 642 DI 10.1016/j.acra.2015.12.008 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK6HA UT WOS:000375022100016 PM 26852248 ER PT J AU Callon, W Saha, S Korthuis, PT Wilson, IB Moore, RD Cohn, J Beach, MC AF Callon, Wynne Saha, Somnath Korthuis, P. Todd Wilson, Ira B. Moore, Richard D. Cohn, Jonathan Beach, Mary Catherine TI Which Clinician Questions Elicit Accurate Disclosure of Antiretroviral Non-adherence When Talking to Patients? SO AIDS AND BEHAVIOR LA English DT Article DE HIV/AIDS; Antiretrovirals; Adherence; Physician-patient communication ID HIV-INFECTED PATIENTS; MEDICATION ADHERENCE; SELF-REPORT; PROVIDER COMMUNICATION; THERAPY; CARE; INSTRUMENTS; BEHAVIOR; OUTCOMES; COHORT AB This study evaluated how clinicians assess antiretroviral (ARV) adherence in clinical encounters, and which questions elicit accurate responses. We conducted conversation analysis of audio-recorded encounters between 34 providers and 58 patients reporting ARV non-adherence in post-encounter interviews. Among 42 visits where adherence status was unknown by providers, 4 providers did not discuss ARVs (10 %), 6 discussed ARVs but did not elicit non-adherence disclosure (14 %), and 32 discussed ARVs which prompted disclosure (76 %). Questions were classified as: (1) clarification of medication ("Are you still taking the Combivir?"); (2) broad ("How's it going with your meds?"); (3) positively-framed ("Are you taking your medications regularly?"); (4) negatively-framed ("Have you missed any doses?"). Clinicians asked 75 ARV-related questions: 23 clarification, 12 broad, 17 positively-framed, and 23 negatively-framed. Negatively-framed questions were 3.8 times more likely to elicit accurate disclosure than all other question types (p < 0.0001). Providers can improve disclosure probability by asking directly about missed doses. C1 [Callon, Wynne; Moore, Richard D.; Beach, Mary Catherine] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Saha, Somnath] Portland VA Med Ctr, Portland, OR USA. [Saha, Somnath; Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Med, Portland, OR USA. [Wilson, Ira B.] Brown Univ, Sch Publ Hlth, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Cohn, Jonathan] Wayne State Univ, Dept Med, Detroit, MI 48202 USA. RP Callon, W (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD USA. EM wcallon1@jhmi.edu FU Health Resources Service Administration; Agency for Healthcare Research and Quality [AHRQ 290-01-0012]; National Institute of Drug Abuse [K23 DA019809, K24 DA037804]; Department of Veterans Affairs FX This research was supported by a contract from the Health Resources Service Administration and the Agency for Healthcare Research and Quality (AHRQ 290-01-0012). In addition, Dr. Korthuis was supported by the National Institute of Drug Abuse (K23 DA019809). Dr. Saha was supported by the Department of Veterans Affairs, Dr. Beach was supported by the National Institute of Drug Abuse (K24 DA037804). None of the funders had a role in the design and conduct of this analysis, nor was it subject to their final approval. None of the authors have any relevant financial conflicts of interest. NR 29 TC 0 Z9 0 U1 1 U2 1 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 MAY PY 2016 VL 20 IS 5 BP 1108 EP 1115 DI 10.1007/s10461-015-1231-7 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DK3XM UT WOS:000374850700017 PM 26499336 ER PT J AU Clairwood, M Yasuda, M Belazarian, L Deng, A AF Clairwood, MariMeg Yasuda, Mariko Belazarian, Leah Deng, April TI Unusual Cutaneous Metastasis of Uterine Carcinosarcoma: A Case Report and Review of the Literature SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Review DE uterine carcinosarcoma; malignant mixed Mullerian tumor; cutaneous metastasis ID MIXED MULLERIAN TUMORS; UTERUS; CARCINOMAS AB Cutaneous metastasis of uterine cancer is rare and is often associated with late-stage disease. Most uterine malignancies are endometrial adenocarcinomas, but a small subset is uterine carcinosarcoma, also known as malignant mixed Mullerian tumors. Uterine carcinosarcomas are highly aggressive tumors with an average 5-year survival rate of 26%-34%. Metastases most commonly occur in the abdominal wall, lung, and bone. Cutaneous metastasis is exceedingly rare and may pose a diagnostic challenge. The authors report a 57-year-old woman with multiple subcutaneous nodules on the face and trunk. A biopsy revealed similar morphology and staining characteristics as the sarcomatous component of the primary uterine carcinosarcoma. Histopathological features and immunophenotypical characteristics of the metastatic tumor are detailed in comparison with the original tumor. A review of the literature is also provided. C1 [Clairwood, MariMeg; Belazarian, Leah] Univ Massachusetts, Div Dermatol, 281 Lincoln St, Worcester, MA 01605 USA. [Yasuda, Mariko] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Deng, April] Univ Massachusetts, Dept Pathol, Amherst, MA 01003 USA. RP Clairwood, M (reprint author), Univ Massachusetts, Div Dermatol, 281 Lincoln St, Worcester, MA 01605 USA. EM mclairwood@gmail.com NR 13 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0193-1091 EI 1533-0311 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD MAY PY 2016 VL 38 IS 5 BP 366 EP 369 PG 4 WC Dermatology SC Dermatology GA DK3QM UT WOS:000374832500012 PM 26675357 ER PT J AU Moe, J Belsky, JB AF Moe, Jessica Belsky, Justin Brett TI Comparing patients who leave the ED prematurely, before vs after medical evaluation: a National Hospital Ambulatory Medical Care Survey analysis SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT; PHYSICIAN; OUTCOMES AB Background: Many patients leave the Emergency Department (ED) before beginning or completing medical evaluation. Some of these patients may be at higher medical risk depending on their timing of leaving the ED. Objectives: To compare patient, hospital, and visit characteristics of patients who leave before completing medical care to patients who leave before ED evaluation. Methods: Retrospective cross-sectional analysis of ED visits using the 2009-2011 National Hospital Ambulatory Medical Care Survey. Results: A total of 100 962 ED visits were documented in the 2009-2011 National Hospital Ambulatory Medical Care Survey, representing a weighted count of 402 211 907 total ED visits. 2646 (2.62%) resulted in a disposition of left without completing medical care. Of these visits, 1792 (67.7%) left before being seen by a medical provider versus 854 (32.3%) who left after medical provider evaluation but before a final disposition. Patients who left after being assessed by a medical provider were older, had higher acuity visits, were more likely to have visited an ED without nursing triage, arrived more often by ambulance, and were more likely to have private insurance than to be self-paying or to have other payment arrangements (e.g. worker's compensation or charity/no charge). Conclusions: When comparing all patients who left the ED before completion of care, those who left after versus before medical provider evaluation differed in their patient, hospital, and visit characteristics and may represent a high risk patient group. (C) 2016 Elsevier Inc. All rights reserved. C1 [Moe, Jessica] Univ Alberta, Dept Emergency Med, Edmonton, AB, Canada. [Belsky, Justin Brett] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Moe, J (reprint author), Univ Alberta, RCPS Emergency Med Residency Program, 750 Univ Terrace,8303-112 St, Edmonton, AB T6G 2T4, Canada. EM Jessica.moe@gmail.com NR 23 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD MAY PY 2016 VL 34 IS 5 BP 830 EP 833 DI 10.1016/j.ajem.2016.01.015 PG 4 WC Emergency Medicine SC Emergency Medicine GA DK6VH UT WOS:000375063100013 PM 26935229 ER PT J AU Yaffe, K AF Yaffe, Kristine TI Moving Beyond Dualism to Advance Geriatric Neuropsychiatry SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Editorial Material ID DEPRESSION C1 [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 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Box 181,4150 Clement St, San Francisco, CA 94121 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA.; Yaffe, K (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAY PY 2016 VL 24 IS 5 BP 339 EP 341 DI 10.1016/j.jagp.2016.01.137 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DK6SF UT WOS:000375054800001 PM 27066734 ER PT J AU Garlo, K Sise, M AF Garlo, Katherine Sise, Meghan TI HYPONATREMIC SEIZURE: ROLE OF DDAVP SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meetings of the National-Kidney Foundation CY APR 27-MAY 01, 2016 CL Boston, MA SP Natl Kidney Fdn C1 [Garlo, Katherine; Sise, Meghan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 MAY PY 2016 VL 67 IS 5 MA 116 BP A47 EP A47 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DK3WZ UT WOS:000374849400117 ER PT J AU Li, NC Ofsthun, N Maddux, F Thadhani, R AF Li, Nien-Chen Ofsthun, Norma Maddux, Frank Thadhani, Ravi TI SMOKING & ONE YEAR OUTCOMES IN US HEMODIALYSIS PATIENTS SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meetings of the National-Kidney Foundation CY APR 27-MAY 01, 2016 CL Boston, MA SP Natl Kidney Fdn C1 Fresenius Med Care North Amer, Waltham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 MAY PY 2016 VL 67 IS 5 MA 197 BP A68 EP A68 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DK3WZ UT WOS:000374849400198 ER PT J AU Nigwekar, SU Weiser, JM Dougherty, SM Wibecan, JL Kalim, S Corapi, KM Eneanya, ND Brown, D Thadhani, RI Paunescu, TG AF Nigwekar, Sagar U. Weiser, Jeremy M. Dougherty, Sarah M. Wibecan, Joshua L. Kalim, Sahir Corapi, Kristin M. Eneanya, Nwamaka D. Brown, Dennis Thadhani, Ravi I. Paunescu, Teodor G. TI OLFACTORY DEFECTS IN RENAL DISEASE SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meetings of the National-Kidney Foundation CY APR 27-MAY 01, 2016 CL Boston, MA SP Natl Kidney Fdn C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU 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 MAY PY 2016 VL 67 IS 5 MA 245 BP A80 EP A80 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DK3WZ UT WOS:000374849400246 ER PT J AU Satake, E Croall, S Smiles, AM Krolewski, AS Pezzolesi, MG AF Satake, Eiichiro Croall, Stephanie Smiles, Adam M. Krolewski, Andrzej S. Pezzolesi, Marcus G. TI CIRCULATING PLASMA MICRORNA PROFILING ASSOCIATED WITH PROTEINURIA AND IMPAIRED KIDNEY FUNCTION IN TYPE 1 DIABETIC PATIENTS WITH NEPHROPATHY SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meetings of the National-Kidney Foundation CY APR 27-MAY 01, 2016 CL Boston, MA SP Natl Kidney Fdn C1 [Satake, Eiichiro; Croall, Stephanie; Smiles, Adam M.; Krolewski, Andrzej S.; Pezzolesi, Marcus G.] Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAY PY 2016 VL 67 IS 5 MA 304 BP A94 EP A94 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DK3WZ UT WOS:000374849400305 ER PT J AU Wakeman, SE AF Wakeman, Sarah E. TI Using Science to Battle Stigma in Addressing the Opioid Epidemic: Opioid Agonist Therapy Saves Lives SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIAL; METHADONE-MAINTENANCE; DEPENDENT PATIENTS; ADDICTION; MEDICATION; COSTS; RISK C1 [Wakeman, Sarah E.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, 55 Fruit St,Founders 880, Boston, MA 02114 USA. RP Wakeman, SE (reprint author), Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, 55 Fruit St,Founders 880, Boston, MA 02114 USA. EM swakeman@partners.org NR 23 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAY PY 2016 VL 129 IS 5 BP 455 EP 456 DI 10.1016/j.amjmed.2015.12.028 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DK7YZ UT WOS:000375144600019 PM 26836384 ER PT J AU Epstein, AE Olshansky, B Naccarelli, GV Kennedy, JI Murphy, EJ Goldschlager, N AF Epstein, Andrew E. Olshansky, Brian Naccarelli, Gerald V. Kennedy, John I., Jr. Murphy, Elizabeth J. Goldschlager, Nora TI Practical Management Guide for Clinicians Who Treat Patients with Amiodarone SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE Adverse drug reactions; Amiodarone; Atrial fibrillation; Ventricular fibrillation; Ventricular tachycardia ID CONGESTIVE-HEART-FAILURE; ANTIARRHYTHMIC-DRUG-THERAPY; LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; ONSET ATRIAL-FIBRILLATION; SUDDEN CARDIAC DEATH; LOW-DOSE AMIODARONE; PULMONARY TOXICITY; RANDOMIZED-TRIAL; INTRAVENOUS AMIODARONE AB Amiodarone, an iodinated benzofuran derivative with Class I, II, III, and IV antiarrhythmic properties, is the most commonly used antiarrhythmic drug used to treat supraventricular and ventricular arrhythmias. Appropriate use of this drug, with its severe and potentially life-threatening adverse effects, requires an essential understanding of its risk-benefit properties in order to ensure safety. The objective of this review is to afford clinicians who treat patients receiving amiodarone an appropriate management strategy for its safe use. The authors of this consensus management guide have thoroughly reviewed and evaluated the existing literature on amiodarone and apply this information, along with the collective experience of the authors, in its development. Provided are management guides on the intravenous and oral dosing of amiodarone, appropriate outpatient follow-up of patients taking the drug, its recognized adverse effects, and recommendations on when to consult specialists to help in patient management. All clinicians must be cognizant of the appropriate use, follow-up, and adverse reactions of amiodarone. The responsibility incurred by those treating such patients cannot be overemphasized. Published by Elsevier Inc. C1 [Epstein, Andrew E.] Univ Penn, Dept Med, Electrophysiol Sect, Cardiovasc Div, Philadelphia, PA 19104 USA. [Olshansky, Brian] Mercy Hosp North Iowa, Mason City, PA USA. [Naccarelli, Gerald V.] Penn State Univ, Penn State Heart & Vasc Inst, Hershey, PA USA. [Kennedy, John I., Jr.] Univ Alabama Birmingham, Dept Med, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Kennedy, John I., Jr.] Birmingham VA Med Ctr, Dept Med, Birmingham, AL USA. [Murphy, Elizabeth J.; Goldschlager, Nora] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Murphy, Elizabeth J.] San Francisco Gen Hosp, Dept Med, Div Endocrinol, San Francisco, CA 94110 USA. [Goldschlager, Nora] San Francisco Gen Hosp, Dept Med, Div Cardiol, San Francisco, CA 94110 USA. RP Epstein, AE (reprint author), Univ Penn, Cardiovasc Div, Electrophysiol Sect, 3400 Spruce St,9 Founders, Philadelphia, PA 19104 USA. EM andrew.epstein@uphs.upenn.edu NR 64 TC 7 Z9 7 U1 4 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAY PY 2016 VL 129 IS 5 BP 468 EP 475 DI 10.1016/j.amjmed.2015.08.039 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DK7YZ UT WOS:000375144600023 PM 26497904 ER PT J AU Brondfield, S Feingold, KR AF Brondfield, Sam Feingold, Kenneth R. TI Symptomatic Graves' Disease After Autoimmune Hypothyroidism SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Brondfield, Sam; Feingold, Kenneth R.] Univ Calif San Francisco, Dept Med, 505 Parnassus Ave,Rm 987, San Francisco, CA 94143 USA. [Brondfield, Sam; Feingold, Kenneth R.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. RP Brondfield, S (reprint author), Univ Calif San Francisco, Dept Med, 505 Parnassus Ave,Rm 987, San Francisco, CA 94143 USA. EM sam.brondfield@ucsf.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAY PY 2016 VL 129 IS 5 BP E19 EP E20 DI 10.1016/j.amjmed.2015.12.017 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DK7YZ UT WOS:000375144600008 PM 26772649 ER PT J AU Lee, MS Venkatesh, KK Growdon, WB Ecker, JL York-Best, CM AF Lee, Malinda S. Venkatesh, Kartik K. Growdon, Whitfield B. Ecker, Jeffrey L. York-Best, Carey M. TI Predictors of 30-day readmission following hysterectomy for benign and malignant indications at a tertiary care academic medical center SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE complication; hysterectomy; malignancy; outcome; readmission ID EPITHELIAL OVARIAN-CARCINOMA; HOSPITAL READMISSION; LAPAROSCOPIC HYSTERECTOMY; SURGICAL CYTOREDUCTION; ENDOMETRIAL CANCER; UNITED-STATES; RISK-FACTORS; APGAR SCORE; SURGERY; COMPLICATIONS AB BACKGROUND: Hospital readmissions are costly, frequent, and increasingly under public scrutiny. With increased financial constraints on the medical environment, understanding the drivers of unscheduled readmissions following gynecologic surgery will become increasingly important to value-driven care. OBJECTIVE: The current study was conducted to identify risk factors for 30-day readmission following hysterectomy for benign and malignant indications. STUDY DESIGN: A retrospective cohort study was conducted from 2008 through 2010 of all nongravid hysterectomies at a single tertiary care academic medical center. Clinical, perioperative, and physician characteristics were collected. Multivariable logistic regression models were used to identify predictors of 30-day readmission, stratified by malignant and benign indications for hysterectomy. RESULTS: Among 1649 women who underwent a hysterectomy (1009 for benign indications and 640 for malignancy), 6% were subsequently readmitted within 30 days (8.9% for malignancy vs 4.2% for benign; P < .0001). The mean time to readmission was 13 days (15 days for malignancy vs 10 days for benign; P = .004). The most common reasons for readmission were gastrointestinal (38%) and infectious (34%) etiologies, and 11.6% of readmitted patients experienced a perioperative complication. Among women undergoing hysterectomy for benign indications, a history of a laparotomy, including cesarean delivery (adjusted odds ratio [AOR], 2.12; 95% confidence interval [CI], 1.06-4.25; P = .03), as well as a perioperative complication (AOR, 2.41; 95% CI, 1.00-6.04; P = .05) were both associated with a >2-fold increased odds of readmission. Among women undergoing hysterectomy for malignancy, an American Society of Anesthesiologists Physical Status Classification of III or IV (AOR, 1.92; 95% CI, 1.05-3.50; P = .03), a longer length of initial hospitalization (3 days AOR, 7.83; 95% CI, 1.33-45.99; P = .02), and an estimated blood loss >500 mL (AOR, 3.29; 95% CI, 1.28-8.45; P = .01) were associated with a higher odds of readmission; however, women who underwent a laparoscopic hysterectomy (AOR, 0.32; 95% CI, 0.12-0.86; P = .02) and who were discharged on postoperative day 1 (AOR, 0.16; 95% CI, 0.03-0.82; P = .02) were at a decreased risk of readmission. Physician and operative characteristics were not significant predictors of readmission. CONCLUSION: This study found that malignancy, perioperative complications, and prior open abdominal surgery, including cesarean delivery, are significant risk factors for consequent 30-day readmission following index hysterectomy. It may be possible to identify patients at highest risk for readmission at the time of hysterectomy, which can assist in developing interventions to reduce such events. C1 [Lee, Malinda S.; Venkatesh, Kartik K.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Integrated Residency Program Obstet & Gynecol, Boston, MA 02114 USA. [Growdon, Whitfield B.; Ecker, Jeffrey L.; York-Best, Carey M.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Lee, Malinda S.; Venkatesh, Kartik K.; Growdon, Whitfield B.; Ecker, Jeffrey L.; York-Best, Carey M.] Harvard Univ, Sch Med, Boston, MA USA. RP York-Best, CM (reprint author), Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA.; York-Best, CM (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM cyorkbest@mgh.harvard.edu FU Partners Center of Expertise Patient Care Quality and Safety Research Grant, Partners Healthcare (Boston, MA) FX Supported by the Partners Center of Expertise Patient Care Quality and Safety Research Grant, Partners Healthcare (Boston, MA). NR 26 TC 3 Z9 3 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2016 VL 214 IS 5 AR 607.e1-e12 DI 10.1016/j.ajog.2015.11.037 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DL2GR UT WOS:000375452100008 PM 26704895 ER PT J AU Saade, GR Boggess, KA Sullivan, SA Markenson, GR Iams, JD Coonrod, DV Pereira, LM Esplin, MS Cousins, LM Lam, GK Hoffman, MK Severinsen, RD Pugmire, T Flick, JS Fox, AC Lueth, AJ Rust, SR Mazzola, E Hsu, C Dufford, MT Bradford, CL Ichetovkin, IE Fleischer, TC Polpitiya, AD Critchfield, GC Kearney, PE Boniface, JJ Hickok, DE AF Saade, George R. Boggess, Kim A. Sullivan, Scott A. Markenson, Glenn R. Iams, Jay D. Coonrod, Dean V. Pereira, Leonardo M. Esplin, M. Sean Cousins, Larry M. Lam, Garrett K. Hoffman, Matthew K. Severinsen, Robert D. Pugmire, Trina Flick, Jeff S. Fox, Angela C. Lueth, Amir J. Rust, Sharon R. Mazzola, Emanuele Hsu, ChienTing Dufford, Max T. Bradford, Chad L. Ichetovkin, Ilia E. Fleischer, Tracey C. Polpitiya, Ashoka D. Critchfield, Gregory C. Kearney, Paul E. Boniface, J. Jay Hickok, Durlin E. TI Development and validation of a spontaneous preterm delivery predictor in asymptomatic women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE biomarker; pregnancy; preterm birth; proteomics; IGFBP4; IBP4; SHBG ID HORMONE-BINDING GLOBULIN; CERVICAL-VAGINAL FLUID; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; INTRAAMNIOTIC INFECTION; PROTEOMIC ANALYSIS; GENE-EXPRESSION; HUMAN PLACENTA; BIRTH; RISK; BIOMARKERS AB BACKGROUND: Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. OBJECTIVE: To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. STUDY DESIGN: A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. RESULTS: The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs >= 35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. CONCLUSION: A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery. C1 [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Boggess, Kim A.] Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chapel Hill, NC 27599 USA. [Sullivan, Scott A.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Markenson, Glenn R.] Baystate Med Ctr, Maternal Fetal Med, Springfield, MA USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Coonrod, Dean V.] Maricopa Integrated Hlth Syst, Dist Med Grp, Dept Obstet & Gynecol, Phoenix, AZ USA. [Pereira, Leonardo M.] Oregon Hlth & Sci Univ, Div Maternal Fetal Med, Portland, OR 97201 USA. [Esplin, M. Sean] Intermt Healthcare, Div Maternal Fetal Med, Murray, UT USA. [Cousins, Larry M.] Rady Childrens Specialists San Diego, San Diego Perinatal Ctr, Div Maternal Fetal Med, San Diego, CA USA. [Lam, Garrett K.] Reg Obstetr Consultants, Chattanooga, TN USA. [Hoffman, Matthew K.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Severinsen, Robert D.; Pugmire, Trina; Flick, Jeff S.; Fox, Angela C.; Lueth, Amir J.; Hsu, ChienTing; Dufford, Max T.; Bradford, Chad L.; Ichetovkin, Ilia E.; Fleischer, Tracey C.; Polpitiya, Ashoka D.; Critchfield, Gregory C.; Boniface, J. Jay; Hickok, Durlin E.] Sera Prognost Inc, Salt Lake City, UT USA. [Mazzola, Emanuele] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kearney, Paul E.] Integrated Diagnost Inc, Seattle, WA USA. [Markenson, Glenn R.] Boston Med Ctr, Maternal Fetal Med, Boston, MA USA. [Coonrod, Dean V.] Univ Arizona, Coll Med, Dept Obstet & Gynecol, Tucson, AZ USA. [Esplin, M. Sean] Univ Utah, Maternal Fetal Med, Salt Lake City, UT USA. [Lam, Garrett K.] UT Coll Med, Dept Obstet & Gynecol, Chattanooga, TN USA. RP Saade, GR (reprint author), Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. EM gsaade@utmb.edu OI ICHETOVKIN, ILIA/0000-0003-4662-3513 FU Sera Prognostics, Inc. FX The study described in this manuscript was supported in full by Sera Prognostics, Inc. The sponsor collaborated with site principal investigators and outside consultants regarding study design, data analysis and interpretation, manuscript writing, and the decision to submit the paper for publication. The sponsor was not involved with specimen collection, specimen processing, or data collection at the clinical sites. The sponsor conducted proteomic analysis of the specimens. NR 61 TC 0 Z9 0 U1 5 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2016 VL 214 IS 5 AR 633.e1-e24 DI 10.1016/j.ajog.2016.02.001 PG 24 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DL2GR UT WOS:000375452100021 PM 26874297 ER PT J AU Yarar-Fisher, C Bickel, CS Kelly, NA Stec, MJ Windham, ST McLain, AB Oster, RA Bamman, MM AF Yarar-Fisher, Ceren Bickel, C. Scott Kelly, Neil A. Stec, Michael J. Windham, Samuel T. McLain, Amie B. Oster, Robert A. Bamman, Marcas M. TI Heightened TWEAK-NF-kappa B signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE TNF-like weak inducer of apoptosis; nuclear factor kappa-light-chain-enhancer of activated B cells ID SKELETAL-MUSCLE; APOPTOSIS TWEAK; WEAK INDUCER; GLUCOSE-TOLERANCE; OLDER-ADULTS; ATROPHY; EXERCISE; MICE; INDIVIDUALS; ACTIVATION AB Individuals with long-standing spinal cord injury (SCI) often present with extreme muscle atrophy and impaired glucose metabolism at both the skeletal muscle and whole body level. Persistent inflammation and increased levels of proinflammatory cytokines in the skeletal muscle are potential contributors to dysregulation of glucose metabolism and atrophy; however, to date no study has assessed the effects of long-standing SCI on their expression or intracellular signaling in the paralyzed muscle. In the present study, we assessed the expression of genes (TNF alpha R, TNF alpha, IL-6R, IL-6, TWEAK, TWEAK R, atrogin-1, and MuRF1) and abundance of intracellular signaling proteins (TWEAK, TWEAK R, NF-kappa B, and p-p65/p-50/105) that are known to mediate inflammation and atrophy in skeletal muscle. In addition, based on the effects of muscle inflammation on promotion of skeletal muscle fibrosis, we assessed the degree of fibrosis between myofibers and fascicles in both groups. For further insight into the distribution and variability of muscle fiber size, we also analyzed the frequency distribution of SCI fiber size. Resting vastus lateralis (VL) muscle biopsy samples were taken from 11 men with long-standing SCI (approximate to 22 yr) and compared with VL samples from 11 able-bodied men of similar age. Our results demonstrated that chronic SCI muscle has heightened TNF alpha R and TWEAK R gene expression and NF-kappa B signaling (higher TWEAK R and phospho-NF-kappa B p65) and fibrosis, along with substantial myofiber size heterogeneity, compared with able-bodied individuals. Our data suggest that the TWEAK/TWEAK R/NF-kappa B signaling pathway may be an important mediator of chronic inflammation and fibrotic adaptation in SCI muscle. C1 [Yarar-Fisher, Ceren; McLain, Amie B.] Univ Alabama Birmingham, Dept Phys Med & Rehabil, Birmingham, AL 35294 USA. [Kelly, Neil A.; Stec, Michael J.; Bamman, Marcas M.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. [Bickel, C. Scott] Univ Alabama Birmingham, Dept Phys Therapy, Birmingham, AL 35294 USA. [Windham, Samuel T.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Oster, Robert A.; Bamman, Marcas M.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Yarar-Fisher, Ceren; Bickel, C. Scott; Kelly, Neil A.; Stec, Michael J.; Windham, Samuel T.; McLain, Amie B.] Univ Alabama Birmingham, UAB Ctr Exercise Med, 966 McCallum Basic Hlth Sci Bldg, Birmingham, AL 35294 USA. [Bamman, Marcas M.] Birmingham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. RP Bamman, MM (reprint author), Univ Alabama Birmingham, UAB Ctr Exercise Med, 966 McCallum Basic Hlth Sci Bldg, Birmingham, AL 35294 USA. EM mbamman@uab.edu FU Veterans Affairs Merit Award; UAB Center for Exercise Medicine, Department of Physical Medicine and Rehabilitation [5T32-DK-62710]; UAB Center for Clinical and Translational Science [UL1-TR-000165] FX This work was supported by a Veterans Affairs Merit Award (M. M. Bamman), the UAB Center for Exercise Medicine, Department of Physical Medicine and Rehabilitation, 5T32-DK-62710, and the UAB Center for Clinical and Translational Science (UL1-TR-000165). NR 45 TC 3 Z9 4 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAY 1 PY 2016 VL 310 IS 9 BP E754 EP E761 DI 10.1152/ajpendo.00240.2015 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA DK9FC UT WOS:000375235200005 PM 26931128 ER PT J AU Elvin, J Buvall, L Jonsson, AL Granqvist, A Lassen, E Bergwall, L Nystrom, J Haraldsson, B AF Elvin, Johannes Buvall, Lisa Jonsson, Annika Lindskog Granqvist, Anna Lassen, Emelie Bergwall, Lovisa Nystrom, Jenny Haraldsson, Borje TI Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE melanocortin 1 receptor; podocyte; actin stress fiber; oxidative stress ID IDIOPATHIC MEMBRANOUS NEPHROPATHY; NEPHROTIC SYNDROME; ADRENOCORTICOTROPIC HORMONE; PUROMYCIN AMINONUCLEOSIDE; GLOMERULAR-DISEASES; ACTIN CYTOSKELETON; HUMAN MELANOCYTES; OXIDATIVE STRESS; MURINE PODOCYTES; MC1 RECEPTOR AB Drugs containing adrenocorticotropic hormone have been used as therapy for patients with nephrotic syndrome. We have previously shown that adrenocorticotropic hormone and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, and improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for MC1R. Podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside, and downstream effects of MC1R activation on podocyte survival, antioxidant defense, and cytoskeleton dynamics were studied. To increase the response and enhance intracellular signals, podocytes were transduced to overexpress MC1R. We showed that puromycin promotes MC1R expression in podocytes and that activation of MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in the dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protect against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R-activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies. C1 [Elvin, Johannes; Jonsson, Annika Lindskog; Granqvist, Anna; Lassen, Emelie; Haraldsson, Borje] Univ Gothenburg, Sahlgrenska Acad, Dept Mol & Clin Med, Inst Med, Gothenburg, Sweden. [Buvall, Lisa; Bergwall, Lovisa; Nystrom, Jenny] Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Inst Neurosci & Physiol, Gothenburg, Sweden. [Buvall, Lisa] Massachusetts Gen Hosp, Dept Nephrol, Boston, MA 02114 USA. [Buvall, Lisa] Harvard Univ, Sch Med, Boston, MA USA. RP Elvin, J (reprint author), Univ Gothenburg, Dept Physiol, Box 430, SE-40530 Gothenburg, Sweden. EM johannes.elvin@gu.se OI Elvin, Johannes/0000-0002-9678-9020 FU Swedish Medical Research Council [9898, 14764]; Vinnova; National Association for Kidney Diseases; John and Brit Wennerstrom Research Foundation; Inga-Britt and Arne Lundberg Research Foundation; Sahlgrenska University Hospital FX Swedish Medical Research Council Grants 9898 and 14764, Vinnova, the National Association for Kidney Diseases, the John and Brit Wennerstrom Research Foundation, the Inga-Britt and Arne Lundberg Research Foundation, and grants from the Sahlgrenska University Hospital supported this work. NR 62 TC 4 Z9 4 U1 2 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAY 1 PY 2016 VL 310 IS 9 BP F846 EP F856 DI 10.1152/ajprenal.00231.2015 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA DK7ON UT WOS:000375115700006 PM 26887829 ER PT J AU Leonpacher, AK Peters, ME Drye, LT Makino, KM Newell, JA Devanand, DP Frangakis, C Munro, CA Mintzer, JE Pollock, BG Rosenberg, PB Schneider, LS Shade, DM Weintraub, D Yesavage, J Lyketsos, CG Porsteinsson, AP AF Leonpacher, Anne K. Peters, Matthew E. Drye, Lea T. Makino, Kelly M. Newell, Jeffery A. Devanand, D. P. Frangakis, Constantine Munro, Cynthia A. Mintzer, Jacobo E. Pollock, Bruce G. Rosenberg, Paul B. Schneider, Lon S. Shade, David M. Weintraub, Daniel Yesavage, Jerome Lyketsos, Constantine G. Porsteinsson, Anton P. CA CitAD Res Grp TI Effects of Citalopram on Neuropsychiatric Symptoms in Alzheimer's Dementia: Evidence From the CitAD Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID PLACEBO-CONTROLLED TRIALS; BEHAVIORAL DISTURBANCES; ANTIPSYCHOTIC-DRUGS; PSYCHOTIC SYMPTOMS; NURSING-HOMES; CACHE COUNTY; RISK-FACTORS; DISEASE; AGITATION; HEALTH AB Objective: Citalopram has been shown to improve agitation in patients with Alzheimer's disease. The authors evaluated whether other neuropsychiatric symptoms improve with citalopram treatment compared with placebo. Method: In this planned secondary analysis of the Citalopram for Agitation in Alzheimer's Disease study, the authors evaluated the effect of citalopram on the 12 neuropsychiatric symptom domains assessed by the Neuropsychiatric Inventory (NPI). They compared caregiver-reported NPI scores at week 9 in patients receiving citalopram(30 mg/day) or placebo with regard to both the presence or absence of individual neuropsychiatric symptoms and individual domain scores (reflecting severity) in participants who had symptoms at week 9. Results: At week 9, participants treated with citalopram were significantly less likely to be reported as showing delusions (odds ratio=0.40), anxiety (odds ratio=0.43), and irritability/lability (odds ratio=0.38). A comparison of median scores of participants with symptoms present at week 9 showed significant differences favoring citalopram for hallucinations and favoring placebo for sleep/nighttime behavior disorders. Conclusions: While dosage constraints must be considered because of citalopram's adverse effect profile, this agent's overall therapeutic effects in patients with Alzheimer's disease and agitation, in addition to efficacy for agitation/aggression, included reductions in the frequency of irritability, anxiety, and delusions; among patients who had these symptoms at week 9, they included a reduction in the severity of hallucinations but an increase in the severity of sleep/nighttime behavior disorders. C1 [Porsteinsson, Anton P.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Rochester, Sch Med & Dent, Alzheimers Dis Care Res & Educ Program, Rochester, NY USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. New York State Psychiat Inst & Hosp, Dept Psychiat, Div Geriatr Psychiat, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. Roper St Francis Healthcare, Clin Biotechnol Res Inst, Charleston, SC USA. Ralph H Johnson VA Med Ctr, Dept Psychiat, Charleston, SC USA. Ctr Addict & Mental Hlth, Campbell Inst, Toronto, ON, Canada. Univ Toronto, Dept Psychiat, Toronto, ON, Canada. Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Porsteinsson, AP (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. EM anton_porsteinsson@urmc.rochester.edu FU National Institute on Aging (NIA); NIMH [R01AG031348]; NIH [P50-AG05142]; Avanir; NIA; Office of the Federal Public Defender; U.S. Attorney's Office; Avanir Pharmaceuticals; Transition Therapeutics; Insys Therapeutics; Takeda Global Research and Development Center; Pfizer; Genentech; Merck; Accera; Elan; Hoffmann-La Roche; Novartis; Baxter; Eli Lilly; Wyeth; Janssen Alzheimer Initiative; Alzheimer's Assocation; Functional Neuromodulation; Abbott; AstraZeneca; Bristol-Myers Squibb; GlaxoSmithKline; Johnson Johnson; Lundbeck; Roche; AbbVie; ACImmune; Forest Laboratories; Forum; Merz; Orion; Otsuka; Servier; Takeda; Toyama/FujiFilm; Zinfandel; Michael J. Fox Foundation for Parkinson's Research; Department of Veterans Affairs; Avid Radiopharmaceuticals; Alzheimer's Disease Cooperative Study; International Parkinson; Movement Disorder Society; Associated Jewish Federation of Baltimore; Weinberg Foundation; Forest; Eisai; Ortho-McNeil; National Football League; Biogen; EnVivo; Genentech/Roche; Medivation; MerckPfizer; Toyama; Department of Defense FX Supported by National Institute on Aging (NIA) and NIMH grant R01AG031348, and in part by NIH grant P50-AG05142 (to University of Southern California and Dr. Schneider).; Dr. Devanand has received research support from Avanir and has served on scientific advisory boards for AbbVie, Astellas, and Lundbeck and as a consultant for Intracellular Therapies. Dr. Munro has received grant funding (to her institution) from NIA, NIH, and NIMH and has received payment for expert testimony from various law firms, from the Office of the Federal Public Defender, and from the U.S. Attorney's Office, as well as payment for lectures for Episcopal Ministries. Dr. Mintzer has received grant support from and served as a consultant for Avanir Pharmaceuticals, Transition Therapeutics, and Insys Therapeutics; he has received support for travel to meetings from NIA and NIMH; he has received grants (to his institution) from NIA, NIH, Takeda Global Research and Development Center, Pfizer, Genentech, Merck, Accera, Elan, Avanir, Hoffmann-La Roche, Novartis, Baxter, Eli Lilly, Wyeth, and Janssen Alzheimer Initiative; he has been employed by NeuroQuest and is founder of BioPharma Connex. Dr. Pollock has received a grant (to his institution) from NIA and NIMH; he has served on a board for Lundbeck Canada and as a consultant for Wyeth; and he has received travel and accommodation support from Lundbeck International Neuroscience Foundation. Dr. Rosenberg has received grant support from the Alzheimer's Assocation, Eli Lilly, Functional Neuromodulation, Merck, NIA, and Novartis; he has served as a consultant to AbbVie, Abide, Insys, Janssen, and Merck; and he has received travel support from Eli Lilly. Dr. Schneider has received grant and clinical trial support from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, NIH, Novartis, Pfizer, and Roche and consultancy fees, including for data monitoring committees and adjudication committees, from Abbott, AbbVie, ACImmune, AstraZeneca, Baxter, Bristol-Myers Squibb, Elan, Eli Lilly, Forest Laboratories, Forum, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Merz, Novartis, Orion, Otsuka, Pfizer, Roche, Servier, Takeda, Toyama/FujiFilm, and Zinfandel. Dr. Weintraub has received research funding or support from the Michael J. Fox Foundation for Parkinson's Research, NIH, Novartis, the Department of Veterans Affairs, Avid Radiopharmaceuticals, the Alzheimer's Disease Cooperative Study, and the International Parkinson and Movement Disorder Society; honoraria from AbbVie, Acadia, Biotie, Clintrex, Novartis, Teva Pharmaceuticals, UCB, and the CHDI Foundation; license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS; royalties from Wolters Kluwer; and fees for legal consultation for a lawsuit related to antipsychotic prescribing in a patient with Parkinson's disease. Dr. Lyketsos has received grant support (for research or CME) from NIMH, NIA, the Associated Jewish Federation of Baltimore, the Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Eli Lilly, Ortho-McNeil, Bristol-Myers Squibb, Novartis, the National Football League, Elan, and Functional Neuromodulation; he has served as a consultant or adviser to AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Eli Lilly, Pfizer, Genentech, Elan, the NFL Players Association, the NFL Benefits Office, Avanir, Zinfandel, Bristol-Myers Squibb, AbbVie, Janssen, Orion, Otsuka, and Astellas; and he has received honoraria or travel support from Pfizer, Forest, GlaxoSmithKline, and Health Monitor. Dr.; Porsteinsson has received grants (to his institution) from AstraZeneca, Avanir, Baxter, Biogen, Bristol-Myers Squibb, Eisai, Elan, EnVivo, Genentech/Roche, the Janssen Alzheimer Initiative, Medivation, Merck, Pfizer, Toyama, Transition Therapeutics, NIH, NIMH, NIA, and the Department of Defense; he has served as a consultant for Elan, the Janssen Alzheimer Initiative, Lundbeck, Pfizer, and TransTech Pharma; and he has been amember on data safety and monitoring boards for Quintiles, Functional Neuromodulation, and the New York State Psychiatric Institute, participated on a speakers bureau for Forest, and participated in the development of educational presentations for CME, Inc., and PVI. The other authors report no financial relationships with commercial interests. NR 38 TC 3 Z9 3 U1 8 U2 11 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAY PY 2016 VL 173 IS 5 BP 473 EP 480 DI 10.1176/appi.ajp.2016.15020248 PG 8 WC Psychiatry SC Psychiatry GA DK9ZS UT WOS:000375291500010 PM 27032628 ER PT J AU Fava, M Memisoglu, A Thase, ME Bodkin, JA Trivedi, MH de Somer, M Du, YC Leigh-Pemberton, R DiPetrillo, L Silverman, B Ehrich, E AF Fava, Maurizio Memisoglu, Asli Thase, Michael E. Bodkin, J. Alexander Trivedi, Madhukar H. de Somer, Marc Du, Yangchun Leigh-Pemberton, Richard DiPetrillo, Lauren Silverman, Bernard Ehrich, Elliot TI Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; TREATMENT-RESISTANT DEPRESSION; RECEPTOR-BINDING PROPERTIES; PARALLEL COMPARISON TRIAL; SUICIDE VICTIMS; CLINICAL-TRIALS; MOOD DISORDERS; RATING-SCALE; ZIPRASIDONE; MONOTHERAPY AB Objective: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a mu- and kappa-opioid partial agonist, buprenorphine, and a mu-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression. Method: A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S). Results: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -22.8, 95% CI= -5.1,-0.6; MADRS: -4.9,95% CI= -8.2,-1.6; CGI-S: -0.5, 95% CI= -0.9,-0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation. Conclusions: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants. C1 [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Alkermes Inc, Waltham, MA USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. McLean Hosp, 115 Mill St, Belmont, MA 02178 USA. Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. RP Fava, M (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM mfava@partners.org FU Acadia; Alkermes; AstraZeneca; Avanir; AXSOME Therapeutics; Biogen; Bristol-Myers Squibb; Cerecor; Dinippon Sumitomo Pharma; Eli Lilly; EnVivo; Euthymics Bioscience; Forest Pharmaceuticals; FORUM Pharmaceuticals; GenOmind; GlaxoSmithKline; Intracellular; Janssen RD; Johnson & Johnson Pharmaceutical Research and Development; Lundbeck; Merck; Methylation Sciences; MSI Methylation Sciences; National Center for Complementary and Alternative Medicine; National Coordinating Center for Integrative Medicine; NIDA; NIMH; Naurex; Nestle Health Sciences; Neuralstem; Novartis AG; Nutrition 21; Osmotica; Otsuka Pharmaceuticals; PamLab; Pfizer; PharmoRx; Therapeutics; Therapeutics, Photothera; PPD; Puretech Ventures; PsychoGenics; RCT Logic (formerly Clinical Trials Solutions); Reckitt Benckiser; Ridge Diagnostics; Roche Pharmaceuticals; Sanofi-Aventis; Servier Laboratories; Stanley Medical Research Institute; Sunovion; Taisho; Takeda; Tal Medical; VistaGen; Agency for Healthcare Research and Quality; Avenir; Forest; Johnson Johnson; Otsuka; PharmaNeuroboost; Roche; CeNeRx; Shire; NIH/NIMH; Neuronetics; Rexahn FX Dr. Fava has received research support from and/or served as an adviser or consultant to Acadia, Alkermes, AstraZeneca, Avanir, AXSOME Therapeutics, Biogen, Bristol-Myers Squibb, Cerecor, Dinippon Sumitomo Pharma, Eli Lilly, EnVivo, Euthymics Bioscience, Forest Pharmaceuticals, FORUM Pharmaceuticals, GenOmind, GlaxoSmithKline, Intracellular, Janssen R&D, Johnson & Johnson Pharmaceutical Research and Development, Lundbeck, Merck, Methylation Sciences, MSI Methylation Sciences, the National Center for Complementary and Alternative Medicine, the National Coordinating Center for Integrative Medicine, NIDA, NIMH, Naurex, Nestle Health Sciences, Neuralstem, Novartis AG, Nutrition 21, Osmotica, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmoRx Therapeutics, Photothera, PPD, Puretech Ventures, PsychoGenics, RCT Logic (formerly Clinical Trials Solutions), Reckitt Benckiser, Ridge Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Servier Laboratories, the Stanley Medical Research Institute, Sunovion, Taisho, Takeda, Tal Medical, and VistaGen; he has had speaking or publishing roles for the American Society of Clinical Psychopharmacology, Belvoir Media Group, CME Institute/Physicians Postgraduate Press, and MGH Psychiatry Academy; he has equity holdings in Compellis and PsyBrain; he is named on patents for sequential parallel comparison design, licensed by MGH to Pharmaceutical Product Development and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; and he is a copyright holder for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER and has publications with Lippincott Williams & Wilkins, Wolkers Kluwer, and World Scientific Publishing. Dr. Thase has served as an adviser or consultant to Alkermes, Allergan (includes Forest Laboratories and Naurex), Avanir, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Lundbeck, Johnson & Johnson (includes Ortho-McNeil and Janssen), MedAvante, Merck (includes Schering-Plough and Organon), Nestle (includes Pamlab), Neuronetics, Novartis, Otsuka, Pfizer (includes Wyeth Ayerst), Roche, Sunovion, and Takeda; he has received grant support from Agency for Healthcare Research and Quality, Alkermes, Avenir, Eli Lilly, Forest, Johnson & Johnson, NIMH, Otsuka, PharmaNeuroboost, and Roche; he has equity holdings in MedAvante and receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton; his spouse is employed by Peloton Advantage, which does business with Pfizer. Dr. Bodkin has received payment for participation in advisory panel meetings related to the investigation of ALKS 5461 as a potential treatment for psychiatric disorders and has served as a consultant and received research support from Bristol-Myers Squibb, Otsuka, and CeNeRx, served as a consultant to MyTomorrows, has received research support from Shire, and has received grant support from NIH/NIMH. Dr. Trivedi has served as a consultant to or received fees from Alkermes, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Forest, Johnson & Johnson, Lundbeck, Merck, Naurex, Neuronetics, Otsuka, Pamlab, Pfizer, Rexahn, Roche, and Shire and has served on a scientific advisory board for Rexahn; he has received research support from NIMH and NIDA. Drs.; Memisoglu, de Somer, Du, Leigh-Pemberton, DiPetrillo, Silverman, and Ehrich are or have been full-time employees of Alkermes, Inc., and have stock options. NR 40 TC 8 Z9 8 U1 2 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAY PY 2016 VL 173 IS 5 BP 499 EP 508 DI 10.1176/appi.ajp.2015.15070921 PG 10 WC Psychiatry SC Psychiatry GA DK9ZS UT WOS:000375291500013 PM 26869247 ER PT J AU Baheti, AD O'Malley, RB Kim, S Keraliya, AR Tirumani, SH Ramaiya, NH Wang, CL AF Baheti, Akshay D. O'Malley, Ryan B. Kim, Sooah Keraliya, Abhishek R. Tirumani, Sree Harsha Ramaiya, Nikhil H. Wang, Carolyn L. TI Soft-Tissue Sarcomas: An Update for Radiologists Based on the Revised 2013 World Health Organization Classification SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE soft-tissue sarcoma; World Health Organization (WHO) classification ID MALIGNANT FIBROUS HISTIOCYTOMA; GASTROINTESTINAL STROMAL TUMORS; NERVE SHEATH TUMORS; FDG PET/CT FINDINGS; DERMATOFIBROSARCOMA PROTUBERANS; HISTOPATHOLOGIC CORRELATION; PATHOLOGICAL CORRELATION; PLEOMORPHIC SARCOMA; MYXOID LIPOSARCOMA; IMATINIB MESYLATE AB OBJECTIVE. Soft-tissue sarcomas are a diverse group of malignancies, and our rapidly improving understanding of their molecular pathogenesis and treatment is leading to better clinical outcomes. The revised 2013 World Health Organization (WHO) classification of soft-tissue sarcomas introduced several important changes. We provide a comprehensive overview of the relevant changes for radiologists. CONCLUSION. Rapid advances in the understanding of the pathogenesis and molecular biology of soft-tissue sarcomas led to major revisions in the 2013 WHO classification. To provide optimal multidisciplinary patient care, radiologists must remain up-to-date with the latest developments in the field of soft-tissue sarcomas to best correlate the histologic and imaging features of the various types of tumors and understand the unique patterns of treatment response and disease recurrence. C1 [Baheti, Akshay D.; O'Malley, Ryan B.; Kim, Sooah; Wang, Carolyn L.] Univ Washington, Med Ctr, Dept Radiol, 1959 NE Pacific St, Seattle, WA 98195 USA. [Baheti, Akshay D.; O'Malley, Ryan B.; Kim, Sooah; Wang, Carolyn L.] Seattle Canc Care Alliance, 1959 NE Pacific St, Seattle, WA 98195 USA. [Keraliya, Abhishek R.; Tirumani, Sree Harsha; Ramaiya, Nikhil H.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Tirumani, Sree Harsha; Ramaiya, Nikhil H.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. RP Baheti, AD (reprint author), Univ Washington, Med Ctr, Dept Radiol, 1959 NE Pacific St, Seattle, WA 98195 USA.; Baheti, AD (reprint author), Seattle Canc Care Alliance, 1959 NE Pacific St, Seattle, WA 98195 USA. EM akshaybaheti@gmail.com NR 56 TC 2 Z9 2 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2016 VL 206 IS 5 BP 924 EP 932 DI 10.2214/AJR.15.15498 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK4BD UT WOS:000374860500012 PM 26998884 ER PT J AU Hayano, K Kulkarni, NM Duda, DG Heist, RS Sahani, DV AF Hayano, Koichi Kulkarni, Naveen M. Duda, Dan G. Heist, Rebecca Suk Sahani, Dushyant V. TI Exploration of Imaging Biomarkers for Predicting Survival of Patients With Advanced Non-Small Cell Lung Cancer Treated With Antiangiogenic Chemotherapy SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE antiangiogenic therapy; CT perfusion; non-small cell lung cancer; PET; texture analysis ID PERFUSION-COMPUTED-TOMOGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; CONTRAST-ENHANCED CT; TEXTURE ANALYSIS; TUMOR HETEROGENEITY; PROGNOSTIC VALUE; BLOOD-FLOW; QUANTITATIVE ASSESSMENT; POTENTIAL MARKER; FDG-PET AB OBJECTIVE. The objective of this study was to compare imaging biomarkers, including F-18-FDG PET, CT perfusion (CTP), and CT texture analysis (CTTA), in predicting the survival of patients with advanced non-small cell lung cancer (NSCLC) treated with antiangiogenic chemotherapy. SUBJECTS AND METHODS. A total of 35 patients (17 men and 18 women; median age, 64.0 years) with advanced NSCLC treated with antiangiogenic chemotherapy were evaluated. CTP and FDG PET were performed before the therapy, and blood flow, blood volume, mean transit time, and the maximum standardized uptake value (SUVmax) of the tumor were measured. Texture parameters, including the mean value of pixels with positive values (MPP) and entropy (a measure of irregularity), were also measured on pretherapeutic unenhanced CT images, using CTTA software with a medium texture scale filtration. The best percent change in the tumor burden was also measured. These image-derived tumor parameters were then compared with progression-free survival (PFS) and overall survival (OS). RESULTS. In univariate Cox regression analysis, MPP and entropy were significantly correlated with PFS (p = 0.01 and p = 0.01, respectively), whereas SUVmax, MPP, and entropy were significantly correlated with OS (p = 0.03, p = 0.04, and p = 0.0008, respectively). In Kaplan-Meier analysis, high MPP and low entropy were significantly associated with favorable PFS (p < 0.0001 and p = 0.03, respectively) and OS (p = 0.0009 and p = 0.005, respectively), and low SUVmax was significantly associated with favorable OS (p = 0.01). CTP parameters and the best change in the tumor burden had no associations with survival. In multivariate analysis, only entropy was identified as an independent prognostic factor for OS (p = 0.02). CONCLUSION. CTTA is the optimal imaging biomarker for predicting the survival of patients with advanced NSCLC treated with antiangiogenic chemotherapy. C1 [Hayano, Koichi; Kulkarni, Naveen M.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. [Duda, Dan G.] Massachusetts Gen Hosp, Steele Lab, Boston, MA 02114 USA. [Heist, Rebecca Suk] Massachusetts Gen Hosp, Dept Thorac Oncol, Ctr Canc, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org NR 43 TC 1 Z9 1 U1 3 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 2016 VL 206 IS 5 BP 987 EP 993 DI 10.2214/AJR.15.15528 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK4BD UT WOS:000374860500019 PM 26934729 ER PT J AU Fleisher, LA Wiener-Kronish, JP AF Fleisher, Lee A. Wiener-Kronish, Jeanine P. TI Ensuring the Future of the Specialty What Is the Best Strategy to Ensure a Pipeline of Physician-scientists? SO ANESTHESIOLOGY LA English DT Editorial Material C1 [Fleisher, Lee A.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Wiener-Kronish, Jeanine P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. RP Fleisher, LA (reprint author), Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. EM lee.fleisher@uphs.upenn.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAY PY 2016 VL 124 IS 5 BP 996 EP 997 DI 10.1097/ALN.0000000000001069 PG 2 WC Anesthesiology SC Anesthesiology GA DK4JA UT WOS:000374882700006 PM 26928350 ER PT J AU Eisenach, JC Kheterpal, S Houle, TT AF Eisenach, James C. Kheterpal, Sachin Houle, Timothy T. TI Reporting of Observational Research in ANESTHESIOLOGY: The Importance of the Analysis Plan SO ANESTHESIOLOGY LA English DT Editorial Material C1 [Eisenach, James C.] Wake Forest Univ, Bowman Gray Sch Med, Dept Anesthesiol, Winston Salem, NC USA. [Kheterpal, Sachin] Univ Michigan, Sch Med, Dept Anesthesiol, Ann Arbor, MI USA. [Houle, Timothy T.] Harvard Univ, Med Ctr, Massachusetts Gen Hosp, Dept Anesthesiol & Crit Care, Boston, MA 02115 USA. RP Eisenach, JC (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Anesthesiol, Winston Salem, NC USA. EM editor-in-chief@anesthesiology.org NR 9 TC 4 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAY PY 2016 VL 124 IS 5 BP 998 EP 1000 DI 10.1097/ALN.0000000000001072 PG 3 WC Anesthesiology SC Anesthesiology GA DK4JA UT WOS:000374882700007 PM 26933796 ER PT J AU Pezone, MJ Peterfreund, RA Maslov, MY Govindaswamy, RR Lovich, MA AF Pezone, Matthew J. Peterfreund, Robert A. Maslov, Mikhail Y. Govindaswamy, Radhika R. Lovich, Mark A. TI Infusion System Architecture Impacts the Ability of Intensive Care Nurses to Maintain Hemodynamic Stability in a Living Swine Simulator SO ANESTHESIOLOGY LA English DT Article ID DRUG-DELIVERY; DEAD-VOLUME; IN-VITRO; FLOW-RATE; DYNAMICS; MODEL; SET AB Background: The authors have previously shown that drug infusion systems with large common volumes exhibit long delays in reaching steady-state drug delivery and pharmacodynamic effects compared with smaller common-volume systems. The authors hypothesized that such delays can impede the pharmacologic restoration of hemodynamic stability. Methods: The authors created a living swine simulator of hemodynamic instability in which occlusion balloons in the aorta and inferior vena cava (IVC) were used to manipulate blood pressure. Experienced intensive care unit nurses blinded to the use of small or large common-volume infusion systems were instructed to maintain mean arterial blood pressure between 70 and 90 mmHg using only sodium nitroprusside and norepinephrine infusions. Four conditions (IVC or aortic occlusions and small or large common volume) were tested 12 times in eight animals. Results: After aortic occlusion, the time to restore mean arterial pressure to range (t(1): 2.4 1.4 vs. 5.0 +/- 2.3 min, P = 0.003, average +/- SD), time-out-of-range (t(OR): 6.2 +/- 3.5 vs. 9.5 +/- 3.4 min, P = 0.028), and area-out-of-range (pressure-time integral: 84 +/- 47 vs. 170 +/- 100 mmHgmin, P = 0.018) were all lower with smaller common volumes. After IVC occlusion, t(1) (3.7 +/- 2.2 vs. 7.1 +/- 2.6 min, P = 0.002), t(OR) (6.3 +/- 3.5 vs. 11 +/- 3.0 min, P = 0.007), and area-out-of-range (110 +/- 93 vs. 270 +/- 140 mmHgmin, P = 0.003) were all lower with smaller common volumes. Common-volume size did not impact the total amount infused of either drug. Conclusions: Nurses did not respond as effectively to hemodynamic instability when drugs flowed through large common-volume infusion systems. These findings suggest that drug infusion system common volume may have clinical impact, should be minimized to the greatest extent possible, and warrants clinical investigations. C1 [Pezone, Matthew J.; Maslov, Mikhail Y.; Govindaswamy, Radhika R.; Lovich, Mark A.] Steward St Elizabeths Med Ctr, Dept Anesthesiol Pain Med & Crit Care, 736 Cambridge St,CMP 2, Boston, MA 02135 USA. [Peterfreund, Robert A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Lovich, MA (reprint author), Steward St Elizabeths Med Ctr, Dept Anesthesiol Pain Med & Crit Care, 736 Cambridge St,CMP 2, Boston, MA 02135 USA. EM mark.lovich@steward.org FU Doran International; Department of Anesthesiology, Pain Medicine, and Critical Care, Steward St. Elizabeth's Medical Center, Boston, Massachusetts FX Supported, in part, by Doran International, the manufacturer of the Edelvaiss Multiline, Toussieu, France, and by the Department of Anesthesiology, Pain Medicine, and Critical Care, Steward St. Elizabeth's Medical Center, Boston, Massachusetts. NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAY PY 2016 VL 124 IS 5 BP 1077 EP 1085 DI 10.1097/ALN.0000000000001075 PG 9 WC Anesthesiology SC Anesthesiology GA DK4JA UT WOS:000374882700015 PM 26933793 ER PT J AU Flanagan, EP Cabre, P Weinshenker, BG St Sauver, J Jacobson, DJ Majed, M Lennon, VA Lucchinetti, CF McKeon, A Matiello, M Kale, N Wingerchuk, DM Mandrekar, J Sagen, JA Fryer, JP Robinson, AB Pittock, SJ AF Flanagan, Eoin P. Cabre, Philippe Weinshenker, Brian G. St Sauver, Jennifer Jacobson, Debra J. Majed, Masoud Lennon, Vanda A. Lucchinetti, Claudia F. McKeon, Andrew Matiello, Marcelo Kale, Nilifur Wingerchuk, Dean M. Mandrekar, Jay Sagen, Jessica A. Fryer, James P. Robinson, Angala Borders Pittock, Sean J. TI Epidemiology of Aquaporin-4 Autoimmunity and Neuromyelitis Optica Spectrum SO ANNALS OF NEUROLOGY LA English DT Article ID FRENCH-WEST-INDIES; MULTIPLE-SCLEROSIS; DIAGNOSTIC-CRITERIA; TRANSVERSE MYELITIS; PREVALENCE; DISORDERS; SYSTEM; COUNTY; ADULTS AB Objective: Neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDDs) with a specific biomarker, aquaporin-4-immunoglobulin G (AQP4-IgG). Prior NMO/NMOSD epidemiological studies have been limited by lack of AQP4-IgG seroprevalence assessment, absence of population-based USA studies, and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across 2 ethnically divergent populations. Methods: We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and AQP4-IgG seroincidence and seroprevalence (sera collected in 80-84% of IDD cases) among patients with IDD diagnosis in Olmsted County, Minnesota (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). AQP4-IgG was measured by M1 isoform fluorescence-activated cell-sorting assays. Results: The age-and sex-adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p < 0.01]) and prevalence (10 vs 3.9/100,000 [p = 0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age-and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p < 0.01]) and seroprevalence (7.9 vs 3.3/100,000 [p = 0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD cases in Martinique than Olmsted County (16% vs 1.4%; p < 0.01). The onset age (median = 35-37 years) and female: male distribution (5-9:1) were similar across both populations; 60% of prevalent cases were either blind in 1 eye, dependent on a gait aid, or both. Interpretation: This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000 to 17,000 in the USA (higher than previous predictions), and demonstrates it disproportionately affects blacks. C1 [Flanagan, Eoin P.; Weinshenker, Brian G.; Majed, Masoud; Lennon, Vanda A.; Lucchinetti, Claudia F.; McKeon, Andrew; Pittock, Sean J.] Mayo Clin, Dept Neurol, 200 First St SW, Rochester, MN 55905 USA. [Cabre, Philippe] Pierre Zobda Quitman Hosp, Ft de France Univ Hosp Ctr, Dept Neurol, Fort De France, Martinique. [St Sauver, Jennifer] Mayo Clin, Dept Epidemiol, Rochester, MN USA. [Jacobson, Debra J.; Mandrekar, Jay; Fryer, James P.] Mayo Clin, Dept Biostat, Rochester, MN USA. [Lennon, Vanda A.; McKeon, Andrew; Fryer, James P.; Pittock, Sean J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Lennon, Vanda A.] Mayo Clin, Dept Immunol, Rochester, MN USA. [Matiello, Marcelo] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Matiello, Marcelo] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Kale, Nilifur] Bakirkoy Prof Mazhar Osman Training & Res Hosp, Istanbul, Turkey. [Wingerchuk, Dean M.] Mayo Clin, Dept Neurol, Scottsdale, AZ USA. [Sagen, Jessica A.] Mayo Clin, Neurol Res, Rochester, MN USA. [Robinson, Angala Borders] Olmsted Med Ctr, Rochester, MN USA. RP Pittock, SJ (reprint author), Mayo Clin, Dept Neurol, 200 First St SW, Rochester, MN 55905 USA. EM pittock.sean@mayo.edu FU Guthy-Jackson Charitable Foundation; NIH National Institute of Neurological Disorders and Stroke [NS065829]; NIH National Center for Advancing Translational Sciences (Clinical and Translational Science Award) [UL1 TR000135] FX Supported by the Guthy-Jackson Charitable Foundation, the NIH National Institute of Neurological Disorders and Stroke (NS065829), and the NIH National Center for Advancing Translational Sciences (Clinical and Translational Science Award grant number UL1 TR000135). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. NR 32 TC 6 Z9 6 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 2016 VL 79 IS 5 BP 775 EP 783 DI 10.1002/ana.24617 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DL6MA UT WOS:000375752100008 ER PT J AU Clavien, PA Lillemoe, KD AF Clavien, Pierre A. Lillemoe, Keith D. TI Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy SO ANNALS OF SURGERY LA English DT Editorial Material ID SURGICAL INNOVATION; RESECTION; RECOMMENDATIONS C1 [Clavien, Pierre A.] Univ Zurich Hosp, Dept Surg & Transplantat, CH-8091 Zurich, Switzerland. [Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Clavien, PA (reprint author), Univ Zurich Hosp, Dept Surg & Transplantat, CH-8091 Zurich, Switzerland. EM clavien@access.uzh.ch NR 11 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAY PY 2016 VL 263 IS 5 BP 835 EP 836 DI 10.1097/SLA.0000000000001534 PG 2 WC Surgery SC Surgery GA DK4FC UT WOS:000374871600006 PM 26727085 ER PT J AU Bohnen, JD Chang, DC Lillemoe, KD AF Bohnen, Jordan D. Chang, David C. Lillemoe, Keith D. TI Reconceiving the Morbidity and Mortality Conference in an Era of Big Data: An "Unexpected" Outcomes Approach SO ANNALS OF SURGERY LA English DT Article DE big data; M&M; quality; outcomes expectedness ID IMPROVEMENT C1 [Bohnen, Jordan D.; Chang, David C.; Lillemoe, Keith D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 55 Fruit St,GRB 425, Boston, MA 02114 USA. [Chang, David C.] Massachusetts Gen Hosp, Codman Ctr Clin Effect Surg, Boston, MA 02114 USA. RP Bohnen, JD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 55 Fruit St,GRB 425, Boston, MA 02114 USA. EM jbohnen@partners.org NR 8 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAY PY 2016 VL 263 IS 5 BP 857 EP 859 DI 10.1097/SLA.0000000000001508 PG 3 WC Surgery SC Surgery GA DK4FC UT WOS:000374871600013 PM 26649585 ER PT J AU Jacobs, LM Warshaw, AL Burns, KJ AF Jacobs, Lenworth M. Warshaw, Andrew L. Burns, Karyl J. TI Empowering the Public to Improve Survival in Mass Casualty Events SO ANNALS OF SURGERY LA English DT Article C1 [Jacobs, Lenworth M.; Burns, Karyl J.] Hartford Hosp, Acad Affairs, 80 Seymour St, Hartford, CT 06102 USA. [Warshaw, Andrew L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jacobs, LM (reprint author), Hartford Hosp, Acad Affairs, 80 Seymour St, Hartford, CT 06102 USA. EM Lenworth.jacobs@hhchealth.org NR 9 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAY PY 2016 VL 263 IS 5 BP 860 EP 861 DI 10.1097/SLA.0000000000001517 PG 2 WC Surgery SC Surgery GA DK4FC UT WOS:000374871600014 PM 27058856 ER PT J AU Fong, ZV Ferrone, CR Lillemoe, KD Fernandez-del Castillo, C AF Fong, Zhi Ven Ferrone, Cristina R. Lillemoe, Keith D. Fernandez-del Castillo, Carlos TI Intraductal Papillary Mucinous Neoplasm of the Pancreas: Current State of the Art and Ongoing Controversies SO ANNALS OF SURGERY LA English DT Review DE biology; intraductal papillary mucinous neoplasm; management; pancreas; prognosis ID INTERNATIONAL-CONSENSUS-GUIDELINES; SINGLE-INSTITUTION EXPERIENCE; LONG-TERM SURVIVAL; BRANCH-DUCT IPMNS; CYSTIC NEOPLASMS; FOLLOW-UP; SURGICAL-MANAGEMENT; MOLECULAR ANALYSIS; REMNANT PANCREAS; RESECTION AB With the widespread use and advances in radiographic imaging, Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are identified with increasing frequency. Although many studies have addressed its biology and treatment, true understanding of its natural history continues to elude us. Its malignant potential places careproviders in a clinical dilemma of balancing the morbidity of pancreatectomy against the risk of malignant transformation while under continuous surveillance. Recently, there have been conflicting data published in the literature, generating more uncertainty in the field. In this article, we critically analyze the contrasting consensus guidelines from the International Association of Pancreatology and the American Gastroenterology Association, and address lingering questions and controversies. We also synthesize newly published data in the context of current standard of care, and provide a comprehensive review and recommendations for the clinical diagnosis, treatment, and follow-up strategy in the management of patients with Intraductal Papillary Mucinous Neoplasms. C1 [Fong, Zhi Ven; Ferrone, Cristina R.; Lillemoe, Keith D.; Fernandez-del Castillo, Carlos] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fernandez-del Castillo, C (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Pkman St, Boston, MA 02114 USA. EM cfernandez@partners.org NR 107 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAY PY 2016 VL 263 IS 5 BP 908 EP 917 DI 10.1097/SLA.0000000000001567 PG 10 WC Surgery SC Surgery GA DK4FC UT WOS:000374871600021 PM 26727096 ER PT J AU Holcomb, CN Graham, LA Richman, JS Itani, KMF Maddox, TM Hawn, MT AF Holcomb, Carla N. Graham, Laura A. Richman, Joshua S. Itani, Kamal M. F. Maddox, Thomas M. Hawn, Mary T. TI The Incremental Risk of Coronary Stents on Postoperative Adverse Events: A Matched Cohort Study SO ANNALS OF SURGERY LA English DT Article DE coronary revascularization; coronary stent; myocardial infarction; noncardiac surgery; postoperative events ID MAJOR NONCARDIAC SURGERY; DRUG-ELUTING STENTS; INCOMPLETE REVASCULARIZATION; MYOCARDIAL INJURY; VASCULAR-SURGERY; CARDIAC EVENTS; TERM MORTALITY; BARE-METAL; OUTCOMES; PREDICTORS AB Objective:To determine the incremental risk of coronary stents on adverse events in surgical patients and whether it varies over time from stent placement.Background:Postoperative adverse cardiac events decrease as the time from stent placement increases, but the risk attributable to the stent versus the underlying cardiac disease is uncertain, as prior studies lack a control surgical population.Methods:Data for patients with coronary stents implanted in a VA hospital from 2000 to 2010 were matched with VA Surgical Quality Improvement Program data to identify noncardiac surgery within 24 months of stent placement. Each patient with stent was matched with 2 surgical patients without stent on surgical characteristics and cardiac risk factors. Outcomes of myocardial infarction (MI), revascularization, and death within 30 days after surgery were modeled using logistic regression. Adjusted risk differences between stented and nonstented populations were compared across time after stent placement.Results:Adverse cardiac events followed surgery in 531 (5.7%) of the 9391 patients with stent and 680 (3.6%) of the 18,782 patients without stent (P < 0.001). In adjusted models, 30-day postoperative MI (odds ratio = 1.90; 95% confidence interval, 1.57-2.30) and revascularization (odds ratio = 2.03; 95% confidence interval, 1.65-2.50) but not mortality (odds ratio = 0.84; 95% confidence interval, 0.69-1.02) were higher in the stented cohort. Assessing trends over the 2 years after stent placement, the incremental risk for MI decreased from 5% immediately after stent placement to 2% at 1 year and then was no longer significantly elevated. The incremental risk did not vary by stent type.Conclusions:Surgery after coronary stent placement is associated with an approximate 2% absolute risk for postoperative MI but no difference in mortality compared with nonstented matched controls. C1 [Holcomb, Carla N.; Richman, Joshua S.; Hawn, Mary T.] Univ Alabama Birmingham, Dept Surg, Sect Gastrointestinal Surg, 1922 7th Ave S,KB 428, Birmingham, AL 35294 USA. [Holcomb, Carla N.; Graham, Laura A.; Hawn, Mary T.] Birmingham Vet Adm Hosp, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL USA. [Richman, Joshua S.; Itani, Kamal M. F.] Boston Univ, VA Boston Hlth Care Syst, Dept Surg, Boston, MA 02215 USA. [Richman, Joshua S.; Itani, Kamal M. F.] Harvard Univ, Sch Med, Boston, MA USA. [Maddox, Thomas M.] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. [Maddox, Thomas M.] Univ Colorado, Sch Med, Denver, CO USA. RP Hawn, MT (reprint author), Univ Alabama Birmingham, Dept Surg, Sect Gastrointestinal Surg, 1922 7th Ave S,KB 428, Birmingham, AL 35294 USA. EM mhawn@uabmc.edu FU VA Health Services Research & Development grant [IIR 09-347]; VA Career Development Awards; Agency for Healthcare Research and Quality, Rockville, MD [T32 HS013852-11] FX Supported by a VA Health Services Research & Development grant (#IIR 09-347). Drs Maddox and Richman are supported by VA Career Development Awards. Dr Holcomb is supported by grant T32 HS013852-11 from the Agency for Healthcare Research and Quality, Rockville, MD. The authors have no conflicts of interest to declare. NR 24 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAY PY 2016 VL 263 IS 5 BP 924 EP 930 DI 10.1097/SLA.0000000000001246 PG 7 WC Surgery SC Surgery GA DK4FC UT WOS:000374871600023 PM 25894416 ER PT J AU Gronchi, A Strauss, DC Miceli, R Bonvalot, S Swallow, CJ Hohenberger, P Van Coevorden, F Rutkowski, P Callegaro, D Hayes, AJ Honore, C Fairweather, M Cannell, A Jakob, J Haas, RL Szacht, M Fiore, M Casali, PG Pollock, RE Raut, CP AF Gronchi, Alessandro Strauss, Dirk C. Miceli, Rosalba Bonvalot, Sylvie Swallow, Carol J. Hohenberger, Peter Van Coevorden, Frits Rutkowski, Piotr Callegaro, Dario Hayes, Andrew J. Honore, Charles Fairweather, Mark Cannell, Amanda Jakob, Jens Haas, Rick L. Szacht, Milena Fiore, Marco Casali, Paolo G. Pollock, Raphael E. Raut, Chandrajit P. TI Variability in Patterns of Recurrence After Resection of Primary Retroperitoneal Sarcoma (RPS): A Report on 1007 Patients From the Multi-institutional Collaborative RPS Working Group SO ANNALS OF SURGERY LA English DT Article DE leiomyosarcoma; liposarcoma; prognostic factors; retroperitoneal sarcoma; sarcoma; solitary fibrous tumor; surgery; survival ID SOFT-TISSUE SARCOMA; HISTOLOGIC SUBTYPE; PREDICT PATTERN; SURVIVAL; SURGERY; LIPOSARCOMA; MANAGEMENT; OUTCOMES; MARGIN; VOLUME AB Background:Retroperitoneal sarcomas (RPS) are rare tumors composed of several well defined histologic subtypes. The aim of this study was to analyze patterns of recurrence and treatment variations in a large population of patients, treated at reference centers.Methods:All consecutive patients with primary RPS treated at 6 European and 2 North American institutions between January 2002 and December 2011 were included. Five, 8, and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were calculated. Multivariate analyses for OS, CCI of LR, and DM were performed.Results:In all, 1007 patients were included. Median follow-up was 58 months (first and third quartile range 36-90). The 5, 8, and 10-year OS were 67% [95% confidence interval (CI), 63, 70), 56% (95% CI, 52, 61), and 46% (95% CI, 40, 53). The 5, 8, and 10-year CCI of LR and DM were 25.9 (95% CI, 23.1, 29.1), 31.3 (95% CI, 27.8, 35.1), 35% (95% CI, 30.5, 40.1), and 21% (95% CI, 18.4, 23.8%), 21.6 (95% CI, 19.0, 24.6), and 21.6 (95% CI, 19.0, 24.6), respectively. Tumour size, histologic subtype, malignancy grade, multifocality, and completeness of resection were significant predictors of outcome. Patterns of recurrence varied depending on histologic subtype. Different treatment policies at participating institutions influenced LR of well differentiated liposarcoma without impacting OS, whereas discrepancies in adjuvant systemic therapies did not impact LR, DM, or OS of leiomyosarcoma.Conclusions:Reference centers are critical to outcomes of RPS patients, as the management strategy requires specific expertise. Histologic subtype predicts patterns of recurrence and should inform management decision. A prospective international registry is under preparation, to further define our understanding of this disease. C1 [Gronchi, Alessandro; Callegaro, Dario; Fiore, Marco] Fdn IRCCS Ist Nazl Tumori, Dept Surg, Via Venezian 1, I-20133 Milan, Italy. [Strauss, Dirk C.; Hayes, Andrew J.] Royal Marsden Hosp NHS Fdn Trust, Dept Surg, London, England. [Miceli, Rosalba] Fdn IRCCS Ist Nazl Tumori, Dept Biostat, Milan, Italy. [Bonvalot, Sylvie; Honore, Charles] Inst Gustave Roussy, Dept Surg, Villejuif, France. [Swallow, Carol J.; Cannell, Amanda] Mt Sinai Hosp, Dept Surg Oncol, Toronto, ON M5G 1X5, Canada. [Swallow, Carol J.; Cannell, Amanda] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Swallow, Carol J.; Cannell, Amanda] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Hohenberger, Peter; Jakob, Jens] Mannheim Univ Hosp, Div Surg Oncol & Thorac Surg, Mannheim, Germany. [Van Coevorden, Frits] Netherlands Canc Inst, Dept Surg Oncol, Amsterdam, Netherlands. [Rutkowski, Piotr; Szacht, Milena] Maria Sklodowska Curie Mem Canc Ctr, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Rutkowski, Piotr; Szacht, Milena] Inst Oncol, Warsaw, Poland. [Fairweather, Mark; Raut, Chandrajit P.] Brigham & Womens Hosp, Div Surg Oncol, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Fairweather, Mark; Raut, Chandrajit P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. [Haas, Rick L.] Netherlands Canc Inst, Dept Radiat Oncol, Amsterdam, Netherlands. [Casali, Paolo G.] Fdn IRCCS Ist Nazl Tumori, Dept Canc Med, Milan, Italy. [Pollock, Raphael E.] Ohio State Univ, Med Ctr, Div Surg Oncol, Dept Surg, Columbus, OH 43210 USA. RP Gronchi, A (reprint author), Fdn IRCCS Ist Nazl Tumori, Dept Surg, Via Venezian 1, I-20133 Milan, Italy. EM alessandro.gronchi@istitutotumori.mi.it RI Miceli, Rosalba/C-1215-2017; Fiore, Marco/M-6587-2016; Callegaro, Dario/C-9493-2017; casali, Paolo Giovanni/D-1524-2017; OI Miceli, Rosalba/0000-0003-0954-375X; Fiore, Marco/0000-0001-8220-424X; Callegaro, Dario/0000-0002-3392-4002; casali, Paolo Giovanni/0000-0003-4056-8023; Rutkowski, Piotr/0000-0002-8920-5429 NR 36 TC 10 Z9 10 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAY PY 2016 VL 263 IS 5 BP 1002 EP 1009 DI 10.1097/SLA.0000000000001447 PG 8 WC Surgery SC Surgery GA DK4FC UT WOS:000374871600035 PM 26727100 ER PT J AU Kurzbard-Roach, N Lewis, M Chow, K Masih, S Modaressi, S AF Kurzbard-Roach, Nicole Lewis, Michael Chow, Kira Masih, Sulabh Modaressi, Shahla TI Stewart-Bluefarb syndrome SO APPLIED RADIOLOGY LA English DT Editorial Material C1 [Kurzbard-Roach, Nicole] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90024 USA. [Lewis, Michael] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Pathol, Los Angeles, CA USA. [Chow, Kira] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Radiol, Los Angeles, CA USA. [Masih, Sulabh; Modaressi, Shahla] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. RP Kurzbard-Roach, N (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90024 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ANDERSON PUBLISHING, INC PI SCOTCH PLAINS PA 180 GLENSIDE AVE, SCOTCH PLAINS, NJ 07076 USA SN 0160-9963 EI 1879-2898 J9 APPL RADIOL JI Appl. Radiol. PD MAY PY 2016 VL 45 IS 5 BP 42 EP 45 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK9EK UT WOS:000375233400010 ER PT J AU Kadar, H Dubus, J Dutot, J Hedjazi, L Srinivasa, S Fitch, KV Grinspoon, SK Nicholson, JK Dumas, ME Gauguier, D AF Kadar, Hanane Dubus, Justine Dutot, Jeremie Hedjazi, Lyamine Srinivasa, Suman Fitch, Kathleen V. Grinspoon, Steven K. Nicholson, Jeremy K. Dumas, Marc-Emmanuel Gauguier, Dominique TI A multiplexed targeted assay for high-throughput quantitative analysis of serum methylamines by ultra performance liquid chromatography coupled to high resolution mass spectrometry SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Trimethylamine; Trimethylamine-N-oxide; Choline; Betaine; L-carnitine; Cardiometabolic diseases ID TRIMETHYLAMINE-N-OXIDE; FISH-ODOR SYNDROME; ELECTROSPRAY-IONIZATION; URINARY TRIMETHYLAMINE; L-CARNITINE; METABOLISM; MICROBIOTA; PLASMA; DISEASE; CHOLINE AB Methylamines are biologically-active metabolites present in serum and urine samples, which play complex roles in metabolic diseases. Methylamines can be detected by proton nuclear magnetic resonance (NMR), but specific methods remain to be developed for their routine assay in human serum in clinical settings. Here we developed and validated a novel reliable "methylamine panel" method for simultaneous quantitative analysis of trimethylamine (TMA), its major detoxification metabolite trimethylamine-N-oxide (TMAO), and precursors choline, betaine and L-carnitine in human serum using Ultra Performance Liquid Chromatography (UPLC) coupled to High Resolution Mass Spectrometry (HRMS). Metabolite separation was carried out on a HILIC stationary phase. For all metabolites, the assay was linear in the range of 0.25-12.5 mu mol/L and enabled to reach limit of detection of about 0.10 mu mol/L. Relative standard deviations were below 16% for the three levels of concentrations. We demonstrated the strong reliability and robustness of the method, which was applied to serum samples from healthy individuals to establish the range of concentrations of the metabolites and their correlation relationships and detect gender differences. Our data provide original information for implementing in a clinical environment a MS-based diagnostic method with potential for targeted metabolic screening of patients at risk of cardiometabolic diseases. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kadar, Hanane; Dutot, Jeremie; Gauguier, Dominique] Univ Paris 06, Sorbonne Univ, Univ Paris Descartes, Sorbonne Paris Cite,INSERM,UMR S 1138,Cordeliers, 15 Rue Ecole Med, F-75006 Paris, France. [Kadar, Hanane; Dubus, Justine; Hedjazi, Lyamine] Univ Paris 06, Inst Cardiometabol & Nutr, Hosp Pitie Salpetriere, 58 Blvd Hop, F-75013 Paris, France. [Dutot, Jeremie; Srinivasa, Suman; Fitch, Kathleen V.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Srinivasa, Suman; Fitch, Kathleen V.; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nicholson, Jeremy K.; Dumas, Marc-Emmanuel; Gauguier, Dominique] Univ London Imperial Coll Sci Technol & Med, Sect Biomol Med, Div Computat Syst Med, Dept Surg & Canc, Sir Alexander Fleming Bldg,Exhibit Rd, London SW7 2AZ, England. [Nicholson, Jeremy K.; Dumas, Marc-Emmanuel] Univ London Imperial Coll Sci Technol & Med, MRC NIHR Natl Phenome Ctr, Dept Surg & Canc, IRDB Bldg,Du Cane Rd, London W12 0NN, England. RP Gauguier, D (reprint author), Cordeliers Res Ctr, 15 Rue Ecole Med, F-75006 Paris, France.; Dumas, ME (reprint author), Univ London Imperial Coll Sci Technol & Med, Sir Alexander Fleming Bldg, London SW7 2AZ, England. EM m.dumas@imperial.ac.uk; dominique.gauguier@crc.jussieu.fr RI Dumas, Marc/C-1736-2008; OI Dumas, Marc/0000-0001-9523-7024; Nicholson, Jeremy/0000-0002-8123-8349 FU European Community [HEALTH-F4-2012-305312]; Ile de France Region [CORDDIM 120167] FX This work was supported by grants from the European Community's Seventh Framework Programme under grant agreement HEALTH-F4-2012-305312 (METACARDIS) and the Ile de France Region (CORDDIM 120167). NR 43 TC 1 Z9 1 U1 9 U2 15 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 MAY 1 PY 2016 VL 597 BP 12 EP 20 DI 10.1016/j.abb.2016.03.029 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DK9GU UT WOS:000375239700002 PM 27036856 ER PT J AU Andersson, C Enserro, D Sullivan, L Wang, TJ Januzzi, JL Benjamin, EJ Vita, JA Hamburg, NM Larson, MG Mitchell, GF Vasan, RS AF Andersson, Charlotte Enserro, Danielle Sullivan, Lisa Wang, Thomas J. Januzzi, James L., Jr. Benjamin, Emelia J. Vita, Joseph A. Hamburg, Naomi M. Larson, Martin G. Mitchell, Gary F. Vasan, Ramachandran S. TI Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with vascular function in the community: The Framingham Heart Study SO ATHEROSCLEROSIS LA English DT Article DE Vascular stiffness; Endothelial function; Biomarkers; ST2; GDF-15; Troponin I; General population ID GROWTH-DIFFERENTIATION FACTOR-15; FLOW-MEDIATED DILATION; ARTERIAL STIFFNESS; SYSTOLIC HYPERTENSION; AORTIC STIFFNESS; SENSITIVE ASSAY; PULSE PRESSURE; ASSOCIATION; POPULATION; MORTALITY AB Background and aims: Growth differentiation factor-15 (GDF-15), soluble (s) ST2, and high-sensitivity troponin-I (hs-TnI) are associated with incident cardiovascular disease (CVD) including heart failure, yet the underlying mechanisms are not fully understood. We investigated if GDF-15, sST2, and hs-TnI are related to subclinical vascular dysfunction in the community, which may explain the relations of these biomarkers with CVD. Methods: We evaluated 1823 Framingham Study participants (mean age 61 +/- 10 years, 54% women) who underwent routine assessment of vascular function. We related circulating GDF-15, sST2, and hs-TnI concentrations to measures of arterial stiffness (carotid-femoral pulse wave velocity, CFPWV; augmentation index; and forward pressure wave amplitude, FW), endothelial-dependent vasodilation (flow-mediated dilation, FMD), and baseline and hyperemic brachial flow velocities using linear regression adjusting for standard risk factors. Results: After multivariable adjustment, GDF-15 levels were positively associated with CFPWV (0.044 [95% confidence interval 0.007-0.081] standard deviation [SD] change per SD increase in log(e)[GDF-15], p = 0.02) and FW (0.076 [0.026-0.126] SD change per SD increase in log(e)[GDF-15], p = 0.003) and inversely related to FMD (-0.051 [-0.101-0.0003] SD change per SD increase in log(e)[GDF-15], p = 0.048). sST2 was positively associated with CFPWV (0.032 [0.0005-0.063] SD change per SD increase in log(e)[sST2], p = 0.046), and hs-TnI inversely associated with hyperemic flow velocity (-0.041 [-0.082 -0.0004] SD change per SD increase in log(e)[hs-TnI], p = 0.048). Conclusion: In our community-based investigation, individual cardiac stress biomarkers were differentially related to select aspects of vascular function. These findings may contribute to the associations of circulating GDF-15, sST2, and hs-TnI with incident CVD and heart failure. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Andersson, Charlotte; Wang, Thomas J.; Benjamin, Emelia J.; Larson, Martin G.; Vasan, Ramachandran S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Andersson, Charlotte; Wang, Thomas J.; Benjamin, Emelia J.; Larson, Martin G.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Enserro, Danielle; Sullivan, Lisa] Boston Univ, Dept Biostat, Framingham, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Januzzi, James L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Andersson, C (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM ca@heart.dk OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NIH Heart, Lung and Blood Institute [N01-HC-25195, R01 HL107385, 1R01HL60040, 1RO1HL70100]; Evans Scholar award from department of Medicine, Boston University School of Medicine; Desanctis Clinical Scholar Endowment; Hutter Family Professorship; Danish Research Council FX This study was funded by the NIH Heart, Lung and Blood Institute (Contract #N01-HC-25195, and R01 HL107385, PI Vasan) and (1R01HL60040; 1RO1HL70100) with additional support from Evans Scholar award from the department of Medicine, Boston University School of Medicine (PI, Vasan). Dr. Januzzi is supported in part by the Desanctis Clinical Scholar Endowment and the Hutter Family Professorship. Dr. Andersson was supported by a grant from the Danish Research Council. NR 31 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 2016 VL 248 BP 245 EP 251 DI 10.1016/j.atherosclerosis.2016.02.013 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DK6MW UT WOS:000375039200032 PM 26972631 ER PT J AU Yetisen, AK Butt, H Volpatti, LR Pavlichenko, I Humar, M Kwok, SJJ Koo, H Kim, KS Naydenova, I Khademhosseini, A Hahn, SK Yun, SH AF Yetisen, Ali K. Butt, Haider Volpatti, Lisa R. Pavlichenko, Ida Humar, Matjaz Kwok, Sheldon J. J. Koo, Heebeom Kim, Ki Su Naydenova, Izabela Khademhosseini, Ali Hahn, Sei Kwang Yun, Seok Hyun TI Photonic hydrogel sensors SO BIOTECHNOLOGY ADVANCES LA English DT Review DE Hydrogels; In vitro diagnostics; Photonic crystals; Inverse opals; Holography; Bragg stacks; Crystalline colloidal arrays; Block copolymers; Layer-by-layer deposition; Plasmonics ID SURFACE-PLASMON RESONANCE; SENSITIVE HOLOGRAPHIC SENSORS; CRYSTALLINE COLLOIDAL ARRAYS; INVERSE OPAL HYDROGELS; MOLECULARLY IMPRINTED HYDROGEL; ACRYLAMIDE-BASED PHOTOPOLYMER; ULTRATHIN MULTILAYER FILMS; CHEMICAL-SENSING MATERIALS; SELF-ASSEMBLY PROCESS; LABEL-FREE AB Analyte-sensitive hydrogels that incorporate optical structures have emerged as sensing platforms for point-of-care diagnostics. The optical properties of the hydrogel sensors can be rationally designed and fabricated through self-assembly, microfabrication or laser writing. The advantages of photonic hydrogel sensors over conventional assay formats include label-free, quantitative, reusable, and continuous measurement capability that can be integrated with equipment-free text or image display. This Review explains the operation principles of photonic hydrogel sensors, presents syntheses of stimuli-responsive polymers, and provides an overview of qualitative and quantitative readout technologies. Applications in clinical samples are discussed, and potential future directions are identified. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yetisen, Ali K.; Humar, Matjaz; Kwok, Sheldon J. J.; Koo, Heebeom; Kim, Ki Su; Yun, Seok Hyun] Harvard Univ, Sch Med, Wellman Ctr Photomed, Massachusetts Gen Hosp, 65 Landsdowne St, Cambridge, MA 02139 USA. [Butt, Haider] Univ Birmingham, Sch Mech Engn, Birmingham B15 2TT, W Midlands, England. [Volpatti, Lisa R.] MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Pavlichenko, Ida] Harvard Univ, Sch Engn & Appl Sci, 9 Oxford St, Cambridge, MA 02139 USA. [Humar, Matjaz] Jozef Stefan Inst, Condensed Matter Dept, Jamova 39, SI-1000 Ljubljana, Slovenia. [Kwok, Sheldon J. J.; Khademhosseini, Ali; Yun, Seok Hyun] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Naydenova, Izabela] Dublin Inst Technol, Coll Sci & Hlth, Ctr Ind & Engn Opt, Sch Phys, Dublin 8, Ireland. [Khademhosseini, Ali] Harvard Univ, Sch Med, Brigham & Womens Hosp, Biomat Innovat Res Ctr,Div Biomed Engn, Cambridge, MA 02139 USA. [Khademhosseini, Ali] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Khademhosseini, Ali] King Abdulaziz Univ, Dept Phys, Jeddah 21413, Saudi Arabia. [Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 790784, Kyungbuk, South Korea. [Khademhosseini, Ali] Konkuk Univ, Coll Anim Biosci & Technol, Dept Bioind Technol, Seoul 143701, South Korea. RP Yetisen, AK; Yun, SH (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Massachusetts Gen Hosp, 65 Landsdowne St, Cambridge, MA 02139 USA. EM ayetisen@mgh.harvard.edu; syun@mgh.harvard.edu RI Humar, Matjaz/I-8862-2012; OI Humar, Matjaz/0000-0003-3338-6723; Khademhosseini, Ali/0000-0001-6322-8852; Butt, Haider/0000-0003-2434-9525 FU National Institutes of Health [P41EB015903]; National Science Foundation [ECCS-1505569, CBET-264356]; Department of Defence [FA9550-11-1-0331]; Bio & Medical Technology Development Program [2012M3A9C6049791]; IT Consilience Creative Program [NIPA-2014-H0201-14-1001]; Marie Curie International Outgoing Fellowship [627274] FX This work was supported in part by the National Institutes of Health (P41EB015903), National Science Foundation (ECCS-1505569, CBET-264356), Department of Defence (FA9550-11-1-0331), the Bio & Medical Technology Development Program (No. 2012M3A9C6049791) and IT Consilience Creative Program (No. NIPA-2014-H0201-14-1001). M.H. was supported by Marie Curie International Outgoing Fellowship (No. 627274). We thank Jeff Blyth, Sanford Asher, and Geoffrey A. Ozin for their discussions. NR 340 TC 12 Z9 12 U1 106 U2 228 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0734-9750 EI 1873-1899 J9 BIOTECHNOL ADV JI Biotechnol. Adv. PD MAY-JUN PY 2016 VL 34 IS 3 SI SI BP 250 EP 271 DI 10.1016/j.biotechadv.2015.10.005 PG 22 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DL2YI UT WOS:000375500700008 PM 26485407 ER PT J AU Cardinal-Fernandez, P Bajwa, EK Dominguez-Calvo, A Menendez, JM Papazian, L Thompson, BT AF Cardinal-Fernandez, Pablo Bajwa, Ednan K. Dominguez-Calvo, Andrea Menendez, Justo M. Papazian, Laurent Thompson, B. Taylor TI The Presence of Diffuse Alveolar Damage on Open Lung Biopsy Is Associated With Mortality in Patients With Acute Respiratory Distress Syndrome A Systematic Review and Meta-Analysis SO CHEST LA English DT Article DE ARDS; diffuse alveolar damage; meta-analysis; open lung biopsy ID MECHANICALLY VENTILATED PATIENTS; BERLIN DEFINITION; PHARMACOLOGICAL-TREATMENTS; RANDOMIZED-TRIALS; ARDS; INJURY; SURVIVAL; AUTOPSY; BEDSIDE; MANAGEMENT AB OBJECTIVE: Diffuse alveolar damage (DAD) is considered the histologic hallmark of ARDS although DAD is absent in approximately half of patients with ARDS. The clinical implications of having the syndrome of ARDS with DAD vs other histologic patterns is unknown. To address this question, we conducted a meta-analysis of lung biopsy series for patients with ARDS. METHODS: Studies were identified using MEDLINE, EMBASE, Cochrane Register of Controlled Trials, LILACS, and citation review from January 1, 1967, to September 1, 2015. Studies were included if they included all of the following: open lung biopsies (OLB) performed after ARDS diagnosis; a clear definition of ARDS and DAD; histologic results of the OLB indicated the presence or absence of DAD; and mortality reported for the DAD and non-DAD groups. We excluded studies conducted solely on a specific histology subgroup (eg, DAD) and studies with fewer than 5 patients. Two authors independently selected studies for inclusion, and there were no language restrictions. RESULTS: Of 8 included studies, 4 were high-quality (n = 228) and 4 were middle-quality trials (n = 122). The meta proportion of DAD between all the groups was 0.45 (95% CI, 0.35-0.56; Q test, 21.1; I2, 66.8%; P <= .01). The pooled OR for mortality in ARDS with DAD compared with ARDS without DAD was 1.81 (95% CI, 1.14-2.80; Q test, 8.8; I-2, 20.2%; P = .269). Age, sex, and days elapsed between ARDS diagnosis and OLB as well as sequential organ failure assessment score and PaO2/FIO2 ratio on the day of OLB did not differ between DAD and non-DAD groups. CONCLUSIONS: This meta-analysis demonstrated that ARDS with DAD is associated with higher mortality than ARDS without DAD. C1 [Cardinal-Fernandez, Pablo; Menendez, Justo M.] Hosp Univ HM Sanchinarro, Emergency Dept, Calle Ona 10, Madrid 28050, Spain. [Dominguez-Calvo, Andrea; Menendez, Justo M.] Hosp Univ HM Sanchinarro, Dept Internal Med, Madrid 28050, Spain. [Menendez, Justo M.] Univ CEU San Pablo, Madrid, Spain. [Bajwa, Ednan K.; Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care, Boston, MA 02114 USA. [Bajwa, Ednan K.; Thompson, B. Taylor] Harvard Univ, Sch Med, Boston, MA USA. [Papazian, Laurent] Aix Marseille Univ, Hop Marseille, Hop Nord, Assistance Publ,Reanimat Detresses Resp & Infect, Chemin Bourrely, Marseille, France. [Papazian, Laurent] Aix Marseille Univ, Fac Med, Marseille, France. [Cardinal-Fernandez, Pablo] Weill Cornell Med Coll, Dept Med Genet, New York, NY USA. RP Cardinal-Fernandez, P (reprint author), Hosp Univ HM Sanchinarro, Emergency Dept, Calle Ona 10, Madrid 28050, Spain.; Cardinal-Fernandez, P (reprint author), Weill Cornell Med Coll, Dept Med Genet, New York, NY USA. EM pablocardinal@hotmail.com NR 50 TC 6 Z9 6 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD MAY PY 2016 VL 149 IS 5 BP 1155 EP 1164 DI 10.1016/j.chest.2016.02.635 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DL2TH UT WOS:000375487600019 PM 26896701 ER PT J AU Wells, JM Morrison, JB Bhatt, SP Nath, H Dransfield, MT AF Wells, J. Michael Morrison, Joshua B. Bhatt, Surya P. Nath, Hrudaya Dransfield, Mark T. TI Pulmonary Artery Enlargement Is Associated With Cardiac Injury During Severe Exacerbations of COPD SO CHEST LA English DT Article DE acute exacerbation of COPD; COPD; CT scan; enzymes (cardiology); pulmonary circulation ID CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; COMPUTED-TOMOGRAPHY; PROGNOSTIC-VALUE; TROPONIN-T; HYPERTENSION; MORTALITY; PREDICTORS; RISK; DYSFUNCTION AB BACKGROUND: Relative pulmonary arterial enlargement, defined by a pulmonary artery to aorta (PA/A) ratio > 1 on CT scanning, predicts hospitalization for acute exacerbations of COPD (AECOPD). However, it is unclear how AECOPD affect the PA/A ratio. We hypothesized that the PA/A ratio would increase at the time of AECOPD and that a ratio > 1 would be associated with worse clinical outcomes. METHODS: Patients discharged with an International Classification of Diseases, Ninth Revision, diagnosis of AECOPD from a single center over a 5-year period were identified. Patients were included who had a CT scan performed during the stable period prior to the index AECOPD episode as well as a CT scan at the time of hospitalization. A subset of patients also underwent postexacerbation CT scans. The pulmonary arterial diameter, ascending aortic diameter, and the PA/A ratio were measured on CT scans. Demographic data, comorbidities, troponin level, and hospital outcome data were analyzed. RESULTS: A total of 134 patients were included in the study. They had a mean age of 65 +/- 10 years, 47% were male, and 69% were white; overall, patients had a mean FEV1 of 47% +/- 19%. The PA/A ratio increased from baseline at the time of exacerbation (0.97 +/- 0.15 from 0.91 +/- 0.17; P < .001). Younger age and known pulmonary hypertension were independently associated with an exacerbation PA/A ratio > 1. Patients with PA/A ratio > 1 had higher troponin values. Those with a PA/A ratio > 1 and troponin levels > 0.01 ng/mL had increased acute respiratory failure, ICU admission, or inpatient mortality compared with those without both factors (P = .0028). The PA/A ratio returned to baseline values following AECOPD. CONCLUSIONS: The PA/A ratio increased at the time of severe AECOPD and a ratio > 1 predicted cardiac injury and a more severe hospital course. C1 [Wells, J. Michael; Morrison, Joshua B.; Bhatt, Surya P.; Dransfield, Mark T.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care, Birmingham, AL USA. [Wells, J. Michael; Morrison, Joshua B.; Bhatt, Surya P.; Dransfield, Mark T.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Wells, J. Michael; Bhatt, Surya P.; Dransfield, Mark T.] Univ Alabama Birmingham, Lung Hlth Ctr, Birmingham, AL USA. [Nath, Hrudaya] Univ Alabama Birmingham, Dept Radiol, Div Cardiothorac Imaging, Birmingham, AL USA. [Wells, J. Michael; Dransfield, Mark T.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Wells, JM (reprint author), 1900 Univ Blvd,THT 422, Birmingham, AL 35294 USA. EM jmwells@uab.edu FU National Institutes of Health/National Heart, Lung, and Blood Institute [K08HL123940]; University of Alabama at Birmingham FX The funding for this study came from the National Institutes of Health/National Heart, Lung, and Blood Institute (K08HL123940) and the Walter B. Frommeyer Jr. Fellowship in Investigational Medicine from the University of Alabama at Birmingham (to Dr Wells). NR 47 TC 1 Z9 1 U1 0 U2 3 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD MAY PY 2016 VL 149 IS 5 BP 1197 EP 1204 DI 10.1378/chest.15-1504 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DL2TH UT WOS:000375487600023 PM 26501747 ER PT J AU Ebert, N Delanaye, P Shlipak, M Jakob, O Martus, P Bartel, J Gaedeke, J van der Giet, M Schuchardt, M Cavalier, E Schaeffner, E AF Ebert, Natalie Delanaye, Pierre Shlipak, Michael Jakob, Olga Martus, Peter Bartel, Jan Gaedeke, Jens van der Giet, Markus Schuchardt, Mirjam Cavalier, Etienne Schaeffner, Elke TI Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate SO CLINICA CHIMICA ACTA LA English DT Article DE Cystatin C; Renal biomarkers; Assay standardization; Glomerular filtration rate ID CHRONIC KIDNEY-DISEASE; SERUM CREATININE; MULTICENTRIC EVALUATION; RENAL-DISEASE; EQUATIONS; CALIBRATION; IMPACT; IMMUNOASSAY; VALIDATION; PREDICTION AB Background: Cystatin C is increasingly used in glomerular filtration rate (GFR) estimation equations. The dependence of cystatin C results upon the analytical method has been a major source of controversy. Methods: Cystatin C was measured with non-standardized turbidimetric Roche Generation 1 and standardized nephelometric Siemens assays in 3666 and additionally with standardized Roche Generation 2 and Siemens in 567 blood samples of the Berlin Initiative Study. Cystatin C-based GFR was assessed with CKD-EPIcys (Chronic Kidney Disease Epidemiology) and CAPA (Caucasian, Asian, Pediatric, Adult) equations and the impact of the assays on GFR estimation was determined. Equation performance compared to measured GFR was evaluated. Results: Concordance of Roche Gen2 and Siemens was high with median difference of 0.003 +/- 0.13 mg/L (limits of agreement: -0.12 to 0.12) and Passing Bablok correlation was essentially perfect. Roche Gen1 assay showed worse concordance with Siemens: median difference was 0.08 +/- 0.13 mg/L (limits of agreement: -0.18 to 034) and correlation was inferior. Mean difference (+/-SD) of estimated GFR(CKD-EPIcys) was 0 +/- 4 mL/min/1.73 m(2) for Gen2 and Siemens compared to -5 +/- 8 with Gen1. Performance of GFR estimating equations was not influenced by the choice of Siemens or Gen2 assays. Conclusions: Standardization of Roche Gen2 assay improved accuracy of cystatin C measurement compared to Siemens. It suggests only negligible method bias and results in equal performance of both assays when estimating GFR indicating that successful calibration has led to major progress in cystatin C analysis. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ebert, Natalie; Schaeffner, Elke] Charite, Inst Publ Hlth, Campus Virchow,Seestr 73, D-13347 Berlin, Germany. [Delanaye, Pierre] Ctr Hosp Univ Sart Tilman, Div Nephrol, Liege, Belgium. [Shlipak, Michael] San Francisco VA Med Ctr, San Francisco, CA USA. [Shlipak, Michael] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Jakob, Olga] Charite, Inst Biostat & Clin Epidemiol, Berlin, Germany. [Martus, Peter] Univ Tubingen, Inst Clin Epidemiol & Med Biostat, Tubingen, Germany. [Bartel, Jan] Limbach Lab, Heidelberg, Germany. [Gaedeke, Jens] Charite, Div Nephrol, Campus Mitte, D-13347 Berlin, Germany. [van der Giet, Markus; Schuchardt, Mirjam] Charite, Div Nephrol, Campus Benjamin Franklin, D-13347 Berlin, Germany. [Cavalier, Etienne] Ctr Hosp Univ Sart Tilman, Dept Clin Chem, Liege, Belgium. RP Ebert, N (reprint author), Charite, Inst Publ Hlth, Campus Virchow,Seestr 73, D-13347 Berlin, Germany. EM natalie.ebert@charite.de OI Bartel, Jan/0000-0001-7602-7224 FU Kuratorium fur Dialyse und Nierentransplantation (KfH) Foundation of Preventive Medicine; Stiftung fur Pathobiochemie und Molelculare Diagnostik FX By the Kuratorium fur Dialyse und Nierentransplantation (KfH) Foundation of Preventive Medicine and the Stiftung fur Pathobiochemie und Molelculare Diagnostik. NR 35 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 EI 1873-3492 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD MAY 1 PY 2016 VL 456 BP 115 EP 121 DI 10.1016/j.cca.2016.03.002 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DL0YG UT WOS:000375357900020 PM 26947968 ER PT J AU Januzzi, JL AF Januzzi, James L., Jr. TI B-Type Natriuretic Peptide Testing in the Era of Neprilysin Inhibition: Are the Winds of Change Blowing? SO CLINICAL CHEMISTRY LA English DT Editorial Material ID HEART-FAILURE; NEUTRAL ENDOPEPTIDASE; ENALAPRIL C1 [Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@parterns.org NR 6 TC 1 Z9 1 U1 1 U2 3 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2016 VL 62 IS 5 BP 663 EP 665 DI 10.1373/clinchem.2016.255455 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DK8JQ UT WOS:000375173400001 PM 26988584 ER PT J AU Flood, JG Khaliq, T Bishop, KA Griggs, DA AF Flood, James G. Khaliq, Tahira Bishop, Kenneth A. Griggs, David A. TI The New Substance Abuse and Mental Health Services Administration Oral Fluid Cutoffs for Cocaine and Heroin-Related Analytes Applied to an Addiction Medicine Setting: Important, Unanticipated Findings with LC-MS/MS SO CLINICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; DETECTION TIMES; DRUGS; URINE; MATRIX; PLASMA; SALIVA; DISPOSITION; METABOLITES; SAMPLES AB BACKGROUND: We implemented oral fluid (OF) as an alternative specimen type to urine for detection of cocaine (COC) and opiate abuse in outpatient addiction medicine clinics. METHODS: We implemented a 2-mu g/L limit of quantification OF LC-MS/MS assay and compiled and reviewed all findings from a 22-month collection period for COC, benzoylecgonine (BZE), codeine (COD), 6-acetylmorphine (MAM), and morphine (MOR). We also compared the results of our clinical samples at different OF cutoffs and analytes specified in the new 2015 SAMHSA OF guidelines. RESULTS: Of 3608 OF samples, COC and BZE were positive in 593 and 508, respectively. COC or BZE was positive in 662 samples. Importantly and unexpectedly, 154 samples were COC positive and BZE negative, with 125 having COC 2.0-7.9 mu g/L. A simulation with the new guideline cutoffs confirmed 65% (430 of 662) of all COC- or BZE-positive data set samples. Similarly, the new guidelines confirmed 44% (263 of 603) of data set samples positive for MOR or COD. Simulation found that the new, lower MAM guideline cutoffs detected 89% of the 382 MAM-positive samples in the data set, 104 of which the new guidelines had identified as negative for MOR and COD. CONCLUSIONS: COC (not BZE) is the dominant low concentration OF analyte in an addiction medicine setting. This information will aid OF test interpretation. It also illustrates the importance of the 2015 guideline's new immunoassay cross-reactivity requirements and the likely improvement in detection Of heroin use stemming from the new, lower MAM cutoffs. (C) 2016 American Association for Clinical Chemistry C1 [Flood, James G.; Khaliq, Tahira; Bishop, Kenneth A.; Griggs, David A.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. [Flood, James G.; Khaliq, Tahira; Bishop, Kenneth A.; Griggs, David A.] Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. RP Flood, JG (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA.; Flood, JG (reprint author), Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM jflood@partners.org NR 21 TC 0 Z9 0 U1 2 U2 7 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2016 VL 62 IS 5 BP 773 EP 780 DI 10.1373/clinchem.2015.251066 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DK8JQ UT WOS:000375173400020 PM 26988581 ER PT J AU Ananthakrishnan, AN AF Ananthakrishnan, Ashwin N. TI Chromoendoscopy Is Better: So Why Am I Not (yet) Using it for Routine Inflammatory Bowel Disease Surveillance? SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Editorial Material ID ULCERATIVE-COLITIS; DETECTING DYSPLASIA; COLORECTAL-CANCER; METAANALYSIS; COLONOSCOPY; MANAGEMENT; CONSENSUS; BIOPSIES; TRIAL; RISK C1 [Ananthakrishnan, Ashwin N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. FU NIDDK NIH HHS [K23 DK097142] NR 15 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 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD MAY PY 2016 VL 14 IS 5 BP 720 EP 722 DI 10.1016/j.cgh.2015.09.016 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK6WS UT WOS:000375067000018 PM 26407751 ER PT J AU Tapper, EB Finkelstein, D Mittleman, MA Piatkowski, G Chang, M Lai, M AF Tapper, Elliot B. Finkelstein, Daniel Mittleman, Murray A. Piatkowski, Gail Chang, Matthew Lai, Michelle TI A Quality Improvement Initiative Reduces 30-Day Rate of Readmission for Patients With Cirrhosis SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE SBP; MELD; HE; Clinical Trial ID HEPATIC-ENCEPHALOPATHY; DECOMPENSATED CIRRHOSIS; HOSPITALIZED-PATIENTS; LIVER-DISEASE; OF-CARE; MODEL; RISK; DATABASES AB BACKGROUND & AIMS: Many hospitalized patients with cirrhosis are readmitted to the hospital within 30 days, particularly those with hepatic encephalopathy (HE). We performed a prospective study to assess the effects of a quality improvement protocol on readmission to a transplant center's liver unit within 30 days. METHODS: We studied the effects of a quality improvement program in 824 unique patients with decompensated cirrhosis or receiving liver transplants (mean Model for End-Stage Liver Disease score, 17.7 +/- 7.4) admitted to an inpatient hepatology unit from 2010 through 2013. The study had a year-long control period (626 admissions receiving usual care) and 2 intervention phases: a hand-held checklist phase (470 admissions) and an electronic phase that incorporated the checklist items into the electronic provider order entry system (624 admissions). The intervention phases included goal-directed lactulose therapy and rifaximin for overt HE, and prompts for antibiotic prophylaxis of spontaneous bacterial peritonitis. The primary endpoint was the difference in 30-day readmissions between the control and intervention phases. Trends in 30-day readmissions were compared with those of patients with decompensated cirrhosis admitted at another center. RESULTS: During the electronic phase, study subjects had 40% lower adjusted odds of 30-day readmission than during the control period. The slope of the decline in readmissions over time was significantly greater than for patients at the other center (P < .0001). The proportion of patients with greater than grade 2 HE and 30-day readmission was 48.9% (66 of 135) in the control period versus 26.0% (27 of 104) in the electronic phase (P = .0003). Treatment of HE with rifaximin and secondary prophylaxis of spontaneous bacterial peritonitis with antibiotics (on discharge) were associated with lower adjusted odds of readmission (odds ratios, 0.39 and 0.40, respectively). The electronic phase was associated with 1.34 fewer hospital days for HE compared with the control period (P = .01). CONCLUSIONS: In a prospective study, a quality improvement initiative that included electronic decision support reduced readmissions of patients with cirrhosis to the hospital within 30 days. C1 [Tapper, Elliot B.; Lai, Michelle] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Gastroenterol & Hepatol, Sch Med, Boston, MA 02215 USA. [Finkelstein, Daniel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mittleman, Murray A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Cardiovasc Epidemiol Res Unit, Sch Med, Boston, MA 02215 USA. [Piatkowski, Gail] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Decis Support, Boston, MA 02215 USA. [Chang, Matthew] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. RP Tapper, EB (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM etapper@bidmc.harvard.edu FU Carl J. Shapiro Institute for Education and Research; Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University FX This work was supported by a grant from the Carl J. Shapiro Institute for Education and Research. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic 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 National Institutes of Health. NR 29 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD MAY PY 2016 VL 14 IS 5 BP 753 EP 759 DI 10.1016/j.cgh.2015.08.041 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK6WS UT WOS:000375067000023 PM 26407750 ER PT J AU Wachen, JS Dondanville, KA Blankenship, AE Wilkinson, C Yarvis, COLJS Resick, PA AF Wachen, Jennifer Schuster Dondanville, Katherine A. Blankenship, Abby E. Wilkinson, Charity Yarvis, C. O. L. Jeffrey S. Resick, Patricia A. CA STRONG STAR Consortium TI Implementing Cognitive Processing Therapy for Posttraumatic Stress Disorder With Active Duty US Military Personnel: Special Considerations and Case Examples SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article DE posttraumatic stress disorder; cognitive processing therapy; active duty military; combat; treatment ID MENTAL-HEALTH-CARE; SERVICE MEMBERS; RAPE VICTIMS; IRAQ-WAR; VETERANS; STIGMA; SYMPTOMS; SOLDIERS; COMBAT; PREDICTORS AB Numerous studies and reports document the prevalence of combat-related posttraumatic stress disorder (PTSD) in military personnel returning from deployments to Iraq and Afghanistan. The Department of Veterans Affairs and Department of Defense recommend cognitive processing therapy (CPT) as one of two first-line treatment options for patients with PTSD. CPT is an evidence-based, trauma-focused cognitive treatment for PTSD that has been shown to be efficacious in a wide variety of populations, but has just begun to be implemented with active duty military. The purpose of this article is to describe treatment considerations that may be pertinent to active duty populations, including stigma related to mental health treatment and minimization of symptoms, duty obligations, and special factors related to rank and occupational specialties. We provide recommendations for navigating these issues within the CPT protocol. Additionally, we discuss common themes that may be especially relevant when conducting CPT with an active duty military population, including blame/responsibility, the military ethos, erroneous blame of others, just-world beliefs, traumatic loss, fear of harming others, and moral injury. Case examples illustrating the use of CPT to address these themes are provided. C1 [Wachen, Jennifer Schuster] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Wachen, Jennifer Schuster] Boston Univ, Sch Med, Boston, MA 02215 USA. [Dondanville, Katherine A.; Blankenship, Abby E.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Yarvis, C. O. L. Jeffrey S.] Carl R Darnall Army Med Ctr, Ft Hood, TX 76544 USA. [Resick, Patricia A.] Duke Univ, Med Ctr, Durham, NC 27706 USA. RP Wachen, JS (reprint author), VA Boston Healthcare Syst 116B 3, Boston, MA 02130 USA. EM jennifer.wachen@va.gov FU U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program [W81XWH-08-02-109, W81XWH-08-02-0116] FX Funding for this work was made possible by the U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program Awards W81XWH-08-02-109 (Alan Peterson) and W81XWH-08-02-0116 (Patricia Resick). The views expressed in this presentation are solely those of the authors and do not reflect an endorsement by or the official policy of the U.S. Army, the Department of Defense, the Department of Veterans Affairs, or the U.S. government. NR 35 TC 1 Z9 1 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD MAY PY 2016 VL 23 IS 2 BP 133 EP 147 PG 15 WC Psychology, Clinical SC Psychology GA DK6HM UT WOS:000375023300001 ER PT J AU Cruzat, A Hamrah, P Cavalcanti, BM Zheng, LX Colby, K Pavan-Langston, D AF Cruzat, Andrea Hamrah, Pedram Cavalcanti, Bernardo M. Zheng, Lixin Colby, Kathryn Pavan-Langston, Deborah TI Corneal Reinnervation and Sensation Recovery in Patients With Herpes Zoster Ophthalmicus: An In Vivo and Ex Vivo Study of Corneal Nerves SO CORNEA LA English DT Article DE herpes zoster ophthalmicus; corneal nerves; corneal sensation; corneal reinnervation; in vivo confocal microscopy ID SCANNING CONFOCAL MICROSCOPY; POSTHERPETIC NEURALGIA; NEUROTROPHIC KERATITIS; NATURAL-HISTORY; VIRAL-ANTIGEN; VIRUS-DNA; INNERVATION; COMPLICATIONS; PLEXUS; OLDER AB Purpose:To study corneal reinnervation and sensation recovery in Herpes zoster ophthalmicus (HZO).Methods:Two patients with HZO were studied over time with serial corneal esthesiometry and laser in vivo confocal microscopy (IVCM). A Boston keratoprosthesis type 1 was implanted, and the explanted corneal tissues were examined by immunofluorescence histochemistry for III-tubulin to stain for corneal nerves.Results:The initial central corneal IVCM performed in each patient showed a complete lack of the subbasal nerve plexus, which was in accordance with severe loss of sensation (0 of 6 cm) measured by esthesiometry. When IVCM was repeated 2 years later before undergoing surgery, case 1 showed a persistent lack of central subbasal nerves and sensation (0 of 6). In contrast, case 2 showed regeneration of the central subbasal nerves (4786 m/mm(2)) with partial recovery of corneal sensation (2.5 of 6 cm). Immunostaining of the explanted corneal button in case 1 showed no corneal nerves, whereas case 2 showed central and peripheral corneal nerves. Eight months after surgery, IVCM was again repeated in the donor tissue around the Boston keratoprosthesis in both patients to study innervation of the corneal transplant. Case 1 showed no nerves, whereas case 2 showed new nerves growing from the periphery into the corneal graft.Conclusions:We demonstrate that regaining corneal innervation and corneal function are possible in patients with HZO as shown by corneal sensation, IVCM, and ex vivo immunostaining, indicating zoster neural damage is not always permanent and it may recover over an extended period of time. C1 [Cruzat, Andrea; Hamrah, Pedram; Cavalcanti, Bernardo M.; Colby, Kathryn; Pavan-Langston, Deborah] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Cornea Serv,Dept Ophthalmol, Boston, MA 02114 USA. [Cruzat, Andrea] Pontificia Univ Catolica Chile, Dept Ophthalmol, Alameda 340, Santiago, Chile. [Hamrah, Pedram] Tufts Univ, Sch Med, Dept Ophthalmol, New England Eye Ctr,Tufts Med Ctr, Boston, MA 02111 USA. [Zheng, Lixin] Cambridge Hlth Alliance, Somerville Hosp, Dept Surg, Ctr Eye, Somerville, MA USA. [Colby, Kathryn] Univ Chicago, Dept Ophthalmol, Chicago, IL 60637 USA. RP Cruzat, A (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM andrea_cruzat@meei.harvard.edu FU Johnstone Fund; NIH [K08-EY020575, K12-EY016335]; Stevens Fund; Falk Medical Research Foundation FX Supported by Johnstone Fund (D.P.-L.), NIH K08-EY020575 (P.H.), NIH K12-EY016335 (P.H.), Stevens Fund (D.P.-L.), and Falk Medical Research Foundation (P.H.). NR 41 TC 0 Z9 0 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD MAY PY 2016 VL 35 IS 5 BP 619 EP 625 DI 10.1097/ICO.0000000000000797 PG 7 WC Ophthalmology SC Ophthalmology GA DK2YU UT WOS:000374781900007 PM 26989956 ER PT J AU de Jongh, A Resick, PA Zoellner, LA van Minnen, A Lee, CW Monson, CM Foa, EB Wheeler, K ten Broeke, E Feeny, N Rauch, SAM Chard, KM Mueser, KT Sloan, DM van der Gaag, M Rothbaum, BO Neuner, F de Roos, C Hehenkamp, LMJ Rosner, R Bicanic, IAE AF de Jongh, Ad Resick, Patricia A. Zoellner, Lori A. van Minnen, Agnes Lee, Christopher W. Monson, Candice M. Foa, Edna B. Wheeler, Kathleen ten Broeke, Erik Feeny, Norah Rauch, Sheila A. M. Chard, Kathleen M. Mueser, Kim T. Sloan, Denise M. van der Gaag, Mark Rothbaum, Barbara Olasov Neuner, Frank de Roos, Carlijn Hehenkamp, Lieve M. J. Rosner, Rita Bicanic, Iva A. E. TI CRITICAL ANALYSIS OF THE CURRENT TREATMENT GUIDELINES FOR COMPLEX PTSD IN ADULTS SO DEPRESSION AND ANXIETY LA English DT Review DE treatment guidelines; PTSD; complex PTSD; phase-based treatment; stabilization ID POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD SEXUAL-ABUSE; COGNITIVE-PROCESSING THERAPY; RANDOMIZED CONTROLLED-TRIAL; SEVERE MENTAL-ILLNESS; PROLONGED EXPOSURE; CLINICAL-TRIAL; BEHAVIORAL THERAPY; INTERPERSONAL VIOLENCE; FEMALE SURVIVORS AB According to current treatment guidelines for Complex PTSD (cPTSD), psychotherapy for adults with cPTSD should start with a stabilization phase. This phase, focusing on teaching self-regulation strategies, was designed to ensure that an individual would be better able to tolerate trauma-focused treatment. The purpose of this paper is to critically evaluate the research underlying these treatment guidelines for cPTSD, and to specifically address the question as to whether a phase-based approach is needed. As reviewed in this paper, the research supporting the need for phase-based treatment for individuals with cPTSD is methodologically limited. Further, there is no rigorous research to support the views that: (1) a phase-based approach is necessary for positive treatment outcomes for adults with cPTSD, (2) front-line trauma-focused treatments have unacceptable risks or that adults with cPTSD do not respond to them, and (3) adults with cPTSD profit significantly more from trauma-focused treatments when preceded by a stabilization phase. The current treatment guidelines for cPTSD may therefore be too conservative, risking that patients are denied or delayed in receiving conventional evidence-based treatments from which they might profit. (C) 2016 Wiley Periodicals, Inc. C1 [de Jongh, Ad] Univ Amsterdam, Dept Social Dent ACTA, NL-1081 LA Amsterdam, Netherlands. [de Jongh, Ad] Vrije Univ Amsterdam, Gustav Mahlerlaan 3004, NL-1081 LA Amsterdam, Netherlands. [de Jongh, Ad] Univ Salford, Sch Hlth Sci, Manchester, Lancs, England. [Resick, Patricia A.] Duke Univ, Sch Med, Durham, NC USA. [Zoellner, Lori A.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [van Minnen, Agnes] Radboud Univ Nijmegen, NijCare, Inst Behav Sci, NL-6525 ED Nijmegen, Netherlands. [van Minnen, Agnes] Ctr Anxiety Disorders Overwaal, MHO Pro Persona, Nijmegen, Netherlands. [Lee, Christopher W.] Murdoch Univ, Sch Psychol & Exercise Sci, Murdoch, WA 6150, Australia. [Monson, Candice M.] Ryerson Univ, Dept Psychol, Toronto, ON, Canada. [Foa, Edna B.] Univ Pennsylvania Perelman SOM, Dept Psychol, Ctr Treatment & Study Anxiety, Philadelphia, PA USA. [Wheeler, Kathleen] Fairfield Univ, Sch Nursing, Fairfield, CT 06430 USA. [Feeny, Norah] Cognit Behav Therapy Deventer Bathmen, Bathmen, Netherlands. [Feeny, Norah] Case Western Reserve Univ, Dept Psychol Sci, Cleveland, OH 44106 USA. [Rauch, Sheila A. M.] Univ Michigan, Sch Med, VA Ann Arbor Healthcare Syst, Ann Arbor, MI 48109 USA. [Rauch, Sheila A. M.] Univ Michigan, VA Ann Arbor Healthcare Syst, Sch Med, Ann Arbor, MI 48109 USA. [Chard, Kathleen M.] Cincinnati VA Med Ctr, Cincinnati, OH USA. [Chard, Kathleen M.] Univ Cincinnati, Cincinnati, OH USA. [Mueser, Kim T.] Boston Univ, Coll Hlth & Rehabil Sci, Ctr Psychiat Rehabilitat, Sargent Coll, Boston, MA 02215 USA. [Sloan, Denise M.] VA Boston Healthcare Syst, VA Natl Ctr PTSD, Boston, MA USA. [Sloan, Denise M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [van der Gaag, Mark] Vrije Univ Amsterdam, Dept Clin Psychol, The Hague, Netherlands. [van der Gaag, Mark] Parnassia Psychiat Inst, EMGO Inst Hlth & Care Res, The Hague, Netherlands. [van der Gaag, Mark] Vrije Univ Amsterdam, Dept Clin Psychol, Amsterdam, Netherlands. [van der Gaag, Mark] Parnassia Psychiat Inst, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Rothbaum, Barbara Olasov] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. [Neuner, Frank] Univ Bielefeld, Dept Psychol, D-33615 Bielefeld, Germany. [de Roos, Carlijn] MHO Rivierduinen, Psychotrauma Ctr Children & Youth, Leiden, Netherlands. [Hehenkamp, Lieve M. J.; Bicanic, Iva A. E.] Univ Med Ctr Utrecht, Natl Psychotrauma Ctr Children & Youth, Utrecht, Netherlands. [Rosner, Rita] Catholic Univ, Dept Psychol, Eichstatt Ingolstadt, Germany. RP de Jongh, A (reprint author), Vrije Univ Amsterdam, Gustav Mahlerlaan 3004, NL-1081 LA Amsterdam, Netherlands.; de Jongh, A (reprint author), Univ Amsterdam, Acad Ctr Dentistry ACTA, Gustav Mahlerlaan 3004, NL-1081 LA Amsterdam, Netherlands. EM a.de.jongh@acta.nl RI van der Gaag, Mark/A-6840-2008 OI van der Gaag, Mark/0000-0002-3525-6415 FU Department of Defense; National Institute of Mental Health; NIAAA; NIDA; EMDR research; US Department of Defense Veterans Affairs; Netherlands Organization of Health Research and Development; Research Support Foundation VCVGZ; NIDILRR; SAMHSA; Brain and Behavior Research Foundation (NARSAD); McCormick Foundation; Transcept Pharmaceuticals; Deutsche Forschungsgemeinschaft; Bundesminesterium fur Bildung und Forschung FX Contract grant sponsor: Department of Defense; National Institute of Mental Health; NIAAA; NIDA; EMDR research; US Department of Defense Veterans Affairs; the Netherlands Organization of Health Research and Development and the Research Support Foundation VCVGZ; NIDILRR; SAMHSA; Brain and Behavior Research Foundation (NARSAD; Department of Defense; McCormick Foundation; Transcept Pharmaceuticals; Deutsche Forschungsgemeinschaft and Bundesminesterium fur Bildung und Forschung. NR 48 TC 7 Z9 7 U1 10 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAY PY 2016 VL 33 IS 5 BP 359 EP 369 DI 10.1002/da.22469 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DK8CM UT WOS:000375154800003 PM 26840244 ER PT J AU Acierno, R Gros, DF Ruggiero, KJ Hernandez-Tejada, BMA Knapp, RG Lejuez, CW Muzzy, W Frueh, CB Egede, LE Tuerk, PW AF Acierno, Ron Gros, Daniel F. Ruggiero, Kenneth J. Hernandez-Tejada, B. Melba A. Knapp, Rebecca G. Lejuez, Carl W. Muzzy, Wendy Frueh, Christopher B. Egede, Leonard E. Tuerk, Peter W. TI BEHAVIORAL ACTIVATION AND THERAPEUTIC EXPOSURE FOR POSTTRAUMATIC STRESS DISORDER: A NONINFERIORITY TRIAL OF TREATMENT DELIVERED IN PERSON VERSUS HOME-BASED TELEHEALTH SO DEPRESSION AND ANXIETY LA English DT Article DE PTSD; major depression; telehealth; telemedicine; telemental health; psychotherapy; home-based ID MENTAL-HEALTH PROBLEMS; PTSD; DEPRESSION; VETERANS; AFGHANISTAN; SERVICE; IRAQ; PSYCHOTHERAPY; TELEMEDICINE; MILITARY AB ObjectiveCombat veterans returning to society with impairing mental health conditions such as PTSD and major depression (MD) report significant barriers to care related to aspects of traditional psychotherapy service delivery (e.g., stigma, travel time, and cost). Hence, alternate treatment delivery methods are needed. Home-based telehealth (HBT) is one such option; however, this delivery mode has not been compared to in person, clinic-based care for PTSD in adequately powered trials. The present study was designed to compare relative noninferiority of evidence-based psychotherapies for PTSD and MD, specifically Behavioral Activation and Therapeutic Exposure (BA-TE), when delivered via HBT versus in person, in clinic delivery. MethodA repeated measures (i.e., baseline, posttreatment, 3-, 6-month follow-up) randomized controlled design powered for noninferiority analyses was used to compare PTSD and MD symptom improvement in response to BA-TE delivered via HBT versus in person, in clinic conditions. Participants were 232 veterans diagnosed with full criteria or predefined subthreshold PTSD. ResultsPTSD and MD symptom improvement following BA-TE delivered by HBT was comparable to that of BA-TE delivered in person at posttreatment and at 3- and 12-month follow-up. ConclusionEvidence-based psychotherapy for PTSD and depression can be safely and effectively delivered via HBT with clinical outcomes paralleling those of clinic-based care delivered in person. HBT, thereby, addresses barriers to care related to both logistics and stigma. C1 [Acierno, Ron; Gros, Daniel F.; Ruggiero, Kenneth J.; Hernandez-Tejada, B. Melba A.; Knapp, Rebecca G.; Muzzy, Wendy; Egede, Leonard E.; Tuerk, Peter W.] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv, Charleston, SC 29401 USA. [Acierno, Ron; Ruggiero, Kenneth J.; Hernandez-Tejada, B. Melba A.; Muzzy, Wendy] Med Univ S Carolina, Coll Nursing, Charleston, SC 29425 USA. [Gros, Daniel F.; Knapp, Rebecca G.; Egede, Leonard E.; Tuerk, Peter W.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. [Lejuez, Carl W.] Univ Maryland, Ctr Addict Personal & Emot Res, College Pk, MD 20742 USA. [Frueh, Christopher B.] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. RP Acierno, R (reprint author), Ralph H Johnson VAMC, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM acierno@musc.edu FU Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award [CX000845] FX Several authors are core and affiliate members of the Ralph H. Johnson VAMC Center of Innovation (CIN 13-418; PI: Egede), the Health Equity and Rural Outreach Innovation Center (HEROIC). Dr. Gros is funded by Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award CX000845 (PI: Gros). 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 or the United States government. There are no conflicts of interest to disclose. There are no conflicts of interest for any of the authors. NR 27 TC 4 Z9 4 U1 5 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAY PY 2016 VL 33 IS 5 BP 415 EP 423 DI 10.1002/da.22476 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DK8CM UT WOS:000375154800008 PM 26864655 ER PT J AU Dhawan, S Dirice, E Kulkarni, RN Bhushan, A AF Dhawan, Sangeeta Dirice, Ercument Kulkarni, Rohit N. Bhushan, Anil TI Inhibition of TGF- Signaling Promotes Human Pancreatic -Cell Replication SO DIABETES LA English DT Article ID BETA-CELLS; GROWTH-FACTOR; INK4A/ARF EXPRESSION; INSULIN-RESISTANCE; DIABETES-MELLITUS; ISLET HYPERPLASIA; CYCLE ARREST; PROLIFERATION; POLYCOMB; MICE AB Diabetes is associated with loss of functional pancreatic -cells, and restoration of -cells is a major goal for regenerative therapies. Endogenous regeneration of -cells via -cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous -cells have been elusive. The regenerative capacity of -cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor- (TGF-) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent -cell replication. Importantly, inhibition of TGF- signaling can result in repression of the Ink4a/Arf locus, resulting in increased -cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF- pathway promote -cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF- signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF- signaling to promote human -cell replication. C1 [Dhawan, Sangeeta] Univ Calif Los Angeles, Dept Med, Div Endocrinol, Los Angeles, CA 90024 USA. [Dirice, Ercument; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Islet Cell & Regenerat Biol, Boston, MA 02115 USA. [Dirice, Ercument; Kulkarni, Rohit N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Bhushan, Anil] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. RP Bhushan, A (reprint author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. EM anil.bhushan@ucsf.edu RI Dirice, Ercument/B-2825-2017 FU Larry L. Hillblom Foundation; JDRF; Diabetes Research Center (University of California, Los Angeles-University of California, San Diego) Pilot and Feasibility Award; National Institute of Diabetes and Digestive and Kidney Diseases; Helmsley Charitable Trust FX This work was supported by a start-up grant from the Larry L. Hillblom Foundation, a transition award from JDRF, and a Diabetes Research Center (University of California, Los Angeles-University of California, San Diego) Pilot and Feasibility Award to S.D.; an advanced postdoctoral fellowship from JDRF to E.D.; grants from National Institute of Diabetes and Digestive and Kidney Diseases to R.N.K. and A.B.; and grants from JDRF and the Helmsley Charitable Trust to A.B. NR 43 TC 2 Z9 2 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAY PY 2016 VL 65 IS 5 BP 1208 EP 1218 DI 10.2337/db15-1331 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6JA UT WOS:000375028000012 PM 26936960 ER PT J AU Nathan, DM Bebu, I Braffett, BH Lachin, JM Orchard, TJ Cowie, CC Lopes-Virella, M Schutta, M AF Nathan, David M. Bebu, Ionut Braffett, Barbara H. Lachin, John M. Orchard, Trevor J. Cowie, Catherine C. Lopes-Virella, Maria Schutta, Mark CA Diabet Control & Complications TI Risk Factors for Cardiovascular Disease in Type 1 Diabetes SO DIABETES LA English DT Article ID CORONARY-HEART-DISEASE; TERM-FOLLOW-UP; PITTSBURGH EPIDEMIOLOGY; COMPLICATIONS TRIAL; ARTERY-DISEASE; INSULIN-RESISTANCE; GLYCEMIC CONTROL; 64 COHORTS; INTERVENTIONS; METAANALYSIS AB Risk factors for cardiovascular disease (CVD) are well-established in type 2 but not type 1 diabetes (T1DM). We assessed risk factors in the long-term (mean 27 years) follow-up of the Diabetes Control and Complications Trial (DCCT) cohort with T1DM. Cox proportional hazards multivariate models assessed the association of traditional and novel risk factors, including HbA(1c), with major atherosclerotic cardiovascular events (MACE) (fatal or nonfatal myocardial infarction [MI] or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Age and mean HbA(1c) were strongly associated with any-CVD and with MACE. For each percentage point increase in mean HbA(1c), the risk for any-CVD and for MACE increased by 31 and 42%, respectively. CVD and MACE were associated with seven other conventional factors, such as blood pressure, lipids, and lack of ACE inhibitor use, but not with sex. The areas under the receiver operating characteristics curves for the association of age and HbA(1c), taken together with any-CVD and for MACE, were 0.70 and 0.77, respectively, and for the final models, including all significant risk factors, were 0.75 and 0.82. Although many conventional CVD risk factors apply in T1DM, hyperglycemia is an important risk factor second only to age. C1 [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Bebu, Ionut; Braffett, Barbara H.; Lachin, John M.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Orchard, Trevor J.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Cowie, Catherine C.] NIDDK, Bethesda, MD 20892 USA. [Lopes-Virella, Maria] Med Univ S Carolina, Charleston, SC 29425 USA. [Schutta, Mark] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. RP Lachin, JM (reprint author), George Washington Univ, Ctr Biostat, Rockville, MD USA. EM jml@bsc.gwu.edu OI orchard, trevor/0000-0001-9552-3215; Lachin, John/0000-0001-9838-2841 FU Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK-094176, U01-DK-094157]; National Eye Institute; National Institute of Neurological Disorders and Stroke; General Clinical Research Centers Program; Clinical and Translational Science Center Program, Bethesda, MD FX DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012-2017) and contracts (1982-2012) with the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant numbers U01-DK-094176 and U01-DK-094157) and through support from the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and the Clinical and Translational Science Center Program (2006-present), Bethesda, MD. Industry contributors have had no role in DCCT/EDIC but have provided free or discounted supplies or equipment to support participants' adherence to the study: Abbott Diabetes Care (Alameda, CA), Animas (Westchester, PA), Bayer Diabetes Care (North America Headquarters, Tarrytown, NY), Becton Dickinson (Franklin Lakes, NJ), Eli Lilly (Indianapolis, IN), Extend Nutrition (St. Louis, MO), Insulet Corporation (Bedford, MA), LifeScan (Milpitas, CA), Medtronic Diabetes (Minneapolis, MN), Nipro Home Diagnostics (Ft. Lauderdale, FL), Nova Diabetes Care (Billerica, MA), Omron (Shelton, CT), Perrigo Diabetes Care (Allegan, MI), Roche Diabetes Care (Indianapolis, IN), and Sanofi (Bridgewater, NJ). NR 43 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 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAY PY 2016 VL 65 IS 5 BP 1370 EP 1379 DI 10.2337/db15-1517 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6JA UT WOS:000375028000026 ER PT J AU Nayak, BK Shanmugasundaram, K Friedrichs, WE Cavaglierii, RC Patel, M Barnes, J Block, K AF Nayak, Bijaya K. Shanmugasundaram, Karthigayan Friedrichs, William E. Cavaglierii, Rita C. Patel, Mandakini Barnes, Jeffrey Block, Karen TI HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice SO DIABETES LA English DT Article ID HYPOXIA-INDUCIBLE FACTORS; RAT MESANGIAL CELLS; FACTOR-I; FACTOR 1-ALPHA; TGF-BETA; NEPHROPATHY; EXPRESSION; MECHANISMS; HIF-1-ALPHA; DISEASE AB Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole], an HIF-1 inhibitor, reduced whole kidney glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation, and urinary albumin excretion as well as NOX4 protein expression and NADPH-dependent reactive oxygen species production, while blood glucose levels remained unchanged. The role of NOX oxidases in HIF-1-mediated extracellular matrix accumulation was explored in vitro using glomerular mesangial cells. Through a series of genetic silencing and adenoviral overexpression studies, we have defined GLUT1 as a critical downstream target of HIF-1 mediating high glucose-induced matrix expression through the NADPH oxidase isoform, NOX4. Together, our data suggest that pharmacological inhibition of HIF-1 may improve clinical manifestations of diabetic nephropathy. C1 [Nayak, Bijaya K.; Shanmugasundaram, Karthigayan; Friedrichs, William E.; Cavaglierii, Rita C.; Patel, Mandakini; Barnes, Jeffrey; Block, Karen] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Barnes, Jeffrey; Block, Karen] South Texas Vet Hlth Care Syst, Audie L Murphy Mem VA Hosp Div, San Antonio, TX USA. RP Block, K (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.; Block, K (reprint author), South Texas Vet Hlth Care Syst, Audie L Murphy Mem VA Hosp Div, San Antonio, TX USA. EM block@uthscsa.edu FU U.S. Department of Veterans Affairs Merit Award; JDRF; National Institute of Diabetes and Digestive and Kidney Diseases [DK-033665] FX This work was supported by the U.S. Department of Veterans Affairs Merit Award (grant to K.B.), a multi-project grant from JDRF (to K.B.), and the National Institute of Diabetes and Digestive and Kidney Diseases (DK-033665 to K.B.). NR 44 TC 3 Z9 3 U1 4 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAY PY 2016 VL 65 IS 5 BP 1387 EP 1397 DI 10.2337/db15-0519 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6JA UT WOS:000375028000028 PM 26908870 ER PT J AU Walford, GA Ma, Y Clish, C Florez, JC Wang, TJ Gerszten, RE AF Walford, Geoffrey A. Ma, Yong Clish, Clary Florez, Jose C. Wang, Thomas J. Gerszten, Robert E. CA Diabet Prevention Program Res Grp TI Metabolite Profiles of Diabetes Incidence and Intervention Response in the Diabetes Prevention Program SO DIABETES LA English DT Article ID TRIMETHYLAMINE-N-OXIDE; NESTED CASE-CONTROL; INSULIN SENSITIVITY; BRANCHED-CHAIN; HEART-FAILURE; AMINO-ACIDS; BETAINE; PLASMA; RISK; MELLITUS AB Identifying novel biomarkers of type 2 diabetes risk may improve prediction and prevention among individuals at high risk of the disease and elucidate new biological pathways relevant to diabetes development. We performed plasma metabolite profiling in the Diabetes Prevention Program (DPP), a completed trial that randomized high-risk individuals to lifestyle, metformin, or placebo interventions. Previously reported markers, branched-chain and aromatic amino acids and glutamine/glutamate, were associated with incident diabetes (P < 0.05 for all), but these associations were attenuated upon adjustment for clinical and biochemical measures. By contrast, baseline levels of betaine, also known as glycine betaine (hazard ratio 0.84 per SD log metabolite level, P = 0.02), and three other metabolites were associated with incident diabetes even after adjustment. Moreover, betaine was increased by the lifestyle intervention, which was the most effective approach to preventing diabetes, and increases in betaine at 2 years were also associated with lower diabetes incidence (P = 0.01). Our findings indicate betaine is a marker of diabetes risk among high-risk individuals both at baseline and during preventive interventions and they complement animal models demonstrating a direct role for betaine in modulating metabolic health. C1 [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Clin Res Ctr, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.; Gerszten, Robert E.] Harvard Univ, Sch Med, Boston, MA USA. [Ma, Yong] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Ma, Yong] George Washington Univ, Milken Inst, Dept Epidemiol & Biostat, Sch Publ Hlth, Washington, DC USA. [Clish, Clary; Gerszten, Robert E.] Broad Inst, Metab Platform, Cambridge, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiol, Med Ctr, Nashville, TN 37232 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Walford, GA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Walford, GA (reprint author), Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Clin Res Ctr, Boston, MA 02114 USA.; Walford, GA (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM dppmail@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK081572, DK099249]; NIDDK; Indian Health Service during the DPP; Office of Minority Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association; DPP FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants DK081572 (to R.E.G. and T.J.W., co-principal investigators, and J.C.F., co-investigator) and DK099249 (G.A.W.). Additional sources of funding were provided for the DPP study but did not contribute to the metabolite profiling or analyses presented in this article. The NIDDK provided funding to the clinical centers and the coordinating center for the design and conduct of the DPP and the collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service during the DPP. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers in the DPP. Funding for data collection and participant support in the DPP was also provided by the Office of Minority Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication in the DPP. The research in the DPP was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health o Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, SlimFast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the coordinating center during the DPP. NR 28 TC 4 Z9 4 U1 6 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAY PY 2016 VL 65 IS 5 BP 1424 EP 1433 DI 10.2337/db15-1063 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6JA UT WOS:000375028000031 PM 26861782 ER PT J AU Maria, MMMS Baker, NL McRae-Clark, AL Prisciandaro, JJ Brady, KT AF Maria, M. M. Moran-Santa Baker, N. L. McRae-Clark, A. L. Prisciandaro, J. J. Brady, K. T. TI Effects of yohimbine and drug cues on impulsivity and attention in cocaine-dependent men and women and sex-matched controls SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cocaine; Sex differences; Yohimbine; Executive control; Stress; Drug-cues ID COGNITIVE-BEHAVIORAL THERAPY; INDUCED REINSTATEMENT; INHIBITORY CONTROL; STRESS; INDIVIDUALS; ADDICTION; DEFICITS; SEEKING; USERS; ENHANCEMENT AB Background: Deficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. Methods: In a double-blind placebo controlled cross-over study, cocaine-dependent men (n = 12), cocaine dependent women (n = 27), control men (n = 31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors' Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session Results: Healthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0-1.3), chi(2)(1)=2.0, p = 0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI) = 0.6 (0.4-0.8), chi(2)(1)=8.6, p = 0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)= 7.2 (3.6-14.7), chi(2)(1) =30.1, p<0.001]. Cocaine-dependent women exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354 +/- 13 vs. Male 415 +/- 14; t(89) = 2.6, p = 0.012]. Conclusions: These data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Maria, M. M. Moran-Santa; McRae-Clark, A. L.; Prisciandaro, J. J.; Brady, K. T.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. [Baker, N. L.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Brady, K. T.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Maria, MMMS (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, Addict Sci Div, 125 Doughty St, Charleston, SC 29425 USA. EM moranm@musc.edu FU Forest Pharmaceuticals FX Authors Moran-Santa Maria, Baker, and Prisciandaro declare no conflict of interest. Kathleen Brady lists: Consultant AstraZeneca Pharmaceuticals. Aimee McRae lists: Forest Pharmaceuticals medication provided for separate NIH grant. NR 44 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAY 1 PY 2016 VL 162 BP 56 EP 63 DI 10.1016/j.drugalcdep.2016.02.021 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DK8GK UT WOS:000375165000007 ER PT J AU Kelly, JF Greene, MC Bergman, BG AF Kelly, John F. Greene, M. Claire Bergman, Brandon G. TI Recovery benefits of the "therapeutic alliance" among 12-step mutual-help organization attendees and their sponsors SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Young adults; 12-step mutual-help organizations; Sponsorship; Therapeutic alliance ID LEEDS-DEPENDENCE-QUESTIONNAIRE; WORKING ALLIANCE; HEALTH-CARE; CLINICAL-TRIAL; REDUCE DEMAND; YOUNG-ADULTS; ALCOHOL; INVENTORY; OUTCOMES; INVOLVEMENT AB Background: The "therapeutic alliance" between clinicians and patients has been associated with treatment response and outcomes in professionally-delivered psychotherapies. Although 12-step mutual help organizations (MHOS), such as Alcoholics Anonymous, are the most commonly sought source of support for individuals with substance use disorder (SUD), little is known about whether a stronger alliance in comparable MHO relationships between 12-step sponsors and those they help ("sponsees") confers benefits similar to those observed in professional contexts. Greater knowledge could inform clinical recommendations and enhance models that explain how individuals benefit from 12-step MHOs. Method: Young adults (N = 302) enrolled in a prospective, clinical effectiveness study of residential SUD treatment were assessed at treatment entry, and 3, 6, and 12 months after discharge on whether they had a sponsor, contact with a sponsor, and degree of sponsor alliance. Hierarchical linear models (HLM) tested their effects on 12-step MHO attendance, involvement, and percent days abstinent (PDA). Results: Approximately two-thirds of the sample (n = 208, 68.87%) reported having a sponsor at one or more follow-up time points. Both having sponsor contact and stronger sponsor alliance were significantly associated with greater 12-step participation and abstinence, on average, during follow-up. Interaction results revealed that more sponsor contact was associated with increasingly higher 12-step participation whereas stronger sponsor alliance was associated with increasingly greater abstinence. Conclusions: Similar to the professional-clinical realm, the "therapeutic alliance" among sponsees and their sponsors predicts better substance use outcomes and may help augment explanatory models estimating effects of MHOs in SUD recovery. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Kelly, John F.; Greene, M. Claire; Bergman, Brandon G.] Massachusetts Gen Hosp, Ctr Addict Med, Recovery Res Inst, Dept Psychiat, Boston, MA 02114 USA. RP Kelly, JF (reprint author), MGH Psychiat, Ctr Addict Med, Recovery Res Inst, 60 Staniford St, Boston, MA 02114 USA. EM jkelly11@mgh.harvard.edu FU U.S. National Institute of Alcohol Abuse and Alcoholism [R21AA018185 A102, K24AA022136] FX This study was supported by funding from the U.S. National Institute of Alcohol Abuse and Alcoholism (R21AA018185 A102; K24AA022136) and by an anonymous donation to the Hazelden Betty Ford Foundation in Minnesota, USA. NR 57 TC 0 Z9 0 U1 3 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAY 1 PY 2016 VL 162 BP 64 EP 71 DI 10.1016/j.drugalcdep.2016.02.028 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DK8GK UT WOS:000375165000008 PM 26961963 ER PT J AU Saunders, GH Frederick, MT Silverman, SC Nielsen, C Laplante-Levesque, A AF Saunders, Gabrielle H. Frederick, Melissa T. Silverman, ShienPei C. Nielsen, Claus Laplante-Levesque, Ariane TI Description of Adults Seeking Hearing Help for the First Time According to Two Health Behavior Change Approaches: Transtheoretical Model (Stages of Change) and Health Belief Model SO EAR AND HEARING LA English DT Article DE Health behavior; Health care seeking behavior; Motivation; Patient acceptance of health care; Rehabilitation of hearing impaired ID OLDER-ADULTS; AID; IMPAIRMENT; ATTITUDES; ADOPTION; PEOPLE; STIGMA AB Objectives: Several models of health behavior change are commonly used in health psychology. This study applied the constructs delineated by two models-the transtheoretical model (in which readiness for health behavior change can be described with the stages of precontemplation, contemplation and action) and the health belief model (in which susceptibility, severity, benefits, barriers, self-efficacy, and cues to action are thought to determine likelihood of health behavior change)-to adults seeking hearing help for the first time. Design: One hundred eighty-two participants (mean age: 69.5 years) were recruited following an initial hearing assessment by an audiologist. Participants' mean four-frequency pure-tone average was 35.4 dB HL, with 25.8% having no hearing impairment, 50.5% having a slight impairment, and 23.1% having a moderate or severe impairment using the World Health Organization definition of hearing loss. Participants' hearing-related attitudes and beliefs toward hearing health behaviors were examined using the University of Rhode Island Change Assessment (URICA) and the health beliefs questionnaire (HBQ), which assess the constructs of the transtheoretical model and the health belief model, respectively. Participants also provided demographic information, and completed the hearing handicap inventory (HHI) to assess participation restrictions, and the psychosocial impact of hearing loss (PIHL) to assess the extent to which hearing impacts competence, self-esteem, and adaptability. Results: Degree of hearing impairment was associated with participation restrictions, perceived competence, self-esteem and adaptability, and attitudes and beliefs measured by the URICA and the HBQ. As degree of impairment increased, participation restrictions measured by the HHI, and impacts of hearing loss, as measured by the PIHL, increased. The majority of first-time help seekers in this study were in the action stage of change. Furthermore, relative to individuals with less hearing impairment, individuals with more hearing impairment were at more advanced stages of change as measured by the URICA (i.e., higher contemplation and action scores relative to their precontemplation score), and they perceived fewer barriers and more susceptibility, severity, benefits and cues to action as measured by the HBQ. Multiple regression analyses showed participation restrictions (HHI scores) to be a highly significant predictor of stages of change explaining 30% to 37% of the variance, as were duration of hearing difficulty, and perceived benefits, severity, self-efficacy and cues to action assessed by the HBQ. Conclusions: The main predictors of stages of change in first-time help seekers were reported participation restrictions and duration of hearing difficulty, with constructs from the health belief model also explaining some of the variance in stages of change scores. The transtheoretical model and the health belief model are valuable for understanding hearing health behaviors and can be applied when developing interventions to promote help seeking. C1 [Saunders, Gabrielle H.; Frederick, Melissa T.; Silverman, ShienPei C.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. [Saunders, Gabrielle H.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. [Nielsen, Claus; Laplante-Levesque, Ariane] Oticon AS, Eriksholm Res Ctr, Snekkersten, Denmark. [Laplante-Levesque, Ariane] Linkoping Univ, Dept Behav Sci & Learning, Linkoping, Sweden. RP Saunders, GH (reprint author), VA Portland Hlth Care Syst, Natl Ctr Rehabilitat Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM gabrielle.saunders@va.gov FU Oticon Foundation; VA Rehabilitation Research and Development Center of Excellence [C9230C] FX This study was supported financially by the Oticon Foundation, with additional support from a VA Rehabilitation Research and Development Center of Excellence award #C9230C. NR 39 TC 3 Z9 3 U1 7 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD MAY-JUN PY 2016 VL 37 IS 3 BP 324 EP 333 DI 10.1097/AUD.0000000000000268 PG 10 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA DK8BM UT WOS:000375151900016 PM 26765286 ER PT J AU Freudenberg, C Jones, RA Livingston, G Goetsch, V Schaffner, A Buchanan, L AF Freudenberg, Cara Jones, Rebecca A. Livingston, Genvieve Goetsch, Virginia Schaffner, Angela Buchanan, Linda TI Effectiveness of individualized, integrative outpatient treatment for females with anorexia nervosa and bulimia nervosa SO EATING DISORDERS LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; BINGE-EATING DISORDER; RANDOMIZED CONTROLLED-TRIALS; 3 PSYCHOLOGICAL TREATMENTS; NATURAL COURSE; PREDICTORS; INVENTORY; 5-YEAR; CARE AB The effectiveness of an individualized outpatient program was investigated in the treatment of bulimia nervosa (BN) and anorexia nervosa (AN). Participants included 151 females who received outpatient eating disorder treatment in the partial hospitalization program, the intensive outpatient program, or a combination of the two programs. Outcome measures included the Eating Disorder Inventory (EDI-2), Beck Depression Inventory (BDI-II), frequency of binge eating and purging, and mean body weight. Findings included significant increases in weight for the AN group, reductions in binge eating frequency for the BN group, and reductions in EDI-2 and BDI-II scores and purging frequency for both groups. This study provides preliminary support for the efficacy of a multimodal program for the treatment of both anorexia nervosa and bulimia nervosa. C1 [Freudenberg, Cara] Tennessee Valley Healthcare Syst, US Dept Vet Affairs, Murfreesboro, TN USA. [Jones, Rebecca A.; Livingston, Genvieve; Goetsch, Virginia] Argosy Univ, Georgia Sch Profess Psychol, 980 Hammond Dr, Atlanta, GA 30328 USA. [Schaffner, Angela] Richmont Grad Univ, Atlanta Ctr Eating Disorders, Atlanta, GA USA. [Schaffner, Angela] Richmont Grad Univ, Sch Counseling, Atlanta, GA USA. [Buchanan, Linda] Atlanta Ctr Eating Disorders, Atlanta, GA USA. RP Jones, RA (reprint author), Argosy Univ, Georgia Sch Profess Psychol, 980 Hammond Dr, Atlanta, GA 30328 USA. EM rjones@argosy.edu NR 60 TC 0 Z9 0 U1 6 U2 11 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1064-0266 EI 1532-530X J9 EAT DISORD JI Eat. Disord PD MAY-JUN PY 2016 VL 24 IS 3 BP 240 EP 254 DI 10.1080/10640266.2015.1090868 PG 15 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DL3UE UT WOS:000375558100003 PM 26467107 ER PT J AU Kwon, CS Neal, J Tellez-Zenteno, J Metcalfe, A Fitzgerald, K Hernandez-Ronquillo, L Hader, W Wiebe, S Jette, N AF Kwon, Churl-Su Neal, Jonathan Tellez-Zenteno, Jose Metcalfe, Amy Fitzgerald, Kathryn Hernandez-Ronquillo, Lizbeth Hader, Walter Wiebe, Samuel Jette, Nathalie CA CASES Investigators TI Resective focal epilepsy surgery - Has selection of candidates changed? A systematic review SO EPILEPSY RESEARCH LA English DT Review DE Epilepsy surgery; Temporal lobe epilepsy; Extra-temporal lobe epilepsy; Systematic review ID TEMPORAL-LOBE EPILEPSY; TRIAL; RECOMMENDATIONS; DEFINITION; REMISSION; CHILDREN AB Objective: No standard, widely accepted criteria exist to determine who should be referred for an epilepsy surgical evaluation. As a result, indications for epilepsy surgery evaluation vary significantly between centers. We review the literature to assess what criteria have been used to select patients for resective epilepsy surgery and examine whether these have changed since the publication of the first epilepsy surgery randomized controlled trial in 2001. Methods: A systematic review was conducted using PubMed and EMBASE, bibliographies of reviews and book chapters identifying focal epilepsy resective series. Abstract, full text review and data abstraction (i.e. indications for surgery) were performed independently by two reviewers. Descriptive historical analysis was done to examine indications over time. Results: Out of 5061 articles related to epilepsy surgery, 384 articles met all eligibility criteria. Most common criteria for selecting patients for evaluation for resective surgery were: AED resistance (n =303, most commonly >2 AEDs = 46), epilepsy duration (n = 53, most commonly >1 year = 42) and seizure frequency (most commonly at least one seizure/month, n =29). Out of the prospective studies the most notable change over time (pre-2000 vs. post-2000) was failure of >= 2 AEDs (8% vs. 43% respectively, p <0.001). Conclusions: Important variations between studies make it difficult to identify consistent criteria to guide surgical candidacy or changes in indications over time. With increasing evidence that earlier surgery is associated with better outcomes, it is recommended that patients be evaluated as soon as they have failed two AEDs, consistent with the new definition of drug resistant epilepsy. Furthermore, low seizure frequency should not be a barrier to epilepsy surgery. Anyone with drug resistant epilepsy should be promptly evaluated for possible surgery, regardless of seizure frequency. (C) 2016 Elsevier B.V. All rights reserved. C1 [Kwon, Churl-Su; Neal, Jonathan] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Tellez-Zenteno, Jose; Hernandez-Ronquillo, Lizbeth] Univ Saskatchewan, Dept Neurol, Saskatoon, SK, Canada. [Metcalfe, Amy] Univ Calgary, Dept Obstet & Gynecol, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada. [Fitzgerald, Kathryn] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Hader, Walter; Wiebe, Samuel; Jette, Nathalie] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary, AB, Canada. [Wiebe, Samuel; Jette, Nathalie] Univ Calgary, Dept Community Hlth Sci, OBrien Inst Publ Hlth, Calgary, AB, Canada. RP Jette, N (reprint author), Foothills Med Ctr, Dept Clin Neurosci, 1403-29 St NW, Calgary, AB, Canada. EM churlsu.kwon@gmail.com; jonbneal@gmail.com; jose.tellez@usask.ca; amy.metcalfe@albertahealthservices.ca; katefitzgrld@gmail.com; liztellez33@hotmail.com; walter.hader@albertahealthservices.ca; swiebe@ucalgary.ca; Nathalie.jette@albertahealthservices.ca RI Hernandez Ronquillo, Lizbeth/J-4826-2015 OI Hernandez Ronquillo, Lizbeth/0000-0001-7057-9343 FU Alberta Innovates Health Solutions (AIHS); Canada Research Chair in Neurological Health Services Research; Royal University Hospital Foundation in Saskatoon trough the Mudjadik Thyssen Mining Professorship in Neurosciences; University of Saskatchewan; Hopewell Professorship of Clinical Neurosciences Research at the University of Calgary; AIHS; Canadian Institutes of Health Research FX Dr. Nathalie Jette holds a salary award from Alberta Innovates Health Solutions (AIHS) and a Canada Research Chair in Neurological Health Services Research. Dr. Jose F. Tellez-Zenteno holds salary award from the Royal University Hospital Foundation in Saskatoon trough the Mudjadik Thyssen Mining Professorship in Neurosciences and also receives operating funds from the University of Saskatchewan. Dr. Samuel Wiebe holds the Hopewell Professorship of Clinical Neurosciences Research at the University of Calgary. This study was funded by AIHS and the Canadian Institutes of Health Research. NR 20 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 EI 1872-6844 J9 EPILEPSY RES JI Epilepsy Res. PD MAY PY 2016 VL 122 BP 37 EP 43 DI 10.1016/j.eplepsyres.2016.02.007 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DK3GM UT WOS:000374805100006 PM 26921855 ER PT J AU Dal-Bianco, JP Bartko, PE Beaudoin, J Aikawa, E Bischoff, J Levine, RA AF Dal-Bianco, Jacob P. Bartko, Philipp E. Beaudoin, Jonathan Aikawa, Elena Bischoff, Joyce Levine, Robert A. TI 3D Ultrasound: seeing is understanding-from imaging to pathophysiology to developing therapies in secondary MR SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Editorial Material ID FUNCTIONAL MITRAL REGURGITATION; VALVE CHORDAE TENDINEAE; MYOCARDIAL-INFARCTION; ADAPTATION; ECHOCARDIOGRAPHY; CARDIOMYOPATHY; MECHANISM; INSIGHTS; GEOMETRY; ANNULUS C1 [Dal-Bianco, Jacob P.; Bartko, Philipp E.; Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. [Beaudoin, Jonathan] Univ Laval, Quebec Heart & Lung Inst, Quebec City, PQ, Canada. [Aikawa, Elena] Brigham & Womens Hosp, Ctr Excellence Vasc Biol, Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Aikawa, Elena] Harvard Univ, Sch Med, Boston, MA USA. [Bischoff, Joyce] Harvard Univ, Sch Med, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA. RP Levine, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM rlevine@partners.org OI Bischoff, Joyce/0000-0002-6367-1974 FU NHLBI NIH HHS [R01 HL128099, HL109506, K24 HL67434, R01 HL72265] NR 23 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD MAY 1 PY 2016 VL 17 IS 5 BP 510 EP 511 DI 10.1093/ehjci/jew029 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL2DH UT WOS:000375442700007 PM 26976355 ER PT J AU Bhushan, A Martucci, NJ Usta, OB Yarmush, ML AF Bhushan, Abhinav Martucci, Nicole J. Usta, O. Berk Yarmush, Martin L. TI New technologies in drug metabolism and toxicity screening: organ-to-organ interaction SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Editorial Material DE Drug metabolism; drug toxicity; humanized mice; microphysiological; systems; organs on chips; induced pluripotent cells ID LIVER; COCULTURES; INTESTINE; MOUSE; SKIN; MICE C1 [Bhushan, Abhinav] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Martucci, Nicole J.] SUNY Binghamton, Dept Biomed Engn, Binghamton, NY USA. [Usta, O. Berk; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA.; Yarmush, ML (reprint author), Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. EM ireis@sbi.org FU NIDDK NIH HHS [R00 DK095984, K99 DK095984] NR 14 TC 1 Z9 1 U1 10 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1742-5255 EI 1744-7607 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD MAY PY 2016 VL 12 IS 5 BP 475 EP 477 DI 10.1517/17425255.2016.1162292 PG 3 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DK5XD UT WOS:000374993600001 PM 26940609 ER PT J AU Ivy, SP Liu, JF Lee, JM Matulonis, UA Kohn, EC AF Ivy, S. Percy Liu, Joyce F. Lee, Jung-Min Matulonis, Ursula A. Kohn, Elise C. TI Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Article DE Germline deleterious BRCA1; 2 mutation; chemical and contextual synthetic lethality; poly(adenosine diphosphate-ribose) polymerase inhibitor; DNA repair defect; homologous recombination repair; high grade serous ovarian cancer; vascular endothelial growth factor receptor inhibitor ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; RECURRENT EPITHELIAL OVARIAN; RANDOMIZED PHASE-2 TRIAL; PEGYLATED LIPOSOMAL DOXORUBICIN; VASCULAR-PERMEABILITY FACTOR; NEGATIVE BREAST-CANCER; FALLOPIAN-TUBE CANCER; NONSMALL CELL LUNG; POLY(ADP-RIBOSE) POLYMERASE AB Introduction: An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill similar to 14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC.Areas covered: Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts.Expert opinion: Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality. C1 [Ivy, S. Percy; Kohn, Elise C.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. [Liu, Joyce F.; Matulonis, Ursula A.] Dana Farber Canc Inst, Gynecol Oncol Program, Boston, MA 02115 USA. [Lee, Jung-Min] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ivy, SP (reprint author), NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. EM ivyp@ctep.nci.nih.gov FU National Cancer Institute, Bethesda; Harvard Medical School, Boston; AstraZeneca; Genentech; Merrimack Pharmaceuticals; Boston Biomedical; Atara Pharmaceuticals FX This paper has been supported by the National Cancer Institute, Bethesda, and Harvard Medical School, Boston. JD Liu is a consultant for AstraZeneca and Genentech, and has acted as principal investigator for clinical trials sponsored by AstraZeneca, Genentech, Merrimack Pharmaceuticals, Boston Biomedical and Atara Pharmaceuticals. U Matulonis has participated in advisory boards for AstraZeneca and Tesaro. 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 88 TC 4 Z9 4 U1 3 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1354-3784 EI 1744-7658 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD MAY PY 2016 VL 25 IS 5 BP 597 EP 611 DI 10.1517/13543784.2016.1156857 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK2XR UT WOS:000374778200009 PM 26899229 ER PT J AU Hobbs, G Mesa, R AF Hobbs, Gabriela Mesa, Ruben TI New drugs for myelofibrosis SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Review DE Myeloproliferative neoplasm; myelofibrosis; JAK inhibitor; targeted therapy ID INTERNATIONAL WORKING GROUP; QUALITY-OF-LIFE; MYELOPROLIFERATIVE NEOPLASMS; JAK2 INHIBITOR; MYELOID METAPLASIA; SCORING SYSTEM; PHASE-2 TRIAL; SOLID TUMORS; THERAPY; MUTATIONS AB Introduction: Myelofibrosis (MF) is a clonal myeloid neoplasm associated with cytopenias, significant symptom burden and risk of transformation to acute leukemia. Discovery of the JAK2V617F mutation in the majority of patients with myeloproliferative neoplasms led to the development and approval of ruxolitinib, the first JAK1/2 inhibitor for use in clinical practice. Better understanding of the molecular biology of MF has led to the development of a variety of new drugs that are currently undergoing testing for MF. Areas covered: Here we discuss the diagnosis and risk stratification of patients with MF. We review the use of ruxolitinib, ongoing studies in combination with this agent, and examine the spectrum of therapies under investigation for MF. Expert opinion: Ruxolitinib represents an important step in the treatment of MF; it can effectively alleviate symptomatic burden and reduce splenomegaly, unfortunately it does not lead to disease remissions. As a result, several new JAK inhibitors are undergoing advanced clinical testing, notably momelotinib and pacritinib. In addition, several trials are focusing on combinations with these agents. Improved understanding of the disease biology of MF has encouraged the development of new agents with a variety of targets, such as fibrosis, telomerase, PI3K, hedgehog, HSP90 and mTOR inhibition among others. C1 [Hobbs, Gabriela] Massachusetts Gen Hosp, Adult Leukemia Serv, Boston, MA 02114 USA. [Hobbs, Gabriela] Harvard Univ, Sch Med, Boston, MA USA. [Mesa, Ruben] Mayo Clin, Div Hematol & Med Oncol, Phoenix, AZ USA. RP Mesa, R (reprint author), Mayo Clin, Div Hematol & Med Oncol, Phoenix, AZ USA. EM mesa.ruben@mayo.edu FU NS Pharma; Incyte; Gilead; CTI; Promedior; Genentech FX R Mesa has received research support from NS Pharma, Incyte, Gilead, CTI, Promedior and Genentech, and has participated as a consultant for Novartis. 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 60 TC 0 Z9 0 U1 2 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD MAY PY 2016 VL 4 IS 5 BP 521 EP 529 DI 10.1517/21678707.2016.1171141 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK5GZ UT WOS:000374949600009 ER PT J AU Leonard, MM Fasano, A AF Leonard, Maureen M. Fasano, Alessio TI The microbiome as a possible target to prevent celiac disease SO EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Editorial Material DE Celiac disease; human leukocyte antigen; Celiac Disease Genomic Environmental Microbiome and Metabolomic; microbiome; autoimmune disease; CDGEMM ID CHILDREN; GLUTEN C1 [Leonard, Maureen M.; Fasano, Alessio] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Ctr Celiac Res & Treatment, Div Pediat Gastroenterol & Nutr,MassGen Hosp Chil, Boston, MA 02114 USA. RP Fasano, A (reprint author), Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Ctr Celiac Res & Treatment, Div Pediat Gastroenterol & Nutr,MassGen Hosp Chil, Boston, MA 02114 USA. EM Afasano@mgh.harvard.edu FU NCATS NIH HHS [UL1 TR001102]; NIDDK NIH HHS [R01 DK104344] NR 10 TC 1 Z9 1 U1 0 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1747-4124 EI 1747-4132 J9 EXPERT REV GASTROENT JI Expert Rev. Gastroenterol. Hepatol. PD MAY PY 2016 VL 10 IS 5 BP 555 EP 556 DI 10.1586/17474124.2016.1166954 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK2YM UT WOS:000374780800001 PM 26999627 ER PT J AU Iverson, KM Stirman, SW Street, AE Gerber, MR Carpenter, SL Dichter, ME Bair-Merritt, M Vogt, D AF Iverson, Katherine M. Stirman, Shannon Wiltsey Street, Amy E. Gerber, Megan R. Carpenter, S. Louisa Dichter, Melissa E. Bair-Merritt, Megan Vogt, Dawne TI Female veterans' preferences for counseling related to intimate partner violence: Informing patient-centered interventions SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Brief counseling; Integrated care; Partner abuse; Patient preferences; Women veterans ID TASK-FORCE RECOMMENDATION; MENTAL-HEALTH; PRIMARY-CARE; DOMESTIC VIOLENCE; WOMEN VETERANS; SCREENING TOOL; ABUSED WOMEN; VHA PATIENTS; SERVICES; SURVIVORS AB Objective: Female veterans are at high risk for intimate partner violence (IPV). A critical issue in the provision of health care to women who experience IPV is the delivery of effective brief counseling interventions that address women's unique needs. We aimed to identify female veterans' priorities and preferences for healthcare-based IPV counseling. Method: A 2014 Web-based survey was administered to a national sample of US female veterans. Among 411 respondents (75% participation rate), 55% (n=226) reported IPV during their lifetime. These women identified priorities for the content focus of IPV-related counseling and preferences for the delivery of these services. Results: Women prioritized counseling that focuses on physical safety and emotional health, with learning about community resources being a relatively lower priority. Participants preferred counseling to focus specifically on enhancing coping skills and managing mental health symptoms. In addition, women want counseling to be individualized and preferred the option to meet with a counselor immediately following disclosure. Affordable services and attention to privacy concerns were of paramount importance in the context of IPV-related counseling. Conclusion: These findings can inform patient-centered brief counseling interventions for women who experience IPV, which may ultimately reduce health disparities and violence among this population. Published by Elsevier Inc. C1 [Iverson, Katherine M.; Stirman, Shannon Wiltsey; Street, Amy E.; Carpenter, S. Louisa; Vogt, Dawne] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Iverson, Katherine M.; Stirman, Shannon Wiltsey; Street, Amy E.; Vogt, Dawne] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Gerber, Megan R.] VA Boston Healthcare Syst, Womens Hlth Ctr, Boston, MA 02130 USA. [Gerber, Megan R.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Dichter, Melissa E.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Dichter, Melissa E.] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bair-Merritt, Megan] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Bair-Merritt, Megan] Boston Med Ctr, Boston, MA USA. RP Iverson, KM (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM katherine.iverson@va.gov FU Department of Veterans Affairs, VHA, Health Services Research and Development (HSR&D) Services as part of Dr. Iverson's HSR&D Career Development Award [CDA 10-029]; HSRD [CDA 10-202]; [USA 14-275] FX This work was supported by the Department of Veterans Affairs, VHA, Health Services Research and Development (HSR&D) Services as part of Dr. Iverson's HSR&D Career Development Award (CDA 10-029) and her Presidential Early Career Award for Scientists and Engineers (USA 14-275). Dr. Dichter's contribution to this manuscript was supported by her HSR&D Career Development Award (CDA 10-202). The authors are grateful to Mr. Jason Wright for his assistance in preparing the WVICS. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the United States Government. NR 53 TC 0 Z9 0 U1 4 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAY-JUN PY 2016 VL 40 BP 33 EP 38 DI 10.1016/j.genhosppsych.2016.03.001 PG 6 WC Psychiatry SC Psychiatry GA DK7VM UT WOS:000375134600006 PM 27083252 ER PT J AU Dayton, TL Gocheva, V Miller, KM Israelsen, WJ Bhutkar, A Clish, CB Davidson, SM Luengo, A Bronson, RT Jacks, T Vander Heiden, MG AF Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn M. Israelsen, William J. Bhutkar, Arjun Clish, Clary B. Davidson, Shawn M. Luengo, Alba Bronson, Roderick T. Jacks, Tyler Vander Heiden, Matthew G. TI Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma SO GENES & DEVELOPMENT LA English DT Article DE HCC; PKM2; metabolism ID PYRUVATE-KINASE M2; FATTY LIVER-DISEASE; CELL-PROLIFERATION; PROTEIN-KINASE; TUMOR-GROWTH; RNA-SEQ; GENE-TRANSCRIPTION; ISOFORM EXPRESSION; CANCER-CELLS; TUMORIGENESIS AB Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2(-/-)). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2(-/-) mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. C1 [Dayton, Talya L.; Gocheva, Vasilena; Miller, Kathryn M.; Israelsen, William J.; Bhutkar, Arjun; Davidson, Shawn M.; Luengo, Alba; Jacks, Tyler; Vander Heiden, Matthew G.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Dayton, Talya L.; Gocheva, Vasilena; Miller, Kathryn M.; Israelsen, William J.; Bhutkar, Arjun; Davidson, Shawn M.; Luengo, Alba] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Israelsen, William J.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Clish, Clary B.] Broad Inst, Metabolite Profiling Platform, Cambridge, MA 02142 USA. [Bronson, Roderick T.] Tufts Univ, Sch Med & Vet Med, Dept Pathol, North Grafton, MA 01536 USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Jacks, T; Vander Heiden, MG (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Jacks, T (reprint author), MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM tjacks@mit.edu; mvh@mit.edu FU Cancer Center Support grant from the National Cancer Institute [P30CA14051]; Howard Hughes Medical Institute; Burroughs Wellcome Fund; Smith Family; Department of Health and Human Services [P01CA117969, R01CA168653]; National Defense Science and Engineering Graduate (NDSEG) Fellowship Award; Jane Coffin Childs Memorial Fund Postdoctoral Fellowship FX We thank Nadya Dimitrova, Francisco Sanchez-Rivera, Laura Danai, and Chengcheng Jin for critical review of the manuscript. We are grateful to Ben Olenchock and Eric Bell for assistance with metabolic phenotyping, Paul L. Boutz for insightful comments on isoform regulation analyses, and Anthony Couvillon for sharing the EIIA-Cre mice. We also thank David Feldser, Nadya Dimitrova, Nikhil Joshi, Hao Yin, Aaron Hosios, Wen Xue, and the entire Jacks and Vander Heiden laboratories for helpful discussions and experimental assistance. We thank the Koch Institute Swanson Biotechnology Center (SBC) for technical support, specifically Denise Crowley and Kathleen Cormier in the Hope Babette Tang (1983) Histology Facility. Additionally, we acknowledge the ENCODE project, the Gingeras laboratory (Cold Spring Harbor Laboratory), and the Illumina Body Map project for RNA-seq data. This work was partially supported by Cancer Center Support grant P30CA14051 from the National Cancer Institute and by grants from the Howard Hughes Medical Institute (T.J.), the Burroughs Wellcome Fund (M.G.V.H.), the Smith Family (M.G.V.H.), and the Department of Health and Human Services (P01CA117969 to T.J., and R01CA168653 to M.G.V.H.). T.L.D. was partially supported by a National Defense Science and Engineering Graduate (NDSEG) Fellowship Award. V.G. was supported by a Jane Coffin Childs Memorial Fund Postdoctoral Fellowship. T.J. is a Howard Hughes Investigator, the David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar at Massachusetts Institute of Technology. M.G.V.H. is a consultant and advisory board member for Agios Pharmaceuticals. We dedicate this paper to the memory of Officer Sean Collier for his caring service to the Massachusetts Institute of Technology community and his sacrifice. NR 62 TC 3 Z9 4 U1 4 U2 9 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 MAY 1 PY 2016 VL 30 IS 9 BP 1020 EP 1033 DI 10.1101/gad.278549.116 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DL1RN UT WOS:000375409800003 PM 27125672 ER PT J AU de Graaf, G Buckley, F Skotko, BG AF de Graaf, Gert Buckley, Frank Skotko, Brian G. TI Live births, natural losses, and elective terminations with Down syndrome in Massachusetts SO GENETICS IN MEDICINE LA English DT Article DE Down syndrome; incidence; prevalence; terminations; trisomy 21 ID MATERNAL AGE; UNITED-STATES; SYNDROME PREGNANCIES; FETAL LOSS; PREVALENCE; RATES; POPULATION; DEFECTS; CALIFORNIA; ENGLAND AB Purpose: No studies to date have reported an estimated number of live births, elective terminations, and natural losses (miscarriages and stillbirths) for Down syndrome (DS) in Massachusetts (MA). These numbers would be helpful to estimate how many expectant parents of children with DS need support and the number of live-born children with DS who require services. Methods: Combining robust data sets, including the Annual Reports of the MA Birth Defects Monitoring Program, we estimated the number of live births, elective terminations, and natural losses with Down syndrome from 1900 to 2010. Results: The live birth prevalence for DS in MA for the most recent years for which data are available (2006-2010) was estimated at 12.4 per 10,000 live births, with a total of approximately 94 live births annually. During this period, an estimated 126 DS-related elective pregnancy terminations were performed in MA annually. As of 2008, the estimated rate at which live births with DS was reduced as a consequence of DS-related elective pregnancy terminations was 49%. Conclusion: The reduction of live births with DS is significantly higher in MA than in the rest of the United States as a whole. However, ethnic and racial differences in reduction rates were similar-highest for Asians/Pacific Islanders, followed by non-Hispanic whites, non-Hispanic blacks/Africans, and Hispanics. C1 [de Graaf, Gert] Dutch Down Syndrome Fdn, Meppel, Netherlands. [Buckley, Frank] Down Syndrome Educ Int, Kirkby Lonsdale, Cumbria, England. [Buckley, Frank] Down Syndrome Educ USA, Newport Beach, CA USA. [Skotko, Brian G.] Massachusetts Gen Hosp, Dept Pediat, Div Med Genet, Boston, MA 02114 USA. [Skotko, Brian G.] Harvard Univ, Sch Med, Boston, MA USA. RP Skotko, BG (reprint author), Massachusetts Gen Hosp, Dept Pediat, Div Med Genet, Boston, MA 02114 USA.; Skotko, BG (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM bskotko@mgh.harvard.edu OI Skotko, Brian/0000-0002-5232-9882; de Graaf, Gert/0000-0002-4990-5711 NR 36 TC 1 Z9 1 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD MAY PY 2016 VL 18 IS 5 BP 459 EP 466 DI 10.1038/gim.2016.15 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DK9PN UT WOS:000375263600006 PM 27126496 ER PT J AU Sun, S Yang, F Tan, GH Costanzo, M Oughtred, R Hirschman, J Theesfeld, CL Bansal, P Sahni, N Yi, S Yu, A Tyagi, T Tie, C Hill, DE Vidal, M Andrews, BJ Boone, C Dolinski, K Roth, FP AF Sun, Song Yang, Fan Tan, Guihong Costanzo, Michael Oughtred, Rose Hirschman, Jodi Theesfeld, Chandra L. Bansal, Pritpal Sahni, Nidhi Yi, Song Yu, Analyn Tyagi, Tanya Tie, Cathy Hill, David E. Vidal, Marc Andrews, Brenda J. Boone, Charles Dolinski, Kara Roth, Frederick P. TI An extended set of yeast-based functional assays accurately identifies human disease mutations SO GENOME RESEARCH LA English DT Article ID CYSTATHIONINE BETA-SYNTHASE; SACCHAROMYCES-CEREVISIAE GENOME; MISSENSE MUTATIONS; CAENORHABDITIS-ELEGANS; COMPUTATIONAL METHODS; MENTAL-RETARDATION; SEQUENCE VARIANTS; CODING VARIATION; ENZYME VARIANTS; COMPLEX DISEASE AB We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease-and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods. C1 [Sun, Song; Yang, Fan; Tan, Guihong; Costanzo, Michael; Bansal, Pritpal; Yu, Analyn; Tyagi, Tanya; Andrews, Brenda J.; Boone, Charles; Roth, Frederick P.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Sun, Song; Yang, Fan; Tan, Guihong; Costanzo, Michael; Bansal, Pritpal; Yu, Analyn; Tyagi, Tanya; Andrews, Brenda J.; Boone, Charles; Roth, Frederick P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Sun, Song; Yang, Fan; Bansal, Pritpal; Yu, Analyn; Tyagi, Tanya; Roth, Frederick P.] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3E1, Canada. [Sun, Song; Yang, Fan; Bansal, Pritpal; Yu, Analyn; Tyagi, Tanya; Tie, Cathy; Roth, Frederick P.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Sun, Song] Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden. [Oughtred, Rose; Hirschman, Jodi; Theesfeld, Chandra L.; Dolinski, Kara] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Sahni, Nidhi; Yi, Song; Hill, David E.; Vidal, Marc; Roth, Frederick P.] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Sahni, Nidhi; Yi, Song; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Roth, Frederick P.] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada. [Sahni, Nidhi] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. RP Roth, FP (reprint author), Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.; Roth, FP (reprint author), Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.; Roth, FP (reprint author), Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3E1, Canada.; Roth, FP (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.; Roth, FP (reprint author), Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA.; Roth, FP (reprint author), Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada. EM fritz.roth@utoronto.ca OI Roth, Frederick/0000-0002-6628-649X FU Swedish Research Council; National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) Centers of Excellence in Genomic Sciences [P50HG004233]; NIH/NHGRI [U01HG001715]; Canada Excellence Research Chairs Program; National Institutes of Health [R24OD011194, R01HG005853]; Canadian Institutes of Health Research [FDN-143264, FDN-143265]; Canadian Institute for Advanced Research; Cancer Prevention and Research Institute of Texas [RR160021] FX We thank N. Yachie for expression vector assistance and M. Cusick and anonymous reviewers for advice. We acknowledge support from a Swedish Research Council International Postdoc Grant (S.S.), National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) Centers of Excellence in Genomic Sciences grant P50HG004233 (M.V. and F.P.R.), NIH/NHGRI grant U01HG001715 (M.V., D.E.H., and F.P.R.), the Canada Excellence Research Chairs Program (F.P.R.), National Institutes of Health grant R24OD011194 (K.D.), National Institutes of Health grant R01HG005853 (B.J.A. and C.B.), Canadian Institutes of Health Research grants FDN-143264 and FDN-143265 (B.J.A. and C.B.), and Fellowships from the Canadian Institute for Advanced Research (B.J.A., C.B., and F.P.R.). N.S. is recipient of a Cancer Prevention and Research Institute of Texas New Investigator award RR160021. NR 84 TC 5 Z9 5 U1 1 U2 2 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 MAY PY 2016 VL 26 IS 5 BP 670 EP 680 DI 10.1101/gr.192526.115 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DL0MV UT WOS:000375328000010 PM 26975778 ER PT J AU Saboo, US Amparo, F Shikari, H Dana, R AF Saboo, Ujwala S. Amparo, Francisco Shikari, Hasanain Dana, Reza TI Prevalence of ocular hypertension and glaucoma in patients with chronic ocular graft-versus-host disease SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE Graft-versus-host disease; Ocular hypertension; Ocular surface disease; Glaucoma ID OPEN-ANGLE GLAUCOMA; STEM-CELL TRANSPLANTATION; BLUE MOUNTAINS EYE; INTRAOCULAR-PRESSURE; SURFACE DISEASE; SYMPTOMS; MEDICATIONS; POPULATION; MANAGEMENT; UPDATE AB Purpose To evaluate the prevalence of ocular hypertension (OHT) and glaucoma in patients with chronic ocular graft-versus-host disease (GVHD). Methods We performed a retrospective chart review of 218 patients diagnosed with chronic ocular GVHD. Ocular hypertension was defined as intraocular pressure (IOP) >= 24 mmHg in either eye without any glaucomatous optic disc changes. Glaucoma suspect was defined as optic disc changes with a cup-to-disc ratio >= 0.7 in either eye or asymmetry of >= 0.3 between the two eyes. Glaucoma was defined by glaucomatous optic disc changes plus glaucomatous visual field defects in two consecutive reliable visual field tests. The number of cases of ocular hypertension, glaucoma, and glaucoma suspects was evaluated. Results Thirty-three patients (15 %) were diagnosed with OHT, eight patients (3.6 %) with suspicion of glaucoma, and one patient (0.4 %) with glaucoma. OHT occurred within 6 months of developing ocular GVHD in 60 % of the cases and within the first year in 76 %. High IOP normalized in 67 % of patients when the dosage of topical or systemic corticosteroids was lowered, and 27 % of patients required anti-glaucoma therapy. Conclusions Ocular hypertension is a common complication in patients with ocular GVHD, with a prevalence of 15 %. The rise in intraocular pressure is often transient and resolves with management of corticosteroids in most cases. However, clinicians should be aware that nearly one-third of the patients with OHT might require anti-glaucoma treatment. The prevalences of glaucoma and suspicion of glaucoma were not higher than in the general population. C1 [Saboo, Ujwala S.; Amparo, Francisco; Shikari, Hasanain; Dana, Reza] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Cornea Serv, 243 Charles St, Boston, MA 02114 USA. RP Dana, R (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM reza_dana@meei.harvard.edu FU National Eye Institute, National Institutes of Health [K24-EY019098]; Research to Prevent Blindness FX National Eye Institute, National Institutes of Health provided financial support in the form of National Institutes of Health (Grant: K24-EY019098) funding. This work was also supported by funding from Research to Prevent Blindness. The sponsor had no role in the design or conduct of this research. NR 47 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X EI 1435-702X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD MAY PY 2016 VL 254 IS 5 BP 923 EP 928 DI 10.1007/s00417-016-3312-3 PG 6 WC Ophthalmology SC Ophthalmology GA DK3SG UT WOS:000374837100012 PM 26968719 ER PT J AU Uppal, S Penn, C del Carmen, MG Rauh-Hain, JA Reynolds, RK Rice, LW AF Uppal, Shitanshu Penn, Courtney del Carmen, Marcela G. Rauh-Hain, J. Alejandro Reynolds, R. Kevin Rice, Laurel W. TI Readmissions after major gynecologic oncology surgery SO GYNECOLOGIC ONCOLOGY LA English DT Article ID HOSPITAL READMISSION; STAPHYLOCOCCUS-AUREUS; QUALITY; PROGRAM; IMPLEMENTATION; HYSTERECTOMY; INFECTIONS; PATIENT; CANCER; NSQIP AB Objectives. To examine the underlying indications, timing, and risk factors associated with unplanned hospital readmissions after major surgery for a gynecologic malignancy. Methods. This is a retrospective database cohort study utilizing the National Surgical Quality Improvement Program database (NSQIP). The association between risk factors with respect to 30-day unplanned readmission was modeled using logistic regression. Timing of readmission and the primary reason of readmission was abstracted from the database. Results. Overall, the unplanned readmission rate was 6.5% (832/12,804). On multivariate analysis, operative time >= 3 h (OR 1.39, p < 0.001), open abdominal surgery (OR 2.2, p < 0.001), any complication prior to discharge (OR 1.6, p < 0.001), two or more additional surgical procedures (OR 1.34, p = 0.003), or cervical cancer as the site of primary disease (OR 1.30, p = 0.05) were noted to be independent predictors of readmission. To provide a convenient calculation of overall probability of readmission, we developed a nomogram of factors significantly predicting readmission. Overall, infections were a cause of 45% of the readmissions. Surgical Site Infections were the most common reason, accounting for 29.2% of all readmissions. A majority of the readmissions (approximately 75%) were within two weeks of discharge from the hospital. Conclusions. Efforts to reduce readmission rates should focus on identifying patients at a high risk of readmission and reducing surgical site infections. Additionally, prospective evaluation of interventions targeted at reducing readmissions should focus on the first two weeks after discharge from the hospital. (C) 2016 Elsevier Inc. All rights reserved. C1 [Uppal, Shitanshu; Penn, Courtney; Reynolds, R. Kevin] Univ Michigan, Div Gynecol Oncol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. [del Carmen, Marcela G.; Rauh-Hain, J. Alejandro] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol,Vincent Program Global Obstet &, 55 Fruit St, Boston, MA 02114 USA. [Rice, Laurel W.] Univ Wisconsin, Div Gynecol Oncol, 600 Highland Ave, Madison, WI 53792 USA. [Uppal, Shitanshu] Univ Michigan, Inst Healthcare Policy & Innovat, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA. RP Uppal, S (reprint author), Univ Michigan, 1500 E Med Dr, Ann Arbor, MI 48109 USA. EM uppal@med.umich.edu NR 20 TC 1 Z9 1 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2016 VL 141 IS 2 BP 287 EP 292 DI 10.1016/j.ygyno.2016.02.031 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DL0YJ UT WOS:000375358200018 PM 26927757 ER PT J AU Hollestelle, A van der Baan, FH Berchuck, A Johnatty, SE Aben, KK Agnarsson, BA Aittomaki, K Alducci, E Andrulis, IL Anton-Culver, H Antonenkova, NN Antoniou, AC Apicella, C Arndt, V Arnold, N Arun, BK Arver, B Ashworth, A Baglietto, L Balleine, R Bandera, EV Barrowdale, D Bean, YT Beckmann, L Beckmann, MW Benitez, J Berger, A Berger, R Beuselinck, B Bisogna, M Bjorge, L Blomqvist, C Bogdanova, NV Bojesen, A Bojesen, SE Bolla, MK Bonanni, B Brand, JS Brauch, H Brenner, H Brinton, L Brooks-Wilson, A Bruinsma, F Brunet, J Bruning, T Budzilowska, A Bunker, CH Burwinkel, B Butzow, R Buys, SS Caligo, MA Campbell, I Carter, J Chang-Claude, J Chanock, SJ Claes, KBM Collee, JM Cook, LS Couch, FJ Cox, A Cramer, D Cross, SS Cunningham, JM Cybulski, C Czene, K Damiola, F Dansonka-Mieszkowska, A Darabi, H de la Hoya, M Defazio, A Dennis, J Devilee, P Dicks, EM Diez, O Doherty, JA Domchek, SM Dorfling, CM Dork, T Silva, ID du Bois, A Dumont, M Dunning, AM Duran, M Easton, DF Eccles, D Edwards, RP Ehrencrona, H Ejlertsen, B Ekici, AB Ellis, SD Engel, C Eriksson, M Fasching, PA Feliubadalo, L Figueroa, J Flesch-Janys, D Fletcher, O Fontaine, A Fortuzzi, S Fostira, F Fridley, BL Friebel, T Friedman, E Friel, G Frost, D Garber, J Garcia-Closas, M Gayther, SA Gentry-Maharaj, A Gerdes, AM Giles, GG Glasspool, R Glendon, G Godwin, AK Goodman, MT Gore, M Greene, MH Grip, M Gronwald, J Kaulich, DG Guenel, P Guzman, SR Haeberle, L Haiman, CA Hall, P Halverson, SL Hamann, U Hansen, TVO Harter, P Hartikainen, JM Healey, S Hein, A Heitz, F Henderson, BE Herzog, J Hildebrandt, MAT Bogdan, CK Hogdall, E Hogervorst, FBL Hopper, JL Humphreys, K Huzarski, T Imyanitov, EN Isaacs, C Jakubowska, A Janavicius, R Jaworska, K Jensen, A Jensen, UB Johnson, N Jukkola-Vuorinen, A Kabisch, M Karlan, BY Kataja, V Kauff, N Kelemen, LE Kerin, MJ Kiemeney, LA Kjaer, SK Knight, JA Knol-Bout, JP Konstantopoulou, I Kosma, VM Krakstad, C Kristensen, V Kuchenbaecker, KB Kupryjanczyk, J Laitman, Y Lambrechts, D Lambrechts, S Larson, MC Lasa, A Laurent-Puig, P Lazaro, C Le, ND Le Marchand, L Leminen, A Lester, J Levine, DA Li, JM Liang, D Lindblom, A Lindor, N Lissowska, J Long, JR Lu, KH Lubinski, J Lundvall, L Lurie, G Mai, PL Mannermaa, A Margolin, S Mariette, F Marme, F Martens, JWM Massuger, LFAG Maugard, C Mazoyer, S McGuffog, L McGuire, V McLean, C McNeish, L Meindi, A Menegaux, F Menendez, P Menkiszak, J Menon, U Mensenkamp, AR Miller, N Milne, RL Modugno, F Montagna, M Moysich, KB Muller, H Mulligan, AM Muranen, TA Narod, SA Nathanson, KL Ness, RB Neuhausen, SL Nevanlinna, H Neven, P Nielsen, FC Nielsen, SF Nordestgaard, BG Nussbaum, RL Odunsi, K Offit, K Olah, E Olopade, OI Olson, JE Olson, SH Oosterwijk, JC Orlow, I Orr, N Orsulic, S Osorio, A Ottini, L Paul, J Pearce, CL Pedersen, IS Peissel, B Pejovic, T Pelttari, LM Perkins, J Permuth-Wey, J Peterlongo, P Peto, J Phelan, CM Phillips, KA Piedmonte, M Pike, MC Platte, R Plisiecka-Halasa, J Poole, EM Poppe, B Pylkas, K Radice, P Ramus, SJ Rebbeck, TR Reed, MWR Rennert, G Risch, HA Robson, M Rodriguez, GC Romero, A Rossing, MA Rothstein, JH Rudolph, A Runnebaum, I Salani, R Salvesen, HB Sawyer, EJ Schildkraut, JM Schmidt, MK Schmutzler, RK Schneeweiss, A Schoemaker, MJ Schrauder, MG Schumacher, F Schwaab, I Scuvera, G Sellers, TA Severi, G Seynaeve, CM Shah, M Shrubsole, M Siddiqui, N Sieh, W Simard, J Singer, CF Sinilnikova, OM Smeets, D Sohn, C Soller, M Song, H Soucy, P Southey, MC Stegmaier, C Stoppa-Lyonnet, D Sucheston, L Swerdlow, A Tangen, IL Tea, MK Teixeira, MR Terry, KL Terry, MB Thomassen, M Thompson, PJ Tihomirova, L Tischkowitz, M Toland, AE Tollenaar, RAEM Tomlinson, I Torres, D Truong, T Tsimiklis, H Tung, N Tworoger, SS Tyrer, JP Vachon, CM Van 't Veer, LJ van Altena, AM Van Asperen, CJ van den Berg, D van den Ouweland, AMW van Doom, HC Van Nieuwenhuysen, E van Rensburg, EJ Vergote, I Verhoef, S Vierkant, RA Vijai, J Vitonis, AF von Wachenfeldt, A Walsh, C Wang, Q Wang-Gohrke, S Wappenschmidt, B Weischer, M Weitzel, JN Weltens, C Wentzensen, N Whittemore, AS Wilkens, LR Winqvist, R Wu, AH Wu, XF Yang, HP Zaffaroni, D Zamora, MP Zheng, W Ziogas, A Chenevix-Trench, G Pharoah, PDP Rookus, MA Hooning, MJ Goode, EL AF Hollestelle, Antoinette van der Baan, Frederieke H. Berchuck, Andrew Johnatty, Sharon E. Aben, Katja K. Agnarsson, Bjarni A. Aittomaki, Kristiina Alducci, Elisa Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Antoniou, Antonis C. Apicella, Carmel Arndt, Volker Arnold, Norbert Arun, Banu K. Arver, Brita Ashworth, Alan Baglietto, Laura Balleine, Rosemary Bandera, Elisa V. Barrowdale, Daniel Bean, Yukie T. Beckmann, Lars Beckmann, Matthias W. Benitez, Javier Berger, Andreas Berger, Raanan Beuselinck, Benoit Bisogna, Maria Bjorge, Line Blomqvist, Carl Bogdanova, Natalia V. Bojesen, Anders Bojesen, Stig E. Bolla, Manjeet K. Bonanni, Bernardo Brand, Judith S. Brauch, Hiltrud Brenner, Hermann Brinton, Louise Brooks-Wilson, Angela Bruinsma, Fiona Brunet, Joan Bruning, Thomas Budzilowska, Agnieszka Bunker, Clareann H. Burwinkel, Barbara Butzow, Ralf Buys, Saundra S. Caligo, Maria A. Campbell, Ian Carter, Jonathan Chang-Claude, Jenny Chanock, Stephen J. Claes, Kathleen B. M. Collee, J. Margriet Cook, Linda S. Couch, Fergus J. Cox, Angela Cramer, Daniel Cross, Simon S. Cunningham, Julie M. Cybulski, Cezary Czene, Kamila Damiola, Francesca Dansonka-Mieszkowska, Agnieszka Darabi, Hatef de la Hoya, Miguel deFazio, Anna Dennis, Joseph Devilee, Peter Dicks, Ed M. Diez, Orland Doherty, Jennifer A. Domchek, Susan M. Dorfling, Cecilia M. Dork, Thilo Dos Santos Silva, Isabel du Bois, Andreas Dumont, Martine Dunning, Alison M. Duran, Mercedes Easton, Douglas F. Eccles, Diana Edwards, Robert P. Ehrencrona, Hans Ejlertsen, Bent Ekici, Arif B. Ellis, Steve D. Engel, Christoph Eriksson, Mikael Fasching, Peter A. Feliubadalo, Lidia Figueroa, Jonine Flesch-Janys, Dieter Fletcher, Olivia Fontaine, Annette Fortuzzi, Stefano Fostira, Florentia Fridley, Brooke L. Friebel, Tara Friedman, Eitan Friel, Grace Frost, Debra Garber, Judy Garcia-Closas, Montserrat Gayther, Simon A. Gentry-Maharaj, Aleksandra Gerdes, Anne-Marie Giles, Graham G. Glasspool, Rosalind Glendon, Gord Godwin, Andrew K. Goodman, Marc T. Gore, Martin Greene, Mark H. Grip, Mervi Gronwald, Jacek Kaulich, Daphne Gschwantler Guenel, Pascal Guzman, Starr R. Haeberle, Lothar Haiman, Christopher A. Hall, Per Halverson, Sandra L. Hamann, Ute Hansen, Thomas V. O. Harter, Philipp Hartikainen, Jaana M. Healey, Sue Hein, Alexander Heitz, Florian Henderson, Brian E. Herzog, Josef Hildebrandt, Michelle A. T. Bogdan, Claus K. Hogdall, Estrid Hogervorst, Frans B. L. Hopper, John L. Humphreys, Keith Huzarski, Tomasz Imyanitov, Evgeny N. Isaacs, Claudine Jakubowska, Anna Janavicius, Ramunas Jaworska, Katarzyna Jensen, Allan Jensen, Uffe Birk Johnson, Nichola Jukkola-Vuorinen, Arja Kabisch, Maria Karlan, Beth Y. Kataja, Vesa Kauff, Noah Kelemen, Linda E. Kerin, Michael J. Kiemeney, Lambertus A. Kjaer, Susanne K. Knight, Julia A. Knol-Bout, Jacoba P. Konstantopoulou, Irene Kosma, Veli-Matti Krakstad, Camilla Kristensen, Vessela Kuchenbaecker, Karoline B. Kupryjanczyk, Jolanta Laitman, Yael Lambrechts, Diether Lambrechts, Sandrina Larson, Melissa C. Lasa, Adriana Laurent-Puig, Pierre Lazaro, Conxi Le, Nhu D. Le Marchand, Loic Leminen, Arto Lester, Jenny Levine, Douglas A. Li, Jingmei Liang, Dong Lindblom, Annika Lindor, Noralane Lissowska, Jolanta Long, Jirong Lu, Karen H. Lubinski, Jan Lundvall, Lene Lurie, Galina Mai, Phuong L. Mannermaa, Arto Margolin, Sara Mariette, Frederique Marme, Frederik Martens, John W. M. Massuger, Leon F. A. G. Maugard, Christine Mazoyer, Sylvie McGuffog, Lesley McGuire, Valerie McLean, Catriona McNeish, Lain Meindi, Alfons Menegaux, Florence Menendez, Primitiva Menkiszak, Janusz Menon, Usha Mensenkamp, Arjen R. Miller, Nicola Milne, Roger L. Modugno, Francesmary Montagna, Marco Moysich, Kirsten B. Mueller, Heiko Mulligan, Anna Marie Muranen, Taru A. Narod, Steven A. Nathanson, Katherine L. Ness, Roberta B. Neuhausen, Susan L. Nevanlinna, Heli Neven, Patrick Nielsen, Finn C. Nielsen, Sune F. Nordestgaard, Berge G. Nussbaum, Robert L. Odunsi, Kunle Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Olson, Janet E. Olson, Sara H. Oosterwijk, Jan C. Orlow, Irene Orr, Nick Orsulic, Sandra Osorio, Ana Ottini, Laura Paul, James Pearce, Celeste L. Pedersen, Inge Sokilde Peissel, Bernard Pejovic, Tanja Pelttari, Liisa M. Perkins, Jo Permuth-Wey, Jenny Peterlongo, Paolo Peto, Julian Phelan, Catherine M. Phillips, Kelly-Anne Piedmonte, Marion Pike, Malcolm C. Platte, Radka Plisiecka-Halasa, Joanna Poole, Elizabeth M. Poppe, Bruce Pylkas, Katri Radice, Paolo Ramus, Susan J. Rebbeck, Timothy R. Reed, Malcolm W. R. Rennert, Gad Risch, Harvey A. Robson, Mark Rodriguez, Gustavo C. Romero, Atocha Rossing, Mary Anne Rothstein, Joseph H. Rudolph, Anja Runnebaum, Ingo Salani, Ritu Salvesen, Helga B. Sawyer, Elinor J. Schildkraut, Joellen M. Schmidt, Marjanka K. Schmutzler, Rita K. Schneeweiss, Andreas Schoemaker, Minouk J. Schrauder, Michael G. Schumacher, Fredrick Schwaab, Ira Scuvera, Giulietta Sellers, Thomas A. Severi, Gianluca Seynaeve, Caroline M. Shah, Mitul Shrubsole, Martha Siddiqui, Nadeem Sieh, Weiva Simard, Jacques Singer, Christian F. Sinilnikova, Olga M. Smeets, Dominiek Sohn, Christof Soller, Maria Song, Honglin Soucy, Penny Southey, Melissa C. Stegmaier, Christa Stoppa-Lyonnet, Dominique Sucheston, Lara Swerdlow, Anthony Tangen, Ingvild L. Tea, Muy-Kheng Teixeira, Manuel R. Terry, Kathryn L. Terry, Mary Beth Thomassen, Mads Thompson, Pamela J. Tihomirova, Laima Tischkowitz, Marc Toland, Amanda Ewart Tollenaar, Rob A. E. M. Tomlinson, Ian Torres, Diana Truong, Therese Tsimiklis, Helen Tung, Nadine Tworoger, Shelley S. Tyrer, Jonathan P. Vachon, Celine M. Van 't Veer, Laura J. van Altena, Anne M. Van Asperen, C. J. van den Berg, David van den Ouweland, Ans M. W. van Doom, Helena C. Van Nieuwenhuysen, Els van Rensburg, Elizabeth J. Vergote, Ignace Verhoef, Senno Vierkant, Robert A. Vijai, Joseph Vitonis, Allison F. von Wachenfeldt, Anna Walsh, Christine Wang, Qin Wang-Gohrke, Shan Wappenschmidt, Barbara Weischer, Maren Weitzel, Jeffrey N. Weltens, Caroline Wentzensen, Nicolas Whittemore, Alice S. Wilkens, Lynne R. Winqvist, Robert Wu, Anna H. Wu, Xifeng Yang, Hannah P. Zaffaroni, Daniela Zamora, M. Pilar Zheng, Wei Ziogas, Argyrios Chenevix-Trench, Georgia Pharoah, Paul D. P. Rookus, Matti A. Hooning, Maartje J. Goode, Ellen L. CA Ovarian Canc Assoc Consortium Breast Canc Assoc Consortium Consortium Modifiers BRCA1 & BRCA2 Australian Ovarian Canc Study Grp Breast Cancer Family Register EMBRACE GEMO Study Collaborators GENICA Network HEBON KConFab Investigators SWE-BRCA TI No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer SO GYNECOLOGIC ONCOLOGY LA English DT Review DE KRAS variant; Breast cancer; Ovarian cancer; Genetic association; Clinical outcome ID GENOME-WIDE ASSOCIATION; MICRORNA-BINDING-SITE; SUSCEPTIBILITY LOCI; RISK; PROSTATE; IDENTIFICATION; POLYMORPHISMS; ENDOMETRIOSIS; WOMEN AB Objective. Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods. Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results. We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 034, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions. rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers. (C) 2015 Elsevier Inc. All rights reserved. C1 [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Box 3079, Durham, NC 27710 USA. [Hollestelle, Antoinette; Martens, John W. M.; Seynaeve, Caroline M.; Hooning, Maartje J.] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands. [van der Baan, Frederieke H.; Knol-Bout, Jacoba P.] Netherlands Canc Inst, Amsterdam, Netherlands. [Johnatty, Sharon E.; Healey, Sue; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Aben, Katja K.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Aben, Katja K.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Agnarsson, Bjarni A.] Landspitali Univ Hosp, Reykjavik, Iceland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Alducci, Elisa] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Antoniou, Antonis C.; Barrowdale, Daniel; Bolla, Manjeet K.; Dennis, Joseph; Easton, Douglas F.; Ellis, Steve D.; Frost, Debra; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Perkins, Jo; Poole, Elizabeth M.; Wang, Qin] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Apicella, Carmel; Baglietto, Laura; Bruinsma, Fiona; Garcia-Closas, Montserrat; Giles, Graham G.; Hopper, John L.; Milne, Roger L.; Orr, Nick; Phillips, Kelly-Anne; Severi, Gianluca] Univ Melbourne, Ctr Epidemiol & Biostat, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynecol & Obstet, Kiel, Germany. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Clin Canc Genet, Houston, TX 77030 USA. [Arver, Brita; von Wachenfeldt, Anna] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Ashworth, Alan; Fletcher, Olivia; Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Breast Canc Res, London SW3 6JB, England. QIMR Berghofer Med Res Inst, Canc Div, Herston, Qld, Australia. Peter MacCallum Canc Inst, 481 Little Lonsdale St, Melbourne, Vic 3000, Australia. [deFazio, Anna] Univ Sydney, Westmead Millennium Inst, Ctr Canc Res, Sydney, NSW 2006, Australia. [Baglietto, Laura; Bruinsma, Fiona; Giles, Graham G.; Milne, Roger L.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Baglietto, Laura; Bruinsma, Fiona; Giles, Graham G.; Severi, Gianluca] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Balleine, Rosemary] Univ Sydney, Westmead Millennium Inst Med Res, Western Sydney & Nepean Blue Mt Local Hlth Dist, Sydney, NSW 2006, Australia. [Bandera, Elisa V.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Bean, Yukie T.; Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Bean, Yukie T.; Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Beckmann, Lars] Inst Qual & Efficiency Hlth Care IQWiG, Cologne, Germany. [Beckmann, Matthias W.; Benitez, Javier; Fasching, Peter A.; Haeberle, Lothar; Schrauder, Michael G.] Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany. [Benitez, Javier] CNIO, Spanish Natl Canc Res Ctr, Ctr Natl Genotipac, Human Canc Genet Program, Madrid, Spain. [Osorio, Ana] CNIO, Spanish Natl Canc Res Ctr, Human Genet Grp, Madrid, Spain. [Benitez, Javier; Osorio, Ana] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Berger, Andreas; Kaulich, Daphne Gschwantler; Singer, Christian F.; Tea, Muy-Kheng] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Berger, Raanan] Sheba Med Ctr, Tel Aviv, Israel. [Beuselinck, Benoit; Neven, Patrick; Weltens, Caroline] Univ Leuven, Univ Hosp Leuven, Multidisciplinary Breast Ctr, Louvain, Belgium. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Bogdanova, Natalia V.; Dork, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bojesen, Anders] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Berge G.; Weischer, Maren] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Berge G.; Weischer, Maren] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Bonanni, Bernardo] Ist Europeo Oncol IEO, Div Canc Prevent & Genet, Milan, Italy. [Brand, Judith S.; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Humphreys, Keith; Li, Jingmei] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud] German Canc Consortium DKTK, Heidelberg, Germany. Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [Brinton, Louise; Chanock, Stephen J.; Figueroa, Jonine; Wentzensen, Nicolas; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Brunet, Joan] IDIBGI Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain. [Bruning, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med German Social Accid In, Bochum, Germany. [Budzilowska, Agnieszka; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta] Maria SklodowskaCurie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Budzilowska, Agnieszka; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Bunker, Clareann H.; Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Muranen, Taru A.; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Buys, Saundra S.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT USA. [Caligo, Maria A.] Univ Pisa, Univ Hosp Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Vic, Australia. [Campbell, Ian; Phillips, Kelly-Anne] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3010, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Carter, Jonathan] Chris OBrien Lifehouse, Gynaecol Oncol, Sydney, NSW, Australia. [Carter, Jonathan] Univ Sydney, Sydney, NSW 2006, Australia. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Claes, Kathleen B. M.] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Collee, J. Margriet; van den Ouweland, Ans M. W.] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Couch, Fergus J.; Guzman, Starr R.; Olson, Janet E.; Vachon, Celine M.; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Couch, Fergus J.; Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN USA. [Cox, Angela; Reed, Malcolm W. R.] Univ Sheffield, Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Cramer, Daniel; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cramer, Daniel; Poppe, Bruce; Terry, Kathryn L.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Cybulski, Cezary] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.] Univ Lyon 1, CNRS UMR5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [de la Hoya, Miguel; Romero, Atocha] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [deFazio, Anna] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Dicks, Ed M.; Dunning, Alison M.; Easton, Douglas F.; Shah, Mitul; Song, Honglin; Tyrer, Jonathan P.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Diez, Orland] Univ Hosp Vail dHebron, Vali Dhebron Inst Oncol VHIO, Oncogenet Lab, Barcelona, Spain. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Lebanon, NH USA. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Basser Res Ctr, Philadelphia, PA 19104 USA. [Dorfling, Cecilia M.; van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa. [Dos Santos Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Dept, London WC1, England. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Klin Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Dumont, Martine; Simard, Jacques; Soucy, Penny] Univ Laval, Ctr Hosp Univ, Quebec Res Ctr, Quebec City, PQ, Canada. [Duran, Mercedes] Univ Valladolid, IBGM UVA, Valladolid, Spain. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton SO9 5NH, Hants, England. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Ehrencrona, Hans] Lund Univ, Dept Clin Genet, Lund, Sweden. [Ejlertsen, Bent] Rigshosp, Copenhagen Univ Hosp, Dept Oncol, DK-2100 Copenhagen, Denmark. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Feliubadalo, Lidia; Lazaro, Conxi] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Fontaine, Annette; Herzog, Josef; Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Fontaine, Annette] New Mexico Canc Ctr, Albuquerque, NM USA. [Fortuzzi, Stefano; Mariette, Frederique; Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol IFOM, Milan, Italy. [Fortuzzi, Stefano; Mariette, Frederique] Cogentech Canc Genet Test Lab, Milan, Italy. [Fostira, Florentia; Konstantopoulou, Irene] Natl Ctr Sci Res Demokritos, Inst Nucl & Radiol Sci & Technol Energy & Safety, Mol Diagnost Lab, Athens, Greece. [Fridley, Brooke L.] Univ Kansas, Ctr Canc, Kansas IDeA Network Biomed Res Excellence Bioinfo, Kansas City, KS USA. [Friebel, Tara] Univ Penn, Philadelphia, PA 19104 USA. [Friedman, Eitan; Laitman, Yael] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Friedman, Eitan; Laitman, Yael] Sheba Med Ctr, Inst Oncol, Tel Hashomer, Israel. [Friel, Grace; Odunsi, Kunle; Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Garber, Judy] Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02115 USA. [Gayther, Simon A.; Haiman, Christopher A.; Henderson, Brian E.; Pearce, Celeste L.; Pike, Malcolm C.; Plisiecka-Halasa, Joanna; Ramus, Susan J.; Schumacher, Fredrick; van den Berg, David; Wu, Anna H.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. UNICANCER Genet Grp, GEMO Study Natl Canc Genet Network, Paris, France. Johanniter Krankenhaus, Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. Univ Bonn, Fac Med, Inst Pathol, Bonn, Germany. Univ Med Ctr Hamburg Eppendorf, Inst Occupat Med & Maritime Med, Hamburg, Germany. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Gentry-Maharaj, Aleksandra; Menon, Usha; Montagna, Marco] UCL, Inst Womens Hlth, Gynaecol Canc Res Ctr, Dept Womens Canc, London, England. [Gerdes, Anne-Marie] Rigshosp, Copenhagen Univ Hosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Glasspool, Rosalind; Paul, James] Beason West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland. [Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Greene, Mark H.; Mai, Phuong L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Grip, Mervi] Univ Oulu, Dept Surg, Oulu Univ Hosp, Oulu, Finland. [Gronwald, Jacek; Huzarski, Tomasz; Jakubowska, Anna; Jaworska, Katarzyna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Guenel, Pascal; Menegaux, Florence; Truong, Therese] INSERM, CESP, Ctr Res Epidemiol & Populat Hlth, U1018,Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Menegaux, Florence; Truong, Therese] Univ Paris 11, UMRS 1018, Villejuif, France. [Halverson, Sandra L.; Long, Jirong; Shrubsole, Martha; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr,Dept Med,Div Epidemiol, Nashville, TN 37212 USA. [Hansen, Thomas V. O.; Nielsen, Finn C.] Rigshosp, Copenhagen Univ Hosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark. [Hartikainen, Jaana M.; Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, SF-70210 Kuopio, Finland. [Hartikainen, Jaana M.; Kataja, Vesa; Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, Sch Med,Inst Clin Med Pathol & Forens Med, Kuopio, Finland. Netherlands Canc Inst, Coordinating Ctr, Hereditary Breast & Ovarian Canc Res Grp Netherla, Amsterdam, Netherlands. [Hein, Alexander] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Ctr Comprehens Canc, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Bogdan, Claus K.; Kjaer, Susanne K.; Lundvall, Lene] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Hogervorst, Frans B. L.; Schmidt, Marjanka K.; Van 't Veer, Laura J.; Verhoef, Senno] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Imyanitov, Evgeny N.] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Janavicius, Ramunas] Vilnius State Univ, Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, State Res Ctr Inst Innovat Med,Dept Mol & Regener, Vilnius, Lithuania. [Jaworska, Katarzyna] Med Univ Warsaw, Postgrad Sch Mol Med, Warsaw, Poland. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kataja, Vesa] Jyvaskyla Cent Hosp, Jyvaskyla, Finland. [Kauff, Noah; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA. Peter MacCallum Canc Ctr, KConFab Kathleen Cuningham Consortium Res Familil, Melbourne, Australia. [Kelemen, Linda E.] Alberta Hlth Serv Cancer Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Oncol, Calgary, AB, Canada. [Kerin, Michael J.; Miller, Nicola] Natl Univ Ireland Univ Coll Galway, Sch Med, Galway, Ireland. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Kristensen, Vessela] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Fac Med, Fac Div Ahus, N-0316 Oslo, Norway. [Lambrechts, Diether; Smeets, Dominiek] Univ Leuven, Dept Oncol, Lab Translat Genet, Louvain, Belgium. [Lambrechts, Diether; Smeets, Dominiek] VIB, VRC, Leuven, Belgium. [Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, Leuven, Belgium. [Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Larson, Melissa C.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Lasa, Adriana; Osorio, Ana] CNIO, Spanish Natl Canc Res Ctr, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Madrid, Spain. [Laurent-Puig, Pierre] Univ Paris, Sorbonne Paris Cite, UMR S775, F-75252 Paris, France. [Le, Nhu D.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Le Marchand, Loic; Lurie, Galina; Wilkens, Lynne R.] Univ Hawaii, Canc Res Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lindor, Noralane] Mayo Clin, Ctr Individualized Med, Scottsdale, AZ USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Margolin, Sara] Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden. [Marme, Frederik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynecol, NL-6525 ED Nijmegen, Netherlands. [Maugard, Christine] CHRU Nouvel Hop Civil, Hop Univ Strasbourg, Lab Diagnost Genet, Strasbourg, France. [Maugard, Christine] CHRU Nouvel Hop Civil, Hop Univ Strasbourg, Serv Oncohematol, Strasbourg, France. [McGuire, Valerie; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA USA. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia. [McNeish, Lain] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Inst Canc Sci, Glasgow, Lanark, Scotland. [Meindi, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Dept Gynecol & Obstet, Div Tumor Genet, D-80290 Munich, Germany. [Menendez, Primitiva] Hosp Monte Naranco, Serv Anat Patol, Oviedo, Spain. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Surg Gynecol & Gynecol Oncol Adults & Adolsc, Szczecin, Poland. [Mensenkamp, Arjen R.; Moysich, Kirsten B.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA USA. [Mueller, Heiko; Offit, Kenneth; Robson, Mark] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.; Plisiecka-Halasa, Joanna] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Oosterwijk, Jan C.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Ottini, Laura] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Pedersen, Inge Sokilde] Aalborg Univ Hosp, Dept Clin Biochem, Sect Mol Diagnost, Aalborg, Denmark. [Peissel, Bernard; Scuvera, Giulietta; Zaffaroni, Daniela] Fdn Ist Ricovero & Cura Carattere Sci, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Permuth-Wey, Jenny; Phelan, Catherine M.; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia. [Piedmonte, Marion; Platte, Radka] NRG Oncol Stat & Data Management Ctr, Buffalo, NY USA. [Poppe, Bruce; Tworoger, Shelley S.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Poppe, Bruce; Tworoger, Shelley S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Oulu Univ Hosp, Dept Clin Genet, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Radice, Paolo] Fdn Ist Ricovero & Cura Carattere Sci, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Rennert, Gad] Technion Israel Inst Technol, Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] Technion Israel Inst Technol, B Rappaport Fac Med, Haifa, Israel. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rodriguez, Gustavo C.] Univ Chicago, NorthShore Univ Hlth Syst, Evanston, IL USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Runnebaum, Ingo] Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Salani, Ritu] Ohio State Univ, Columbus, OH 43210 USA. [Sawyer, Elinor J.] Kings Coll London, Guys & St Thomas NHS Fdn Trust, NIHR Comprehens Biomed Res Ctr, Div Canc Studies, London, England. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, CMMC, Cologne, Germany. [Schoemaker, Minouk J.; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Sinilnikova, Olga M.] Ctr Leon Berard, Hosp Civils Lyon, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France. [Soller, Maria] Univ Lund Hosp, Dept Clin Genet, Univ & Reg Labs, S-22185 Lund, Sweden. [Southey, Melissa C.; Tsimiklis, Helen] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Stoppa-Lyonnet, Dominique] Inst Curie, Dept Tumour Biol, Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM, U830, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 07, Sorbonne Paris Cite, F-75221 Paris 05, France. Lund Univ, Dept Oncol, Lund, Sweden. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton, Surrey, England. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Tischkowitz, Marc] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Canc Genet, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Tomlinson, Ian] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX1 2JD, England. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [Van Asperen, C. J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [van Doom, Helena C.] Erasmus MC Canc Inst, Dept Gynecol, Rotterdam, Netherlands. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Zamora, M. Pilar] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Dept Epidemiol, Irvine, CA 92717 USA. [Rookus, Matti A.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Agnarsson, Bjarni A.] Univ Iceland, Sch Med, Reykjavik, Iceland. [Brauch, Hiltrud] Canc Res Ctr DKFZ, Heidelberg, Germany. [Cramer, Daniel; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. RP Hollestelle, A (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, Box 3079, Durham, NC 27710 USA. EM berch001@mc.duke.edu RI Hein, Alexander/F-6999-2010; Johnatty, Sharon/R-8890-2016; Bruning, Thomas/G-8120-2015; Hartikainen, Jaana/E-6256-2015; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Osorio, Ana/I-4324-2014; Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; Li, Jingmei/I-2904-2012; Menkiszak, Janusz/I-4036-2014; Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012; Feliubadalo, Lidia/G-4577-2016; OI Hein, Alexander/0000-0003-2601-3398; Johnatty, Sharon/0000-0002-7888-1966; Bruning, Thomas/0000-0001-9560-5464; Osorio, Ana/0000-0001-8124-3984; Shrubsole, Martha/0000-0002-5591-7575; Li, Jingmei/0000-0001-8587-7511; Zheng, Wei/0000-0003-1226-070X; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150; Phillips, Kelly-Anne/0000-0002-0475-1771; Teixeira, Manuel/0000-0002-4896-5982; Ramus, Susan/0000-0003-0005-7798; Menon, Usha/0000-0003-3708-1732; Feliubadalo, Lidia/0000-0002-1736-0112; Ehrencrona, Hans/0000-0002-5589-3622; Dunning, Alison Margaret/0000-0001-6651-7166; Muranen, Taru/0000-0002-5895-1808; Brunet, Joan/0000-0003-1945-3512; Kauff, Noah/0000-0001-7242-6156; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Arndt, Volker/0000-0001-9320-8684 FU European Commission [223175 HEALTH-F2-2009-223175]; Ovarian Cancer Research Fund [PPD/RPCI.07]; US National Cancer Institute GAME-ON Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113]; National Health and Medical Research Council; Deutsche Krebshilfe; American Cancer Society [SIOP-06-258-01-COUN]; Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society [SIOP-06-090-06]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2110200]; Canadian Institutes for Health Research; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]; Celma Mastry Ovarian Cancer Foundation the Danish Cancer Society [94-222-52]; ELAN Funds of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Imperial Experimental Cancer Research Centre [C1312/A15589]; Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; L AMP; S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute [K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P3O-CA15083, P5O-CA105009, P50-CA136393]; US Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital "Women's Health Theme"; Royal Marsden Hospital; WorkSafeBC; The US National Cancer Institute [R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA076016, R01-CA080978, R01-CA087538, R01-CA092044]; A US National Cancer Institute [R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R01CA83918, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966] FX The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113.r G.C.-T. and P.M.W. are supported by the National Health and Medical Research Council; P.A.F. is supported by the Deutsche Krebshilfe; B.K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN); K.-A.P. is an Australian National Breast Cancer Foundation Fellow; and A.B. holds the Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society (SIOP-06-090-06). R. Balleine was a Cancer Institute NSW Clinical Research Fellow.r OCAC, in particular, acknowledges D. Bowtell, A. deFazio, D. Gertig, A. Green, P. Parsons, N. Hayward and D. Whiteman (AUS); G. Peuteman, T. Van Brussel and D. Smeets (BEL); U. Eilber and T. Koehler (GER); L. Gacucova (HMO); P. Schtirmann, F. Kramer, W. Zheng, T.-W. Park Simon, K. Beer-Grondke and D. Schmidt (HJO); Sharon Windebank, Christopher Hilker and Jason Vollenweider (MAY); the state cancer registries of AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK OR, PA, RI, SC, TN, TX, VA, WA, and WY (NHS); L. Paddock, M. King, U. Chandran, A. Samoila, and Y. Bensman (NJO); L. Brinton, M. Sherman, A. Hutchinson, N. SzeszeniaDabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL); C. Luccarini, P. Harrington, the SEARCH team and ECRIC (SEA); the Scottish Gynaecological Clinical Trails group and SCOTROCI investigators (SRO); W -H. Chow and Y -T. Gao (SWH); I. Jacobs, M. Widschwendter, E. Wozniak, N. Balogun, A. Ryan and J. Ford (UKO); and Carole Pye (UKR).; Funding of the constituent OCAC studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2110200); the Canadian Institutes for Health Research; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation the Danish Cancer Society (94-222-52); ELAN Funds of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Imperial Experimental Cancer Research Centre (C1312/A15589); the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P3O-CA15083, P5O-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA076016, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R01CA83918, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V.r Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Women's Health Theme" and the Royal Marsden Hospital; and WorkSafeBC. NR 39 TC 2 Z9 3 U1 89 U2 104 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2016 VL 141 IS 2 BP 386 EP 401 DI 10.1016/j.ygyno.2015.04.034 PG 16 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DL0YJ UT WOS:000375358200032 ER PT J AU Morris, BJ Chen, R Donlon, TA Evans, DS Tranah, GJ Parimi, N Ehret, GB Newton-Cheh, C Seto, T Willcox, DC Masaki, K Kamide, K Ryuno, H Oguro, R Nakama, C Kabayama, M Yamamoto, K Sugimoto, K Ikebe, K Masui, Y Arai, Y Ishizaki, T Gondo, Y Rakugi, H Willcox, BJ AF Morris, B. J. Chen, R. Donlon, T. A. Evans, D. S. Tranah, G. J. Parimi, N. Ehret, G. B. Newton-Cheh, C. Seto, T. Willcox, D. C. Masaki, K. Kamide, K. Ryuno, H. Oguro, R. Nakama, C. Kabayama, M. Yamamoto, K. Sugimoto, K. Ikebe, K. Masui, Y. Arai, Y. Ishizaki, T. Gondo, Y. Rakugi, H. Willcox, B. J. TI ASSOCIATION ANALYSIS OF FOXO3 LONGEVITY VARIANTS WITH BLOOD PRESSURE AND ESSENTIAL HYPERTENSION SO HYPERTENSION LA English DT Meeting Abstract CT 37th Annual Scientific Meeting of the High-Blood-Pressure-Research-Council-of-Australia (HBPRCA) CY DEC 02-04, 2015 CL Melbourne, AUSTRALIA SP High Blood Pressure Res Council Australia C1 [Morris, B. J.; Chen, R.; Donlon, T. A.; Masaki, K.; Willcox, B. J.] Kuakini Med Ctr, Honolulu Heart Program, Honolulu Asia Aging Study, Honolulu, HI USA. [Morris, B. J.; Masaki, K.; Willcox, B. J.] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Morris, B. J.] Univ Sydney, Sch Med Sci, Basic & Clin Genom Lab, Sydney, NSW 2006, Australia. [Morris, B. J.] Univ Sydney, Bosch Inst, Sydney, NSW 2006, Australia. [Evans, D. S.; Tranah, G. J.; Parimi, N.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Ehret, G. B.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Newton-Cheh, C.] Harvard Univ, Broad Inst Harvard & MIT, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Seto, T.] Queens Med Ctr, Dept Cardiol, Honolulu, HI USA. [Willcox, D. C.] Okinawa Int Univ, Dept Human Welf, Ginowan, Okinawa, Japan. [Kamide, K.; Ryuno, H.; Kabayama, M.] Osaka Univ, Grad Sch Med, Dept Hlth Sci, Suita, Osaka, Japan. [Kamide, K.; Oguro, R.; Nakama, C.; Yamamoto, K.; Sugimoto, K.; Rakugi, H.] Osaka Univ, Grad Sch Med, Dept Geriatr Med & Nephrol, Suita, Osaka, Japan. [Ikebe, K.] Osaka Univ, Grad Sch Dent, Dep Prosthodont Gerodontol & Oral Rehabil, Suita, Osaka, Japan. [Masui, Y.; Ishizaki, T.] Tokyo Metropolitan Geriatr Hosp, Tokyo 173, Japan. [Masui, Y.; Ishizaki, T.] Inst Gerontol, Tokyo, Japan. [Arai, Y.] Keio Univ, Sch Med Tokyo, Tokyo 108, Japan. [Gondo, Y.] Osaka Univ, Grad Sch Human Sci, Dept Clin Thanatol & Geriatr Behav Sci, Suita, Osaka, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD MAY PY 2016 VL 67 IS 5 BP E13 EP E13 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DK2WZ UT WOS:000374776400023 ER PT J AU Rodriguez, RM Friedman, B Langdorf, MI Baumann, BM Nishijima, DK Hendey, GW Medak, AJ Raja, AS Mower, WR AF Rodriguez, Robert M. Friedman, Benjamin Langdorf, Mark I. Baumann, Brigitte M. Nishijima, Daniel K. Hendey, Gregory W. Medak, Anthony J. Raja, Ali S. Mower, William R. TI Pulmonary contusion in the pan-scan era SO INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED LA English DT Article DE Pulmonary contusion; Chest trauma; Chest CT ID RESPIRATORY-DISTRESS-SYNDROME; CHEST COMPUTED-TOMOGRAPHY; BLUNT TRAUMA PATIENTS; CLINICAL-SIGNIFICANCE; THORACIC INJURY; X-RAY; MULTICENTER; CT AB Background: Although pulmonary contusion (PC) is traditionally considered a major injury requiring intensive monitoring, more frequent detection by chest CT in blunt trauma evaluation may diagnose clinically irrelevant PC. Objectives: We sought to determine (1) the frequency of PC diagnosis by chest CT versus chest X-ray (CXR), (2) the frequency of PC-associated thoracic injuries, and (3) PC patient clinical outcomes (mortality, length of stay [LOS], and need for mechanical ventilation), considering patients with PC seen on chest CT only (SOCTO) and isolated PC (PC without other thoracic injury). Methods: Focusing primarily on patients who had both CXR and chest CT, we conducted a pre-planned analysis of two prospectively enrolled cohorts with the following inclusion criteria: age > 14 years, blunt trauma within 24 h of emergency department presentation, and receiving CXR or chest CT during trauma evaluation. We defined PC and other thoracic injuries according to CT reports and followed patients through their hospital course to determine clinical outcomes. Results: Of 21,382 enrolled subjects, 8661 (40.5%) had both CXR and chest CT and 1012 (11.7%) of these had PC, making it the second most common injury after rib fracture. PC was SOCTO in 739 (73.0%). Most (73.5%) PC patients had other thoracic injury. PC patients had higher admission rates (91.9% versus 61.7%; mean difference 30.2%; 95% confidence interval [CI] 28.1-32.1%) and mortality (4.7% versus 2.0%: mean difference 2.8%; 95% CI 1.6-4.3%) than non-PC patients, but mortality was restricted to patients with other injuries (injury severity scores > 10). Patients with PC SOCTO had low rates of associated mechanical ventilation (4.6%) and patients with isolated PC SOCTO had low mortality (2.6%), comparable to that of patients without PC. Conclusions: PC is commonly diagnosed under current blunt trauma imaging protocols and most PC are SOCTO with other thoracic injury. Given that they are associated with low mortality and uncommon need for mechanical ventilation, isolated PC and PC SOCTO may be of limited clinical significance. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Rodriguez, Robert M.; Friedman, Benjamin] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94110 USA. [Langdorf, Mark I.] Univ Calif Irvine, Dept Emergency Med, Irvine, CA 92717 USA. [Baumann, Brigitte M.] Rowan Univ, Cooper Med Sch, Dept Emergency Med, Glassboro, NJ USA. [Nishijima, Daniel K.] Univ Calif Davis, Dept Emergency Med, Davis, CA USA. [Hendey, Gregory W.] Univ Calif San Francisco, Fresno Med Educ Program, Dept Emergency Med, San Francisco, CA 94110 USA. [Medak, Anthony J.] Univ Calif San Diego, Sch Med, Dept Emergency Med, La Jolla, CA 92093 USA. [Raja, Ali S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Cambridge, MA 02138 USA. [Mower, William R.] Univ Calif Los Angeles, Dept Emergency Med, Los Angeles, CA 90024 USA. RP Rodriguez, RM (reprint author), Univ Calif San Francisco, Sch Med, Dept Emergency Med, San Francisco Gen Hosp, San Francisco, CA 94110 USA. EM Robert.rodriguez@emergency.ucsf.edu OI Hendey, Gregory/0000-0002-0170-8743 FU Centers for Disease Control [RO-1 1 R01/CE001589-01]; University of California Center for Health Quality and Innovation (CHQI) FX Funded by Centers for Disease Control RO-1 1 R01/CE001589-01 and the University of California Center for Health Quality and Innovation (CHQI). NR 29 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-1383 EI 1879-0267 J9 INJURY JI Injury-Int. J. Care Inj. PD MAY PY 2016 VL 47 IS 5 BP 1031 EP 1034 DI 10.1016/j.injury.2015.11.043 PG 4 WC Critical Care Medicine; Emergency Medicine; Orthopedics; Surgery SC General & Internal Medicine; Emergency Medicine; Orthopedics; Surgery GA DK6TA UT WOS:000375057000010 PM 26708426 ER PT J AU Lennerz, JK van der Sloot, KWJ Le, LP Batten, JM Han, JY Fan, KC Siegel, CA Srivastava, A Park, DY Chen, JH Sands, BE Korzenik, JR Odze, RD Dias-Santagata, D Borger, DR Khalili, H Iafrate, AJ Lauwers, GY AF Lennerz, Jochen K. van der Sloot, Kimberley W. J. Le, Long Phi Batten, Julie M. Han, Jae Young Fan, Kenneth C. Siegel, Corey A. Srivastava, Amitabh Park, Do Youn Chen, Jey-Hsin Sands, Bruce E. Korzenik, Joshua R. Odze, Robert D. Dias-Santagata, Dora Borger, Darrell R. Khalili, Hamed Iafrate, A. John Lauwers, Gregory Y. TI Colorectal cancer in Crohn's colitis is comparable to sporadic colorectal cancer SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Crohn's colitis; Colorectal cancer; SNaPshot; Targeted re-sequencing ID INFLAMMATORY-BOWEL-DISEASE; COMPLICATING ULCERATIVE-COLITIS; K-RAS; CARCINOMA; RISK; ADENOCARCINOMA; EXPRESSION; MUTATIONS; DYSPLASIA; FEATURES AB It is now recognized that Crohn's disease (CD), similar to ulcerative colitis (UC), carries an up to 20-fold higher cancer risk, and the development of colorectal carcinoma (CRC) is a major long-term complication. Once CRC is present, molecular profiling is one of the components in selecting appropriate treatment strategies; however, in contrast to UC, genetic alterations in Crohn's colitis-associated CRC are poorly understood. In a series of 227 patients with Crohn's colitis, we identified 33 cases of CRC (similar to 14 %) and performed targeted mutational analysis of BRAF/KRAS/NRAS and determined microsatellite status as well as immunophenotype of the tumors. In the CRC cohort, the median age at time of cancer diagnosis was 58 (range 34-77 vs. 59.5 in sporadic; P = 0.81) and the median CD duration was 29 years (range 6-45). As a group, CRC complicating Crohn's colitis is BRAF (97 %) and NRAS (100 %) wild type and the vast majority is microsatellite stable (94 %); KRAS-mutations were found in six cases (18 %). Stage grouping, anatomic distribution, and overall survival were similar to sporadic CRC; however, long-standing CD (a parts per thousand yen25 years) as well as gastric-immunophenotype (MUC5AC+) was associated with significantly shorter overall survival (P = 0.0029; P = 0.036, respectively). In summary, the clinicopathological and molecular profile of CD-associated CRC is similar to that observed in sporadic CRC. C1 [Lennerz, Jochen K.; Le, Long Phi; Batten, Julie M.; Han, Jae Young; Fan, Kenneth C.; Iafrate, A. John; Lauwers, Gregory Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02116 USA. [van der Sloot, Kimberley W. J.; Dias-Santagata, Dora; Khalili, Hamed] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA 02116 USA. [Han, Jae Young] Univ Texas Houston, MD Anderson Canc Ctr, Sch Hlth Profess, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Siegel, Corey A.] Dartmouth Hitchcock Med Ctr, Dartmouth Hitchcock Inflammatory Bowel Dis Ctr, Lebanon, NH 03766 USA. [Srivastava, Amitabh; Odze, Robert D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Park, Do Youn] Pusan Natl Univ Hosp, Dept Pathol, Busan, South Korea. [Park, Do Youn] Pusan Natl Univ, Sch Med, Busan, South Korea. [Chen, Jey-Hsin] Swedish Med Ctr, CellNetix Pathol & Labs, Seattle, WA USA. [Sands, Bruce E.] Icahn Sch Med Mt Sinai, Dr Henry Janowitz Div Gastroenterol, New York, NY 10029 USA. [Korzenik, Joshua R.] Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy, 75 Francis St, Boston, MA 02115 USA. [Borger, Darrell R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Hematol Oncol, Boston, MA 02116 USA. [Khalili, Hamed] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin & Translat Epidemiol Unit, Boston, MA 02116 USA. RP Lennerz, JK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02116 USA. EM JLennerz@partners.org NR 42 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 EI 1432-1262 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD MAY PY 2016 VL 31 IS 5 BP 973 EP 982 DI 10.1007/s00384-016-2574-x PG 10 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DJ7OX UT WOS:000374401800003 PM 27026089 ER PT J AU Damp, J Givertz, MM Semigran, M Alharethi, R Ewald, G Felker, GM Bozkurt, B Boehmer, J Haythe, J Skopicki, H Hanley-Yanez, K Pisarcik, J Halder, I Gorcsan, J Rana, S Arany, Z Fatt, JD McNamara, DM AF Damp, Julie Givertz, Michael M. Semigran, Marc Alharethi, Rami Ewald, Gregory Felker, G. Michael Bozkurt, Biykem Boehmer, John Haythe, Jennifer Skopicki, Hal Hanley-Yanez, Karen Pisarcik, Jessica Halder, Indrani Gorcsan, John, III Rana, Sarosh Arany, Zoltan Fatt, James D. McNamara, Dennis M. CA IPAC Investigators TI Relaxin-2 and Soluble FM Levels in Peripartum Cardiomyopathy Results of the Multicenter IPAC Study SO JACC-HEART FAILURE LA English DT Article DE cardiomyopathy; heart failure; hormones; pregnancy and post-partum ID ENDOTHELIAL GROWTH-FACTOR; ACUTE HEART-FAILURE; RACIAL-DIFFERENCES; UNITED-STATES; WOMEN; BROMOCRIPTINE; DYSFUNCTION; MECHANISMS; EXPRESSION; PREGNANCY AB OBJECTIVES This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM). BACKGROUND PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology. METHODS In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months. RESULTS Mean age was 30 6 years, with a baseline of LVEF 0.35 +/- 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004). CONCLUSIONS In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955) (C) 2016 by the American College of Cardiology Foundation. C1 [Damp, Julie] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37232 USA. [Givertz, Michael M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Semigran, Marc] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Alharethi, Rami] Intermt Med Ctr, Div Cardiol, Salt Lake City, UT USA. [Ewald, Gregory] Washington Univ, Div Cardiol, St Louis, MO USA. [Felker, G. Michael] Duke Univ, Div Cardiol, Durham, NC USA. [Bozkurt, Biykem] Baylor Coll Med, Sect Cardiovasc Med, Houston, TX 77030 USA. [Boehmer, John] Penn State Hershey Med Ctr, Div Cardiol, Hershey, PA USA. [Haythe, Jennifer] Columbia Univ, Div Cardiol, New York, NY USA. [Skopicki, Hal] Stony Brook Med Ctr, Div Cardiol, Stony Brook, NY USA. [Hanley-Yanez, Karen; Pisarcik, Jessica; Halder, Indrani; Gorcsan, John, III; Fatt, James D.; McNamara, Dennis M.] Univ Pittsburgh, Inst Heart & Vasc, Pittsburgh, PA USA. [Rana, Sarosh] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Arany, Zoltan] Univ Penn, Div Cardiol, Philadelphia, PA 19104 USA. RP Damp, J (reprint author), Vanderbilt Univ, Cardiovasc Med, 1215 21st Ave South,MCE 5th Floor South Tower, Nashville, TN 37232 USA. EM julie.boyd@vanderbilt.edu FU National Heart, Lung, and Blood Institute [RC1HL102429]; Roche Diagnostics; Novartis FX This study was funded by National Heart, Lung, and Blood Institute contract RC1HL102429. Dr. Felker has received grant funding from Roche Diagnostics; and served as a consultant and received grant funding from Novartis. Dr. Skopicki is a site investigator for the Relax study, Novartis; and has received lecture fees from Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this paper. NR 32 TC 4 Z9 4 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD MAY PY 2016 VL 4 IS 5 BP 380 EP 388 DI 10.1016/j.jchf.2016.01.004 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL0UD UT WOS:000375347200008 PM 26970832 ER PT J AU Santos, GM Coffin, P Santos, D Huffaker, S Matheson, T Euren, J DeMartini, A Rowe, C Hahn, JA Vlahov, D Vittinghoff, E Batki, SL AF Santos, Glenn-Milo Coffin, Phillip Santos, Deirdre Huffaker, Shannon Matheson, Tim Euren, Jason DeMartini, Anna Rowe, Christopher Hahn, Judith A. Vlahov, David Vittinghoff, Eric Batki, Steven L. TI Feasibility, Acceptability, and Tolerability of Targeted Naltrexone for Nondependent Methamphetamine-Using and Binge-Drinking Men Who Have Sex with Men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE methamphetamine; alcohol; HIV; men who have sex with men; HIV prevention; pharmacotherapy ID HIV BEHAVIORAL SURVEILLANCE; RANDOMIZED CONTROLLED-TRIAL; MESSENGER-RNA EXPRESSION; MU-OPIOID RECEPTOR; SUBSTANCE USE; GAY MEN; RISK BEHAVIORS; DRUG-USE; AMPHETAMINE DEPENDENCE; TESTING BEHAVIORS AB Background: There are no effective pharmacologic strategies for nondependent methamphetamine (meth)-using and binge-drinking men who have sex with men (MSM) at high-risk for HIV. We sought to determine the feasibility of enrolling and retaining this population in a pharmacologic trial; the acceptability of pharmacotherapy study procedures; and the tolerability of targeted naltrexone versus placebo. Methods: Thirty meth-using and binge-drinking MSM were randomly assigned 1: 1 to 50 mg naltrexone or placebo for 8 weeks for targeted administration (ie, during craving or in anticipation of meth or alcohol use). Substance use counseling and behavioral assessments were conducted every 2 weeks. Medication use was measured using WisePill dispensers. Results: Trial completion was 93%; visit completion rate was 95%. Mean weekly number of medication pills taken was 2.1 and was similar between arms. Participant satisfaction rate was 96%. There were neither serious adverse events nor differences in adverse event rates between arms. In exploratory intention-to-treat analyses, there were no differences in meth use and drinking. Naltrexone participants had greater reductions in serodiscordant receptive anal intercourse [incident rate ratio (IRR) = 0.15; 95% CI = 0.05 to 0.42] and serodiscordant condomless receptive anal intercourse (IRR = 0.11; 95% CI = 0.03 to 0.37), compared with placebo. In subgroup analyses among frequent meth users, naltrexone participants had greater reductions in meth-using days (IRR = 0.78; 95% CI = 0.62 to 0.99). In as-treated analyses, frequent study medication users in the naltrexone arm had greater reductions in binge drinking days (IRR = 0.72; 95% CI = 0.54 to 0.97). Conclusions: Targeted naltrexone is a feasible, acceptable, and tolerable intervention strategy for nondependent meth-using and binge-drinking MSM. Naltrexone was associated with significant sexual risk reductions; and for some individuals, naltrexone was associated with meth and binge-drinking reductions. C1 [Santos, Glenn-Milo; Coffin, Phillip; Santos, Deirdre; Huffaker, Shannon; Matheson, Tim; Euren, Jason; DeMartini, Anna; Rowe, Christopher] San Francisco Dept Publ Hlth, Ctr Publ Hlth, Res Branch, San Francisco, CA USA. [Santos, Glenn-Milo; Vlahov, David] Univ Calif San Francisco, Sch Nursing, Dept Community Hlth Syst, San Francisco, CA 94143 USA. [Coffin, Phillip; Hahn, Judith A.] Univ Calif San Francisco, Sch Med, Div HIV AIDS, San Francisco, CA USA. [Hahn, Judith A.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA USA. [Vlahov, David; Vittinghoff, Eric] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Batki, Steven L.] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Batki, Steven L.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Santos, GM (reprint author), Univ Calif San Francisco, San Francisco Dept Publ Hlth, San Francisco, CA 94107 USA. EM glenn-milo.santos@ucsf.edu FU National Institutes of Drug Abuse (NIDA) [R36DA035109]; [K24AA022586] FX This study was funded by the National Institutes of Drug Abuse (NIDA), grant number R36DA035109. JAH was funded by K24AA022586. NR 83 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAY 1 PY 2016 VL 72 IS 1 BP 21 EP 30 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DK6WY UT WOS:000375067600013 PM 26674372 ER PT J AU Bhattacharya, D Tseng, CH Tate, JP Lo Re, V Gibert, CL Butt, AA Brown, ST Lim, JK Rodriguez-Barradas, MC Rimland, D Kaufman, E Justice, AC Goetz, MB AF Bhattacharya, Debika Tseng, Chi-hong Tate, Janet P. Lo Re, Vincent, III Gibert, Cynthia L. Butt, Adeel A. Brown, Sheldon T. Lim, Joseph K. Rodriguez-Barradas, Maria C. Rimland, David Kaufman, Erica Justice, Amy C. Goetz, Matthew Bidwell TI Isolated Hepatitis B Core Antibody is Associated With Advanced Hepatic Fibrosis in HIV/HCV Infection But Not in HIV Infection Alone SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Letter ID SIMPLE NONINVASIVE INDEX; VIRUS INFECTION; LIVER-DISEASE; COINFECTION; PREVALENCE; COHORT; PREDICT; DNA C1 [Bhattacharya, Debika; Goetz, Matthew Bidwell] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Bhattacharya, Debika; Tseng, Chi-hong; Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Tate, Janet P.; Lim, Joseph K.; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Tate, Janet P.; Lim, Joseph K.; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Lo Re, Vincent, III] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Lo Re, Vincent, III] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gibert, Cynthia L.] Washington DC VA Med Ctr, Washington, DC USA. [Gibert, Cynthia L.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Butt, Adeel A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Brown, Sheldon T.] James J Peters VA Med Ctr, Bronx, NY USA. [Rodriguez-Barradas, Maria C.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Rimland, David] Atlanta VA Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Kaufman, Erica] St Louis Univ, Sch Med, St Louis, MO USA. RP Bhattacharya, D (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.; Bhattacharya, D (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. FU NIAAA NIH HHS [U24 AA020794, U01 AA020790, U10 AA013566]; NIDDK NIH HHS [P30 DK034989] NR 17 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAY 1 PY 2016 VL 72 IS 1 BP E14 EP E17 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DK6WY UT WOS:000375067600005 PM 26829660 ER PT J AU Bateman, BT Choudhry, NK AF Bateman, Brian T. Choudhry, Niteesh K. TI Limiting the Duration of Opioid Prescriptions Balancing Excessive Prescribing and the Effective Treatment of Pain SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID TERM C1 [Bateman, Brian T.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. [Bateman, Brian T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Choudhry, Niteesh K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. [Choudhry, Niteesh K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Healthcare Delivery Sci,Dept Med, Boston, MA 02115 USA. RP Bateman, BT (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. EM bbateman@partners.org NR 8 TC 2 Z9 2 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAY PY 2016 VL 176 IS 5 BP 583 EP 584 DI 10.1001/jamainternmed.2016.0544 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DL0AC UT WOS:000375292500001 PM 27043188 ER PT J AU Au, DH AF Au, David H. TI Screening for Chronic Obstructive Pulmonary Disease D Is the New F SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID COPD C1 [Au, David H.] VA Puget Sound Hlth Care Syst, Ctr Innovat Veteran Centered & Value Driven Care, 1660 S Columbian Way,MS 152, Seattle, WA 98101 USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care Med, 1660 S Columbian Way,MS 152, Seattle, WA 98101 USA. RP Au, DH (reprint author), VA Puget Sound Hlth Care Syst, Ctr Innovat Veteran Centered & Value Driven Care, 1660 S Columbian Way,MS 152, Seattle, WA 98101 USA.; Au, DH (reprint author), Univ Washington, Div Pulm & Crit Care Med, 1660 S Columbian Way,MS 152, Seattle, WA 98101 USA. EM dau@uw.edu NR 6 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAY PY 2016 VL 176 IS 5 BP 601 EP 602 DI 10.1001/jamainternmed.2016.1115 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DL0AC UT WOS:000375292500011 PM 27046674 ER PT J AU Keyhani, S Cheng, EM Naseri, A Halm, EA Williams, LS Johanning, J Madden, E Rofagha, S Woodbridge, A Abraham, A Ahn, R Saba, S Eilkhani, E Hebert, P Bravata, DM AF Keyhani, Salomeh Cheng, Eric M. Naseri, Ayman Halm, Ethan A. Williams, Linda S. Johanning, Jason Madden, Erin Rofagha, Soraya Woodbridge, Alexandra Abraham, Ann Ahn, Rosa Saba, Susan Eilkhani, Elnaz Hebert, Paul Bravata, Dawn M. TI Common Reasons That Asymptomatic Patients Who Are 65 Years and Older Receive Carotid Imaging SO JAMA INTERNAL MEDICINE LA English DT Article ID ENDARTERECTOMY; STROKE; STENOSIS; TRIAL; APPROPRIATENESS; PREVENTION AB IMPORTANCE National guidelines do not agree on the role of carotid screening in asymptomatic patients (ie, patients who have not had a stroke or transient ischemic attack). Recently, several physician organizations participating in the Choosing Wisely campaign have identified carotid imaging in selected asymptomatic populations as being of low value. However, the majority of patients who are evaluated for carotid stenosis and subsequently revascularized are asymptomatic. OBJECTIVE To better understand why asymptomatic patients who undergo revascularization receive initial carotid imaging. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 4127 Veterans Health Administration patients 65 years and older undergoing carotid revascularization for asymptomatic carotid stenosis between 2005 and 2009. MAIN OUTCOMES AND MEASURES Indications for carotid ultrasounds were extracted using trained abstractors. Frequency of indications and appropriateness of initial carotid ultrasound imaging for patients within each rating category after the intervention were reported. RESULTS The mean (SD) age of this cohort of 4127 patients was 73.6 (5.9) years; 4014 (98.8%) were male. Overall, there were 5226 indications for 4063 carotid ultrasounds. The most common indications listed were carotid bruit (1578 [30.2% of indications]) and follow-up for carotid disease (stenosis/history of carotid disease) in patients who had previously documented carotid stenosis (1087 [20.8% of indications]). Multiple vascular risk factors were the next most common indication listed. Rates of appropriate, uncertain, and inappropriate imaging were 5.4%(227 indications), 83.4%(3387 indications), and 11.3%(458 indications), respectively. Among the most common inappropriate indications were dizziness/vertigo and syncope. Among the 4063 patients, 3373 (83.0%) received a carotid endarterectomy. Overall, 663 procedures were performed in patients 80 years and older. CONCLUSIONS AND RELEVANCE Carotid bruit and follow-up for carotid disease accounted for approximately half of all indications provided by physicians for carotid testing. Strong consideration should be given to improving the evidence base around carotid testing, especially around monitoring stenosis over long periods and evaluating carotid bruits. Targeting carotid ultrasound ordering with decision support tools may also be an important step in reducing use of low-value imaging. C1 [Keyhani, Salomeh; Naseri, Ayman; Madden, Erin; Rofagha, Soraya; Woodbridge, Alexandra; Abraham, Ann; Ahn, Rosa; Saba, Susan; Eilkhani, Elnaz] San Francisco VA Med Ctr, San Francisco, CA USA. [Keyhani, Salomeh; Rofagha, Soraya] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Cheng, Eric M.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA USA. [Cheng, Eric M.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Naseri, Ayman] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Williams, Linda S.; Bravata, Dawn M.] Richard L Roudebush Vet Affairs Med Ctr, Ctr Excellence Implementing Evidence Based Practi, Vet Hlth Adm, Hlth Serv Res & Dev Serv, 1481 W 10th St, Indianapolis, IN 46202 USA. [Williams, Linda S.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Bravata, Dawn M.] Indiana Univ Sch Med, Dept Internal Med, Indianapolis, IN 46202 USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Johanning, Jason] Univ Nebraska Med Ctr, Dept Surg, Omaha, NE USA. [Johanning, Jason] Omaha Vet Affairs Nebraska Western Iowa Hlth Care, Omaha, NE USA. [Hebert, Paul] Puget Sound Vet Affairs Med Ctr, Seattle, WA USA. [Hebert, Paul] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. RP Keyhani, S (reprint author), 4150 Clement St, San Francisco, CA 94121 USA. EM salomeh.keyhani@ucsf.edu FU National Institutes of Health/National Heart, Lung, and Blood Institute [RO1 HL114563-01A1] FX The project reported was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant RO1 HL114563-01A1. NR 16 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAY PY 2016 VL 176 IS 5 BP 626 EP 633 DI 10.1001/jamainternmed.2016.0678 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DL0AC UT WOS:000375292500016 PM 27088224 ER PT J AU Schonberg, MA Smith, AK AF Schonberg, Mara A. Smith, Alexander K. TI Discussing Long-term Prognosis in Primary Care Hard but Necessary SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID SURVIVAL; ADULTS C1 [Schonberg, Mara A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Div Gen Med & Primary Care, Boston, MA 02215 USA. [Smith, Alexander K.] Univ Calif San Francisco, Dept Med, Div Geriatr, 4150 Clement St,181G, San Francisco, CA 94121 USA. [Smith, Alexander K.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Smith, AK (reprint author), Univ Calif San Francisco, Dept Med, Div Geriatr, 4150 Clement St,181G, San Francisco, CA 94121 USA. EM aksmith@ucsf.edu FU NCI NIH HHS [R01 CA181357]; NIA NIH HHS [K23 AG040772] NR 10 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAY PY 2016 VL 176 IS 5 BP 678 EP 680 DI 10.1001/jamainternmed.2016.0972 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DL0AC UT WOS:000375292500026 PM 27064576 ER PT J AU Weintraub, D Chiang, C Kim, HM Wilkinson, J Marras, C Stanislawski, B Mamikonyan, E Kales, HC AF Weintraub, Daniel Chiang, Claire Kim, Hyungjin Myra Wilkinson, Jayne Marras, Connie Stanislawski, Barbara Mamikonyan, Eugenia Kales, Helen C. TI Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease SO JAMA NEUROLOGY LA English DT Article ID OLDER-ADULTS; LEWY BODIES; DEMENTIA; MANAGEMENT; SYMPTOMS; PSYCHOSIS; MEDICATIONS; PATTERNS; DISORDER; FRACTURE AB IMPORTANCE As many as 60% of patients with Parkinson disease (PD) experience psychosis, 80% develop dementia, and the use of antipsychotics (APs) in the population with PD is common. The use of APs by patients with dementia in the general population is associated with increased mortality, but whether this risk extends to patients with PD remains unknown. OBJECTIVE To determine whether AP use in patients with PD is associated with increased mortality. DESIGN, SETTING, AND PARTICIPANTS This retrospective matched-cohort study used data from a Veterans Health Administration database from fiscal years 1999 to 2010 to examine the risk associated with AP use in a cohort of patients with idiopathic PD and recent stable physical health. The rates of 180-day mortality were compared in 7877 patients initiating AP therapy and 7877 patients who did not initiate AP therapy (matched for age +/- 2.5 years, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new nonpsychiatric medications). Data were analyzed from October 19, 2012, to September 21, 2015. MAIN OUTCOMES AND MEASURES Mortality rates at 180 days in those patients who initiated AP therapy compared with matched patients who did not use APs. Cox proportional hazards regression models were used with intent-to-treat (ITT) and exposure-only analyses. RESULTS The study population included 7877 matched pairs of patients with PD (65 women [0.8%] and 7812 men [99.2%] in each cohort; mean [SD] age, 76.3 [7.7] years for those who initiated AP therapy and 76.4 [7.6] years for those who did not). Antipsychotic use was associated with more than twice the hazard ratio (HR) of death compared with nonuse (ITT HR, 2.35; 95% CI, 2.08-2.66; P < .001). The HR was significantly higher for patients who used typical vs atypical APs (ITT HR, 1.54; 95% CI, 1.24-1.91; P < .001). Among the atypical APs used, HRs relative to nonuse of APs in descending order were 2.79 (95% CI, 1.97-3.96) for olanzapine, 2.46 (95% CI, 1.94-3.12) for risperidone, and 2.16 (95% CI, 1.88-2.48) for quetiapine fumarate. CONCLUSIONS AND RELEVANCE Use of APs is associated with a significantly increased mortality risk in patients with PD, after adjusting for measurable confounders. This finding highlights the need for cautious use of APs in patients with PD. Future studies should examine the role of nonpharmacologic strategies in managing psychosis in PD. In addition, new pharmacologic treatments that do not increase mortality in patients with neurodegenerative diseases need to be developed. C1 [Weintraub, Daniel; Wilkinson, Jayne] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Weintraub, Daniel; Wilkinson, Jayne; Mamikonyan, Eugenia] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19014 USA. [Weintraub, Daniel; Wilkinson, Jayne; Mamikonyan, Eugenia] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19014 USA. [Chiang, Claire; Kim, Hyungjin Myra; Stanislawski, Barbara; Kales, Helen C.] US Dept Vet Affairs, Hlth Serv Res & Dev, Ctr Clin Management Res, Ann Arbor, MI USA. [Kim, Hyungjin Myra] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. [Marras, Connie] Univ Toronto, Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Morton & Gloria Shulman Movement Disorder Ctr, Toronto, ON M5T 2S8, Canada. [Kales, Helen C.] Vet Affairs Ann Arbor Healthcare Syst, Geriatr Res Educ & Clin Ctr, Ann Arbor, MI USA. [Kales, Helen C.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Weintraub, D (reprint author), Univ Penn, Perelman Sch Med, 3615 Chestnut St,Ste 330, Philadelphia, PA 19014 USA. EM daniel.weintraub@uphs.upenn.edu FU Veterans Health Administration [IIR 12-144-2]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center [SDR 02-237, 98-004] FX This study was supported by merit review award IIR 12-144-2 from the Veterans Health Administration. Support for the Veterans Administration and Centers for Medicare & Medicaid data is provided by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (project SDR 02-237 and 98-004). NR 34 TC 14 Z9 14 U1 4 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAY PY 2016 VL 73 IS 5 BP 535 EP 541 DI 10.1001/jamaneurol.2016.0031 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DL2JW UT WOS:000375461900015 PM 26999262 ER PT J AU Koenig, MK Emrick, L Karaa, A Korson, M Scaglia, F Parikh, S Goldstein, A AF Koenig, Mary Kay Emrick, Lisa Karaa, Amel Korson, Mark Scaglia, Fernando Parikh, Sumit Goldstein, Amy TI Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes SO JAMA NEUROLOGY LA English DT Review ID NITRIC-OXIDE; ARGININE SUPPLEMENTATION; CLINICAL-FEATURES; MELAS SYNDROME; MUTATION; DISEASE; GENE; ENCEPHALOPATHY; EPIDEMIOLOGY; MYOPATHY AB IMPORTANCE Strokelike episodes are a cardinal feature of several mitochondrial syndromes, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). Recent advances in the understanding of the pathophysiologic mechanisms of strokelike episodes in MELAS have led to improved treatment options. OBSERVATIONS Current understanding of the cause of strokelike episodes in MELAS and present recommendations to assist in the identification and treatment of patients with MELAS who present with stroke are presented. Mounting evidence points toward a benefit of the nitric oxide precursors, arginine, to both prevent and reduce the severity of strokes in patients with MELAS. CONCLUSIONS AND RELEVANCE Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, urgent administration of nitric oxide precursors in patients with MELAS ameliorates the clinical symptoms associated with strokelike episodes. C1 [Koenig, Mary Kay] Univ Texas Houston, Med Sch Houston, Dept Pediat, Houston, TX 77030 USA. [Koenig, Mary Kay] Univ Texas Houston, Med Sch Houston, Dept Neurol, Houston, TX 77030 USA. [Emrick, Lisa] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Emrick, Lisa; Scaglia, Fernando] Texas Childrens Hosp, Houston, TX 77030 USA. [Karaa, Amel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Genet & Metab, Boston, MA USA. [Korson, Mark] Genet Metab Ctr Educ, Salem, MA USA. [Scaglia, Fernando] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Parikh, Sumit] Cleveland Clin, Inst Neurosci, Ctr Pediat Neurol, Cleveland, OH 44106 USA. [Goldstein, Amy] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA USA. RP Koenig, MK (reprint author), Univ Texas Houston, Med Sch Houston, 6410 Fannin St,UTPB 732, Houston, TX 77030 USA. EM Mary.K.Koenig@uth.tmc.edu NR 24 TC 2 Z9 2 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAY PY 2016 VL 73 IS 5 BP 591 EP 594 DI 10.1001/jamaneurol.2015.5072 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA DL2JW UT WOS:000375461900022 PM 26954033 ER PT J AU Yehuda, R Hoge, CW AF Yehuda, Rachel Hoge, Charles W. TI The Meaning of Evidence-Based Treatments for Veterans With Posttraumatic Stress Disorder SO JAMA PSYCHIATRY LA English DT Editorial Material ID PTSD C1 [Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Dept Psychiat, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. [Yehuda, Rachel] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Hoge, Charles W.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Yehuda, R (reprint author), James J Peters Vet Affairs Med Ctr, Dept Psychiat, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM rachel.yehuda@mssm.edu NR 7 TC 7 Z9 7 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAY PY 2016 VL 73 IS 5 BP 433 EP 434 DI 10.1001/jamapsychiatry.2015.2878 PG 2 WC Psychiatry SC Psychiatry GA DL2KD UT WOS:000375462600002 PM 26886229 ER PT J AU Sherva, R Wang, Q Kranzler, H Zhao, HY Koesterer, R Herman, A Farrer, LA Gelernter, J AF Sherva, Richard Wang, Qian Kranzler, Henry Zhao, Hongyu Koesterer, Ryan Herman, Aryeh Farrer, Lindsay A. Gelernter, Joel TI Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks SO JAMA PSYCHIATRY LA English DT Article ID PSYCHIATRIC-DISORDERS; NICOTINE DEPENDENCE; EUROPEAN-AMERICANS; AFRICAN-AMERICANS; LINKAGE ANALYSIS; DRUG-USE; SCHIZOPHRENIA; LOCI; SUSCEPTIBILITY; IDENTIFICATION AB IMPORTANCE Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated. OBJECTIVE To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015. MAIN OUTCOMES AND MEASURES Criterion count for DSM-IV CAD. RESULTS Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (beta = 0.54, P = 4.32 x 10(-10) for the meta-analysis) in novel antisense transcript RP11-206M11.7; rs146091982 (beta = 0.54, P = 1.33 x 10(-9) for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (beta = 0.29, P = 2.13 x 10(-8) for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development. CONCLUSIONS AND RELEVANCE These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia. C1 [Sherva, Richard; Koesterer, Ryan; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Sect Biomed Genet, Boston, MA 02118 USA. [Wang, Qian; Zhao, Hongyu] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA. [Kranzler, Henry] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kranzler, Henry] Philadelphia VA Med Ctr, Vet Affairs VA Stars & Stripes Healthcare Network, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Zhao, Hongyu] Yale Univ, Sch Med, Dept Genet, West Haven, CT 06516 USA. [Zhao, Hongyu] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Zhao, Hongyu; Gelernter, Joel] VA Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Herman, Aryeh; Gelernter, Joel] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Gelernter, Joel] Yale Univ, Sch Med, VA Connecticut Healthcare Ctr, Dept Psychiat, West Haven, CT 06516 USA. [Gelernter, Joel] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. RP Gelernter, J (reprint author), Yale Univ, Sch Med, Vet Affairs Connecticut Healthcare Ctr, Dept Psychiat, 116A2,950 Campbell Ave, West Haven, CT 06516 USA. EM joel.gelernter@yale.edu RI Wang, Qian/Q-4664-2016 OI Wang, Qian/0000-0002-5615-4506 FU National Institutes of Health (NIH) [RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535]; Veterans Affairs Connecticut Healthcare Center; Philadelphia Veterans Affairs Mental Illness Research, Education and Clinical Center; NIH Genes, Environment and Health Initiative [U01 HG004422, U01HG004438]; Gene Environment Association Studies under the Genes, Environment and Health Initiative; National Institute on Alcohol Abuse and Alcoholism [HHSN268200782096C]; National Institute on Drug Abuse, NIH; NIH [HHSN268200782096C, U10 AA008401, P01 CA089392, R01 DA013423, HHSN268201100011I] FX This study was supported by grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, and R01 AA017535 from the National Institutes of Health (NIH), the Veterans Affairs Connecticut Healthcare Center, and the Philadelphia Veterans Affairs Mental Illness Research, Education and Clinical Center. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided by grant U01 HG004422 from the NIH Genes, Environment and Health Initiative. SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies under the Genes, Environment and Health Initiative. The portion of the genotyping that was performed at the Johns Hopkins University Center for Inherited Disease Research was supported by grant U01HG004438 from the NIH Genes, Environment and Health Initiative, and by contract HHSN268200782096C (High Throughput Genotyping for Studying the Genetic Contributions to Human Disease) from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, NIH. Support for collection of datasets and samples was provided by grant U10 AA008401 (Collaborative Study on the Genetics of Alcoholism), grant P01 CA089392 (Collaborative Genetic Study of Nicotine Dependence), and grant R01 DA013423 (Family Study of Cocaine Dependence) from the NIH. The International Consortium on the Genetics of Heroin Dependence (principal investigator, Elliot Nelson, MD) was funded by HHSN268200782096C (NIH contract: High Throughput Genotyping for Studying the Genetic Contributions to Human Disease) and HHSN268201100011I (NIH contract: High Throughput Genotyping for Studying the Genetic Contributions to Human Disease). NR 50 TC 11 Z9 11 U1 3 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAY PY 2016 VL 73 IS 5 BP 472 EP 480 DI 10.1001/jamapsychiatry.2016.0036 PG 9 WC Psychiatry SC Psychiatry GA DL2KD UT WOS:000375462600012 PM 27028160 ER PT J AU Kaup, AR Byers, AL Falvey, C Simonsick, EM Satterfield, S Ayonayon, HN Smagula, SF Rubin, SM Yaffe, K AF Kaup, Allison R. Byers, Amy L. Falvey, Cherie Simonsick, Eleanor M. Satterfield, Suzanne Ayonayon, Hilsa N. Smagula, Stephen F. Rubin, Susan M. Yaffe, Kristine TI Trajectories of Depressive Symptoms in Older Adults and Risk of Dementia SO JAMA PSYCHIATRY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; LATE-LIFE DEPRESSION; ALZHEIMERS-DISEASE; BODY-COMPOSITION; PRIMARY-CARE; HEALTH ABC; DECLINE; WOMEN; ASSOCIATION; PREDICTORS AB IMPORTANCE Depression has been identified as a risk factor for dementia. However, most studies have measured depressive symptoms at only one time point, and older adults may show different patterns of depressive symptoms over time. OBJECTIVE To investigate the association between trajectories of depressive symptoms and risk of dementia in older adults. DESIGN, SETTING, AND PARTICIPANTS This was a prospective cohort investigation of black and white community-dwelling older adults in the Health, Aging, and Body Composition study. Participants were enrolled between May 1997 and June 1998 and followed up through 2001-2002. The dates of this analysis were September 2014 to December 2015. The setting was community research centers in Memphis, Tennessee, and Pittsburgh, Pennsylvania. Trajectories of depressive symptoms were assessed from baseline to year 5. Symptoms were measured with the Center for Epidemiologic Studies Depression Scale Short Form, and trajectories were calculated using latent class growth curve analysis. MAIN OUTCOMES AND MEASURES Incident dementia through year 11, determined by dementia medication use, hospital records, or significant cognitive decline (>= 1.5 SD race-specific decline on the Modified Mini-Mental State Examination). We examined the association between depressive symptom trajectories and dementia incidence using Cox proportional hazards regression models adjusted for demographics, health factors that differed between groups, and cognition during the depressive symptom assessment period (baseline to year 5). RESULTS The analytic cohort included 2488 black and white older adults with repeated depressive symptom assessments from baseline to year 5 who were free of dementia throughout that period. Their mean (SD) age at baseline was 74.0 (2.8) years, and 53.1% (n = 1322) were female. The following 3 depressive symptom trajectories were identified: consistently minimal symptoms (62.0% [n = 1542] of participants), moderate and increasing symptoms (32.2%[n = 801] of participants), and high and increasing symptoms (5.8% [n = 145] of participants). Compared with the consistently minimal trajectory, having a high and increasing depressive symptom trajectory was associated with significantly increased risk of dementia (fully adjusted hazard ratio, 1.94; 95% CI, 1.30-2.90), while the moderate and increasing trajectory was not associated with risk of dementia after full adjustment. Sensitivity analyses indicated that the high and increasing trajectory was associated with dementia incidence, while depressive symptoms at individual time points were not. CONCLUSIONS AND RELEVANCE Older adults with a longitudinal pattern of high and increasing depressive symptoms are at high risk for dementia. Individuals' trajectory of depressive symptoms may inform dementia risk more accurately than one-time assessment of depressive symptoms. C1 [Kaup, Allison R.; Byers, Amy L.] San Francisco VA Med Ctr, Res Serv, 4150 Clement St,Mail Code 116H, San Francisco, CA 94121 USA. [Kaup, Allison R.; Byers, Amy L.; Falvey, Cherie; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Ayonayon, Hilsa N.; Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Smagula, Stephen F.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 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 94121 USA. RP Kaup, AR (reprint author), San Francisco VA Med Ctr, Res Serv, 4150 Clement St,Mail Code 116H, San Francisco, CA 94121 USA. EM allison.kaup@ucsf.edu FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24AG031155]; National Institute for Nursing Research [R01-NR012459]; Intramural Research Program of the National Institute on Aging; US Department of Veterans Affairs, Rehabilitation Research and Development Service [1IK2RX001629]; National Institute of Mental Health [T32 MH019986]; Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment; Medical Research Service of the San Francisco Veterans Affairs Medical Center; Department of Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center FX This research was supported by contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging; by grant R01-AG028050 from the National Institute on Aging; by grant R01-NR012459 from the National Institute for Nursing Research; and in part by the Intramural Research Program of the National Institute on Aging. The research described herein was also supported in part by Career Development Award 1IK2RX001629 from the US Department of Veterans Affairs, Rehabilitation Research and Development Service (Dr Kaup); by research training grant T32 MH019986 from the National Institute of Mental Health (Dr Smagula); by grant K24AG031155 from the National Institute on Aging (Dr Yaffe); and by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the San Francisco Veterans Affairs Medical Center, and the Department of Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center. NR 35 TC 5 Z9 5 U1 3 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAY PY 2016 VL 73 IS 5 BP 525 EP 531 DI 10.1001/jamapsychiatry.2016.0004 PG 7 WC Psychiatry SC Psychiatry GA DL2KD UT WOS:000375462600018 PM 26982217 ER PT J AU Chabner, BA AF Chabner, Bruce A. TI NCI-60 Cell Line Screening: A Radical Departure in Its Time SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID NATIONAL-CANCER-INSTITUTE; ANTICANCER DRUG SCREEN; SYSTEMS PHARMACOLOGY; LUNG-CANCER; INHIBITION; DISCOVERY; TUMORS; PANEL AB The year 2015 marked the 30th anniversary of National Cancer Institute's (NCI's) initial effort to establish a human cell line panel as the basis for discovering new cancer drugs. At its inception, the NCI-60 panel was a controversial departure, born of frustration with previous efforts that employed murine tumors and grounded in the hope that the biology of human tumors was diverse and somehow quite different than the murine leukemia used for the previous 30 years. And while the NCI-60 has not revolutionized cancer drug discovery in terms of the new drugs that resulted, it represents a turning point in the philosophy and practice of cancer drug research. C1 [Chabner, Bruce A.] Massachusetts Gen Hosp, Ctr Canc, 10 North Grave St,Lawrence House 214, Boston, MA 02114 USA. RP Chabner, BA (reprint author), Massachusetts Gen Hosp, Ctr Canc, 10 North Grave St,Lawrence House 214, Boston, MA 02114 USA. EM bchabner@partners.org 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 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2016 VL 108 IS 5 AR djv388 DI 10.1093/jnci/djv388 PG 7 WC Oncology SC Oncology GA DL1PQ UT WOS:000375404600005 ER PT J AU Tucker-Seeley, RD Yabroff, KR AF Tucker-Seeley, Reginald D. Yabroff, K. Robin TI Minimizing the "Financial Toxicity" Associated With Cancer Care: Advancing the Research Agenda SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BREAST-CANCER; OLDER-ADULTS; HARDSHIP; HEALTH; CHEMOTHERAPY; EXPERIENCE; MORTALITY; SURVIVORS; STRESS; STRAIN C1 [Tucker-Seeley, Reginald D.] Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW743, Boston, MA 02115 USA. [Tucker-Seeley, Reginald D.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Tucker-Seeley, RD (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW743, Boston, MA 02115 USA. EM retucker@hsph.harvard.edu NR 25 TC 1 Z9 1 U1 3 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2016 VL 108 IS 5 AR djv410 DI 10.1093/jnci/djv410 PG 3 WC Oncology SC Oncology GA DL1PQ UT WOS:000375404600014 ER PT J AU Rhee, SH Friedman, NP Corley, RP Hewitt, JK Hink, LK Johnson, DP Watts, AKS Young, SE Robinson, J Waldman, ID Zahn-Waxler, C AF Rhee, Soo Hyun Friedman, Naomi P. Corley, Robin P. Hewitt, John K. Hink, Laura K. Johnson, Daniel P. Watts, Ashley K. Smith Young, Susan E. Robinson, JoAnn Waldman, Irwin D. Zahn-Waxler, Carolyn TI An Examination of the Developmental Propensity Model of Conduct Problems SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE conduct problems; antisocial behavior; development; antisocial propensity; etiology ID COLORADO TWIN REGISTRY; ANTISOCIAL-BEHAVIOR; EARLY-CHILDHOOD; ENVIRONMENTAL-INFLUENCES; ADOLESCENT DISPOSITIONS; LONGITUDINAL TWIN; FIT INDEXES; TEMPERAMENT; PERSONALITY; CHILDREN AB The present study tested specific hypotheses advanced by the developmental propensity model of the etiology of conduct problems in the Colorado Longitudinal Twin Study, a prospective, longitudinal, genetically informative sample. High negative emotionality, low behavioral inhibition, low concern and high disregard for others, and low cognitive ability assessed during toddlerhood (age 14 to 36 months) were examined as predictors of conduct problems in later childhood and adolescence (age 4 to 17 years). Each hypothesized antisocial propensity dimension predicted conduct problems, but some predictions may be context specific or due to method covariance. The most robust predictors were observed disregard for others (i.e., responding to others' distress with active, negative responses such as anger and hostility), general cognitive ability, and language ability, which were associated with conduct problems reported by parents, teachers, and adolescents, and change in observed negative emotionality (i.e., frustration tolerance), which was associated with conduct problems reported by teachers and adolescents. Furthermore, associations between the most robust early predictors and later conduct problems were influenced by the shared environment rather than genes. We conclude that shared environmental influences that promote disregard for others and detract from cognitive and language development during toddlerhood also predispose individuals to conduct problems in later childhood and adolescence. The identification of those shared environmental influences common to early antisocial propensity and later conduct problems is an important future direction, and additional developmental behavior genetic studies examining the interaction between children's characteristics and socializing influences on conduct problems are needed. C1 [Rhee, Soo Hyun; Friedman, Naomi P.; Hewitt, John K.; Hink, Laura K.; Johnson, Daniel P.; Watts, Ashley K. Smith] Univ Colorado, Dept Psychol & Neurosci, Campus Box 345, Boulder, CO 80309 USA. [Rhee, Soo Hyun; Friedman, Naomi P.; Corley, Robin P.; Hewitt, John K.; Hink, Laura K.; Johnson, Daniel P.; Watts, Ashley K. Smith] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Young, Susan E.] Univ Colorado Denver, Div Substance Dependence, Denver, CO USA. [Robinson, JoAnn] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT USA. [Waldman, Irwin D.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Zahn-Waxler, Carolyn] Univ Wisconsin, Madison, WI 53706 USA. [Johnson, Daniel P.] VA Boston Hlth Care Syst, Boston, MA USA. [Watts, Ashley K. Smith] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Providence, RI 02912 USA. RP Rhee, SH (reprint author), Univ Colorado, Dept Psychol & Neurosci, Campus Box 345, Boulder, CO 80309 USA. EM soo.rhee@colorado.edu FU MacArthur Foundation; Fetzer Foundation; National Institutes of Health [MH016880, HD010333, HD050346, DA011015, AG046938] FX This study was supported by the MacArthur Foundation, the Fetzer Foundation, and National Institutes of Health Grants MH016880, HD010333, HD050346, DA011015, and AG046938. We thank Benjamin Lahey, Corinne Gunn, Sally Ann Rhea, and the participants. Preliminary results of this study were presented at the annual meeting of the Behavior Genetics Association on June 25, 2012 in Edinburgh, Scotland. NR 79 TC 0 Z9 0 U1 10 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X EI 1939-1846 J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD MAY PY 2016 VL 125 IS 4 BP 550 EP 564 DI 10.1037/abn0000128 PG 15 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA DK8ZJ UT WOS:000375218300009 PM 26653135 ER PT J AU Horan, WP Wynn, JK Hajcak, G Altshuler, L Green, MF AF Horan, William P. Wynn, Jonathan K. Hajcak, Greg Altshuler, Lori Green, Michael F. TI Distinct Patterns of Dysfunctional Appetitive and Aversive Motivation in Bipolar Disorder Versus Schizophrenia: An Event-Related Potential Study SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE schizophrenia; bipolar disorder; event-related potentials; psychological distance; motivation ID BEHAVIORAL ACTIVATION SYSTEM; RATING-SCALE; EMOTIONAL PICTURES; CORTICAL ACTIVITY; NEGATIVE EMOTION; REWARD; ANTICIPATION; IMPULSIVITY; DEPRESSION; SPECTRUM AB Schizophrenia and bipolar disorder are associated with different clinical profiles of disturbances in motivation, yet few studies have compared the neurophysiological correlates of such disturbances. Outpatients with schizophrenia (n = 34), or bipolar disorder I (n = 33), and healthy controls (n = 31) completed a task in which the late positive potential (LPP), an index of motivated attention, was assessed along motivational gradients determined by apparent distance from potential rewards or punishments. Sequences of cues signaling possible monetary gains or losses appeared to loom progressively closer to the viewer; a reaction time (RT) task after the final cue determined the outcome. Controls showed the expected pattern with LPPs for appetitive and aversive cues that were initially elevated, smaller during intermediate positions, and escalated just prior to the RT task. The clinical groups showed different patterns in the final positions just prior to the RT task: the bipolar group's LPPs to both types of cues peaked relatively early during looming sequences and subsequently decreased, whereas the schizophrenia group showed relatively small LPP escalations, particularly for aversive cues. These distinct patterns suggest that the temporal unfolding of attentional resource allocation for motivationally significant events may qualitatively differ between these disorders. C1 [Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat, MIRECC 210A,Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90024 USA. [Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY USA. [Altshuler, Lori] Univ Calif Los Angeles, Los Angeles, CA USA. RP Horan, WP (reprint author), Univ Calif Los Angeles, Dept Psychiat, MIRECC 210A,Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90024 USA.; Horan, WP (reprint author), VA Greater Los Angeles Healthcare Syst, MIRECC 210A,Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM horan@ucla.edu FU National Institute of Mental Health [MH091468, MH065707, MH43292]; Amgen; Forum FX Support for this study came from a National Institute of Mental Health Grants MH091468 (William P. Horan) and MH065707 and MH43292 (Michael F. Green). We thank Amanda Bender, Michelle Dolinsky, Crystal Gibson, Cory Tripp, and Katherine Weiner for assistance in data collection. Michael F. Green has been a consultant to AbbVie, DSP, Forum, and Takeda, and he is on the scientific advisory board of Mnemosyne. He has received research funds from Amgen and Forum. The rest of the authors report no biomedical financial interests or potential conflicts of interest. NR 57 TC 1 Z9 1 U1 0 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X EI 1939-1846 J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD MAY PY 2016 VL 125 IS 4 BP 576 EP 587 DI 10.1037/abn0000142 PG 12 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA DK8ZJ UT WOS:000375218300011 PM 26845261 ER PT J AU Tsai, TY Dimitriou, D Liow, MHL Rubash, HE Li, GA Kwon, YM AF Tsai, Tsung-Yuan Dimitriou, Dimitris Liow, Ming Han Lincoln Rubash, Harry E. Li, Guoan Kwon, Young-Min TI Three-Dimensional Imaging Analysis of Unicompartmental Knee Arthroplasty Evaluated in Standing Position: Component Alignment and In Vivo Articular Contact SO JOURNAL OF ARTHROPLASTY LA English DT Article DE unicompartmental knee arthroplasty; biplanar radiograph; component position; articular contact; lower limb alignment ID COMPUTED-TOMOGRAPHY; NAVIGATION SYSTEM; TIBIAL COMPONENT; EARLY FAILURE; REPLACEMENT; 3D; PROSTHESIS; KINEMATICS; ACCURACY; IMPLANT AB Background: Component malalignment in unicompartmental knee arthroplasty (UKA) has been associated with contact stress concentration and poor clinical outcomes. However, there is a paucity of data regarding UKA component alignment and in vivo articular contact in weight-bearing position. This study aims to (1) quantify three-dimensional UKA component alignment and (2) evaluate the association between the component alignment and in vivo articular contact in standing position. Methods: Seventy-seven UKAs in 68 consecutive patients were imaged in standing position using a biplanar X-ray imaging acquisition system. The UKA models were imported into a virtual imaging environment and registered with component silhouette on X-ray image for determination of component position and contact location. Anatomic bony landmarks of the lower limb were digitized for quantification of the bone alignment. Results: The femoral component (FC) showed 1.6 degrees +/- 3.3 degrees valgus, 6.5 degrees +/- 6.4 degrees external rotation, and 2.4 degrees +/- 4.6 degrees flexion. The tibial component (TC) showed 3.9 degrees +/- 4.5 degrees varus, 4.4 degrees +/- 6.7 degrees internal rotation, and 10.1 degrees +/- 4.6 degrees tibial slope. The average contact point was located medially and posteriorly by 7.8 +/- 7.6% and 0.7 +/- 7.7% of TC dimensions to its center. Multiple regression analysis identified FC flexion as a significant variable affecting UKA anterior and/or posterior contact position (R = 0.549, P < .001). Conclusion: This study demonstrated the highest variability of UKA component positioning in axial plane rotation for FC and TC. The association between FC flexion and anterior contact position suggests accurate implant positioning may be important in optimizing in vivo UKA contact behavior. Further studies are required to gain understanding of the influence of axial rotation variability on in vivo UKA contact kinematics during functional activities. (C) 2016 Elsevier Inc. All rights reserved. C1 [Tsai, Tsung-Yuan; Dimitriou, Dimitris; Liow, Ming Han Lincoln; Rubash, Harry E.; Li, Guoan; Kwon, Young-Min] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Liow, Ming Han Lincoln] Singapore Gen Hosp, Dept Orthopaed Surg, Singapore, Singapore. RP Kwon, YM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. OI Dimitriou, Dimitris/0000-0002-9558-7080; LIOW, MING HAN LINCOLN/0000-0002-4496-8035 FU Zimmer FX Partial funding from Zimmer. NR 39 TC 0 Z9 0 U1 1 U2 1 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 MAY PY 2016 VL 31 IS 5 BP 1096 EP 1101 DI 10.1016/j.arth.2015.11.027 PG 6 WC Orthopedics SC Orthopedics GA DL2KK UT WOS:000375463400032 PM 26730450 ER PT J AU Crowley, JT Strle, K Drouin, EE Pianta, A Arvikar, SL Wang, Q Costello, CE Steere, AC AF Crowley, Jameson T. Strle, Klemen Drouin, Elise E. Pianta, Annalisa Arvikar, Sheila L. Wang, Qi Costello, Catherine E. Steere, Allen C. TI Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Lyme arthritis; Autoimmunity; MMP-10; HLA-DR-presented peptides; Autoimmunity; Erythema migrans ID BURGDORFERI-INDUCED EXPRESSION; BORRELIA-BURGDORFERI; RHEUMATOID-ARTHRITIS; GROWTH-FACTOR; ANTIPHOSPHOLIPID-SYNDROME; CEREBROSPINAL-FLUID; TISSUE INHIBITORS; ERYTHEMA MIGRANS; UNITED-STATES; ANNEXIN A2 AB Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant auto antigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the "first autoimmune hit" in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic refractory arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory arthritis had both T and B cell responses to the protein, providing evidence for a "second autoimmune hit". Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of arthritis. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Crowley, Jameson T.; Strle, Klemen; Drouin, Elise E.; Pianta, Annalisa; Arvikar, Sheila L.; Steere, Allen C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA USA. [Wang, Qi; Costello, Catherine E.] Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, Boston, MA 02118 USA. RP Crowley, JT (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, CNY 149-8301,149 13th St, Charlestown, MA 02129 USA. EM jcrowley6@mgh.harvard.edu FU NIH [R01 AI-110175, K01-AR062098, P41 GM104603, S10 OD010724]; Mathers Foundation; English, Bonter, Mitchell Foundation; Littauer Foundation; Eshe Fund; Lillian B. Davey Foundation; Proteomics Center [HHSN268201000031C] FX This work was supported by funding from the NIH [R01 AI-110175 to A.C.S., K01-AR062098 to K.S., and P41 GM104603 and S10 OD010724 to C.E.C], the Mathers Foundation; English, Bonter, Mitchell Foundation; Littauer Foundation; Eshe Fund; and the Lillian B. Davey Foundation to [A.C.S.], and Proteomics Center Contract [HHSN268201000031C to C.E.C.]. NR 94 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD MAY PY 2016 VL 69 BP 24 EP 37 DI 10.1016/j.jaut.2016.02.005 PG 14 WC Immunology SC Immunology GA DK4WB UT WOS:000374919900003 PM 26922382 ER PT J AU Chimote, AA Hajdu, P Kottyan, LC Harley, JB Yun, YH Conforti, L AF Chimote, Ameet A. Hajdu, Peter Kottyan, Leah C. Harley, John B. Yun, Yeoheung Conforti, Laura TI Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Autoimmunity; T cell; Kv1.3 ion channel; CD40 ligand; Lipid nanoparticles; Ca2+ signaling ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INFLAMMATORY-BOWEL-DISEASE; ION CHANNELS; MULTIPLE-SCLEROSIS; POTASSIUM CHANNELS; K+ CHANNELS; LYMPHOCYTES; ACTIVATION; CALCINEURIN AB Ca2+ signaling controls activation and effector functions of T lymphocytes. Ca2+ levels also regulate NFAT activation and CD40 ligand (CD40L) expression in T cells. CD40L in activated memory T cells binds to its cognate receptor, CD40, on other cell types resulting in the production of antibodies and pro inflammatory mediators. The CD40L/CD40 interaction is implicated in the pathogenesis of autoimmune disorders and CD40L is widely recognized as a therapeutic target. Ca2+ signaling in T cells is regulated by Kv1.3 channels. We have developed lipid nanoparticles that deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to CD45RO(+) memory T cells and reduce the activation-induced Ca2+ influx. Herein we report that Kv1.3-NPs reduced NFAT activation and CD40L expression exclusively in CD45RO(+) T cells. Furthermore, Kv1.3-NPs suppressed cytokine release and induced a phenotype switch of T cells from predominantly memory to naive. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chimote, Ameet A.; Hajdu, Peter; Conforti, Laura] Univ Cincinnati, Div Nephrol, Dept Internal Med, 231 Albert Sabin Way, Cincinnati, OH 45267 USA. [Kottyan, Leah C.; Harley, John B.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45267 USA. [Yun, Yeoheung] N Carolina Agr & Tech State Univ, Biol & Bioengn Dept, Greensboro, NC 27411 USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. RP Conforti, L (reprint author), Univ Cincinnati, Div Nephrol, Dept Internal Med, 231 Albert Sabin Way, Cincinnati, OH 45267 USA. EM Laura.Conforti@uc.edu RI Chimote, Ameet/R-5357-2016; OI Kottyan, Leah/0000-0003-3979-2220 FU NIH [R21AR060966, R01CA095286]; Dialysis Clinic, Inc. FX This project was funded in part by NIH grants R21AR060966, R01CA095286 and a research grant from Dialysis Clinic, Inc. to LC. All flow cytometry experiments were performed at the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center and Shriner's Hospital for Children Flow Cytometry Core, Cincinnati OH. We thank Dr. Heather Duncan for her assistance with IRB regulatory affairs and Dr. Giovanni Pauletti for making the Zetasizer Nano ZS instrument available to us. We are also grateful to Dr. Judith Heiny and Dr. Christy Holland for the use of the lyophilizer. All authors discussed the results and commented on the manuscript. NR 42 TC 1 Z9 1 U1 2 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD MAY PY 2016 VL 69 BP 86 EP 93 DI 10.1016/j.jaut.2016.03.004 PG 8 WC Immunology SC Immunology GA DK4WB UT WOS:000374919900009 PM 26994905 ER PT J AU Schopfer, DW Priano, S Allsup, K Helfrich, CD Ho, PM Rumsfeld, JS Forman, DE Whooley, MA AF Schopfer, David W. Priano, Susan Allsup, Kelly Helfrich, Christian D. Ho, P. Michael Rumsfeld, John S. Forman, Daniel E. Whooley, Mary A. TI Factors Associated With Utilization of Cardiac Rehabilitation Among Patients With Ischemic Heart Disease in the Veterans Health Administration A QUALITATIVE STUDY SO JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION LA English DT Article DE cardiac rehabilitation; program delivery; qualitative; utilization ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; EXERCISE; CARE; PREDICTORS; PREVENTION; CARDIOLOGY; MORTALITY; PROGRAM; SYSTEM AB BACKGROUND: Cardiac rehabilitation (CR) programs reduce morbidity and mortality in patients with ischemic heart disease but are vastly underutilized in the United States, including the Veterans Health Administration (VA) Healthcare System. Numerous barriers affecting utilization have been identified in other health care systems, but the specific factors affecting Veterans are unknown. We sought to identify barriers and facilitators associated with utilization of CR in VA facilities. METHODS: We performed a qualitative study of 56 VA patients, providers, and CR program managers at 30 VA facilities across the United States. We conducted semistructured interviews with key informants to explore their attitudes and knowledge toward CR. Interviews were conducted until thematic saturation occurred. Analyses using grounded theory to identify key themes were conducted using the qualitative data analysis package ATLAS.ti. RESULTS: We identified 6 themes as barriers and 5 as facilitators. The most common barriers to participation in CR were patient transportation issues (68%), lack of patient willingness to participate (41%), and no access to a nearby VA hospital with a CR program (30%). The most common facilitators were involvement of a dedicated provider or "clinical champion" (50%), provider knowledge of or experience with CR (48%), and patient desire for additional medical support (32%). CONCLUSIONS: Our findings suggest that addressing access issues and educating and activating providers on CR may increase utilization of CR programs. Targeting these specific factors may improve utilization of CR programs. C1 [Schopfer, David W.; Whooley, Mary A.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Schopfer, David W.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Priano, Susan] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Allsup, Kelly; Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Helfrich, Christian D.] Vet Affairs Puget Sound Healthcare Syst, Northwest Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. [Ho, P. Michael; Rumsfeld, John S.] Denver Vet Affairs Med Ctr, Div Cardiol, Denver, CO USA. [Ho, P. Michael; Rumsfeld, John S.] Univ Colorado, Hlth Sci Ctr, Div Cardiol, Dept Med, Denver, CO 80262 USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Geriatr Cardiol Sect, Pittsburgh, PA USA. [Forman, Daniel E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Schopfer, DW (reprint author), 4150 Clement St 111A1, San Francisco, CA 94121 USA. EM david.schopfer@gmail.com FU Department of Veterans Affairs (Health Services Research RRP) [12-232]; National Center for Advancing Translational Sciences of the NIH [KL2TR000143] FX This study was supported by a grant from the Department of Veterans Affairs (Health Services & Research RRP #12-232). Dr Schopfer is supported by the National Center for Advancing Translational Sciences of the NIH under Award Number KL2TR000143. NR 38 TC 2 Z9 2 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1932-7501 EI 1932-751X J9 J CARDIOPULM REHABIL JI J. Cardiopulm. Rehabil. Prev. PD MAY-JUN PY 2016 VL 36 IS 3 BP 167 EP 173 DI 10.1097/HCR.0000000000000166 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK7QH UT WOS:000375120300003 PM 27115074 ER PT J AU Lee, J Fei, P Packard, RRS Kang, H Xu, H Baek, KI Jen, N Chen, JJ Yen, H Kuo, CCJ Chi, NC Ho, CM Li, RS Hsiai, TK AF Lee, Juhyun Fei, Peng Packard, Rene R. Sevag Kang, Hanul Xu, Hao Baek, Kyung In Jen, Nelson Chen, Junjie Yen, Hilary Kuo, C-C Jay Chi, Neil C. Ho, Chih-Ming Li, Rongsong Hsiai, Tzung K. TI 4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID VENTRICULAR NONCOMPACTION CARDIOMYOPATHY; ZEBRAFISH HEART; IN-VIVO; MESENCHYMAL TRANSITION; BLOOD-VESSELS; NADPH OXIDASE; NOTCH; EMBRYOS; FORCE; PROLIFERATION AB Hemodynamic shear forces are intimately linked with cardiac development, during which trabeculae form a network of branching outgrowths from the myocardium. Mutations that alter Notch signaling also result in trabeculation defects. Here, we assessed whether shear stress modulates trabeculation to influence contractile function. Specifically, we acquired 4D (3D + time) images with light sheets by selective plane illumination microscopy (SPIM) for rapid scanning and deep axial penetration during zebrafish morphogenesis. Reduction of blood viscosity via gata1a morpholino oligonucleotides (MO) reduced shear stress, resulting in downregulation of Notch signaling and attenuation of trabeculation. Arrest of cardiomyocyte contraction either by troponin T type 2a (tnnt2a) MO or in weak atrium(m58) (wea) mutants resulted in reduced shear stress and downregulation of Notch signaling and trabeculation. Integrating 4D SPIM imaging with synchronization algorithm demonstrated that coinjection of neuregulin1 mRNA with gata1 MO rescued trabeculation to restore contractile function in association with upregulation of Notch-related genes. Crossbreeding of Tg(flk:mCherry) fish, which allows visualization of the vascular system with the Tg(tp1:gfp) Notch reporter line, revealed that shear stress-mediated Notch activation localizes to the endocardium. Deleting endocardium via the cloche(sk4) mutants downregulated Notch signaling, resulting in nontrabeculated ventricle. Subjecting endothelial cells to pulsatile flow in the presence of the ADAM10 inhibitor corroborated shear stress-activated Notch signaling to modulate trabeculation. C1 [Lee, Juhyun; Baek, Kyung In; Jen, Nelson; Chen, Junjie; Yen, Hilary; Hsiai, Tzung K.] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Fei, Peng] Huazhong Univ Sci & Technol, Sch Opt & Elect Informat, Wuhan 430074, Peoples R China. [Fei, Peng; Ho, Chih-Ming] Univ Calif Los Angeles, Dept Mech Engn, Los Angeles, CA USA. [Packard, Rene R. Sevag; Kang, Hanul; Li, Rongsong; Hsiai, Tzung K.] Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. [Kang, Hanul; Li, Rongsong; Hsiai, Tzung K.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Cardiol, Los Angeles, CA USA. [Xu, Hao; Kuo, C-C Jay] Univ So Calif, Dept Elect Engn, Los Angeles, CA 90089 USA. [Chi, Neil C.] UCSD, Dept Med, Inst Genom Med, La Jolla, CA USA. [Hsiai, Tzung K.] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA USA. RP Hsiai, TK (reprint author), Univ Calif Los Angeles, Dept Med Cardiol & Bioengn, 10833 Le Conte,CHS 17-054, Los Angeles, CA 90095 USA. EM thsiai@mednet.ucla.edu OI Packard, Rene/0000-0002-8520-5843 FU NIH [HL118650, HL083015, HD069305, HL111437, HL129727, T32HL007895]; American Heart Association [15PRE21400019] FX The authors would like to express gratitude to William Talbot from Stanford University for providing the human Nrg1 plasmid and to Deborah Yelon from UCSD for providing the wea mutants. In addition, the authors also thank David Traver at UCSD and Nathan Lawson at the University of Massachusetts Medical School (Worcester, Massachusetts, USA) for generously providing the Tg(tp1:gfp) line. This study was supported by grants NIH HL118650 (to T.K. Hsiai), HL083015 (to T.K. Hsiai), HD069305 (to N.C. Chi and T.K. Hsiai.), HL111437 (to T.K. Hsiai and N.C. Chi), HL129727 (to T.K. Hsiai), T32HL007895 (to R.R. Sevag Packard), and American Heart Association Pre-Doctoral Fellowship 15PRE21400019 (to J. Lee). NR 71 TC 3 Z9 3 U1 2 U2 10 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 MAY PY 2016 VL 126 IS 5 BP 1679 EP 1690 DI 10.1172/JCI83496 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DK8MX UT WOS:000375182100010 PM 27018592 ER PT J AU Ma, F Ye, HH He, HSH Gerrin, SJ Chen, S Tanenbaum, BA Cai, CM Sowalsky, AG He, LF Wang, HY Balk, SP Yuan, X AF Ma, Fen Ye, Huihui He, Housheng Hansen Gerrin, Sean J. Chen, Sen Tanenbaum, Benjamin A. Cai, Changmeng Sowalsky, Adam G. He, Lingfeng Wang, Hongyun Balk, Steven P. Yuan, Xin TI SOX9 drives WNT pathway activation in prostate cancer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TO-MESENCHYMAL TRANSITION; AUTOSOMAL SEX REVERSAL; NUCLEAR BETA-CATENIN; SRY-RELATED GENE; ANDROGEN RECEPTOR; CAMPOMELIC DYSPLASIA; SIGNALING AXIS; CELL FACTOR; PTEN LOSS; EXPRESSION AB The transcription factor SOX9 is critical for prostate development, and dysregulation of SOX9 is implicated in prostate cancer (PCa). However, the SOX9-dependent genes and pathways involved in both normal and neoplastic prostate epithelium are largely unknown. Here, we performed SOX9 ChIP sequencing analysis and transcriptome profiling of PCa cells and determined that SOX9 positively regulates multiple WNT pathway genes, including those encoding WNT receptors (frizzled [FZD] and lipoprotein receptor-related protein [LRP] family members) and the downstream beta-catenin effector TCF4. Analyses of PCa xenografts and clinical samples both revealed an association between the expression of SOX9 and WNT pathway components in PCa. Finally, treatment of SOX9-expressing PCa cells with a WNT synthesis inhibitor (LGK974) reduced WNT pathway signaling in vitro and tumor growth in murine xenograft models. Together, our data indicate that SOX9 expression drives PCa by reactivating the WNT/beta-catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy. C1 [Ma, Fen; Chen, Sen; Tanenbaum, Benjamin A.; Cai, Changmeng; Sowalsky, Adam G.; He, Lingfeng; Wang, Hongyun; Balk, Steven P.; Yuan, Xin] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol Oncol,Dept Med, Boston, MA 02215 USA. [Ye, Huihui; Gerrin, Sean J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [He, Housheng Hansen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [He, Housheng Hansen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, 44 Binney St, Boston, MA 02115 USA. RP Balk, SP; Yuan, X (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, 330 Brookline Ave,CLS 0439, Boston, MA 02215 USA. EM sbalk@bidmc.harvard.edu; xyuan@bidmc.harvard.edu OI Sowalsky, Adam/0000-0003-2760-1853; Cai, Changmeng/0000-0002-8701-2586 FU NIH [R01 DK 079962, R01 CA 168393, P01 CA163227, P50 CA090381, K99 CA166507]; Department of Defense Prostate Cancer Research Program [W81XWH-12-1-0158, W81XWH-15-1-0151]; Prostate Cancer Foundation; Koch Institute for Integrative Cancer Research at MIT; Dana-Farber/Harvard Cancer Center; American Association of Cancer Research [14-40-38-MA] FX This work was supported by grants from the NIH (R01 DK 079962, R01 CA 168393, P01 CA163227, and P50 CA090381), the Department of Defense Prostate Cancer Research Program (W81XWH-12-1-0158 and W81XWH-15-1-0151), a challenge grant from the Prostate Cancer Foundation, and a grant from the Bridge Project (partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center). F. Ma was supported by a Millennium Fellowship in Prostate Cancer Research from the American Association of Cancer Research (14-40-38-MA). C. Cai was supported by an NIH Pathway to Independence award (K99 CA166507). NR 74 TC 5 Z9 6 U1 3 U2 6 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 MAY PY 2016 VL 126 IS 5 BP 1745 EP 1758 DI 10.1172/JCI78815 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DK8MX UT WOS:000375182100015 PM 27043282 ER PT J AU Zhang, G Frederick, DT Wu, L Wei, Z Krepler, C Srinivasan, S Chae, YC Xu, XW Choi, H Dimwamwa, E Ope, O Shannan, B Basu, D Zhang, DM Guha, M Xiao, M Randell, S Sproesser, K Xu, W Liu, J Karakousis, GC Schuchter, LM Gangadhar, TC Amaravadi, RK Gu, MN Xu, CY Ghosh, A Xu, WT Tian, T Zhang, J Zha, SJ Liu, Q Brafford, P Weeraratna, A Davies, MA Wargo, JA Avadhani, NG Lu, YL Mills, GB Altieri, DC Flaherty, KT Herlyn, M AF Zhang, Gao Frederick, Dennie T. Wu, Lawrence Wei, Zhi Krepler, Clemens Srinivasan, Satish Chae, Young Chan Xu, Xiaowei Choi, Harry Dimwamwa, Elaida Ope, Omotayo Shannan, Batool Basu, Devraj Zhang, Dongmei Guha, Manti Xiao, Min Randell, Sergio Sproesser, Katrin Xu, Wei Liu, Jephrey Karakousis, Giorgos C. Schuchter, Lynn M. Gangadhar, Tara C. Amaravadi, Ravi K. Gu, Mengnan Xu, Caiyue Ghosh, Abheek Xu, Weiting Tian, Tian Zhang, Jie Zha, Shijie Liu, Qin Brafford, Patricia Weeraratna, Ashani Davies, Michael A. Wargo, Jennifer A. Avadhani, Narayan G. Lu, Yiling Mills, Gordon B. Altieri, Dario C. Flaherty, Keith T. Herlyn, Meenhard TI Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MEK INHIBITION; OXIDATIVE-PHOSPHORYLATION; METASTATIC MELANOMA; IMPROVED SURVIVAL; BRAF; CANCER; CELLS; PGC1-ALPHA; LEUKEMIA; ONCOGENE AB Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAF(V600E) melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi. C1 [Zhang, Gao; Wu, Lawrence; Krepler, Clemens; Chae, Young Chan; Choi, Harry; Dimwamwa, Elaida; Ope, Omotayo; Shannan, Batool; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Caiyue; Ghosh, Abheek; Liu, Qin; Brafford, Patricia; Altieri, Dario C.; Herlyn, Meenhard] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA. [Frederick, Dennie T.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. [Wei, Zhi; Gu, Mengnan; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Srinivasan, Satish; Guha, Manti; Avadhani, Narayan G.] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Xu, Xiaowei] Hosp Univ Penn, Dept Pathol & Lab Med, 3400 Spruce St, Philadelphia, PA 19104 USA. [Basu, Devraj] Univ Penn, Perelman Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Basu, Devraj] Vet Adm Med Ctr, Philadelphia, PA 19104 USA. [Zhang, Dongmei] Univ Penn, Dept Obstet & Gynecol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Xu, Wei; Liu, Jephrey; Schuchter, Lynn M.; Gangadhar, Tara C.; Amaravadi, Ravi K.] Hosp Univ Penn, Dept Med, Abramson Canc Ctr, 3400 Spruce St, Philadelphia, PA 19104 USA. [Karakousis, Giorgos C.] Hosp Univ Penn, Dept Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. [Weeraratna, Ashani] Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, 3601 Spruce St, Philadelphia, PA 19104 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Flaherty, Keith T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Div Med Oncol, Boston, MA USA. RP Herlyn, M (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM herlynm@wistar.org RI Zhang, Gao/D-3471-2017; OI Wu, Lawrence/0000-0002-8013-1275 FU NIH [P01 CA114046, P01 CA025874, P30 CA010815, R01 CA047159]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Melanoma Research Foundation; Cancer Center Support Grant (CCSG) [CA010815] FX We thank all former and current laboratory members for their comments and helpful discussions; J. Hayden (Wistar Microscopy Facility), C. Chang, S. Billouin, and T. Nguyen (Wistar Genomics Facility), J.S. Faust, and D. Ambrose (Wistar Flow Cytometry Facility) for their technical support; M.B. Powell for providing human melanoma cells (Stanford University); and M. S. Soengas and E. Riveiro-Falkenbach for providing plasmids (Centro Nacional de Investigaciones Oncologicas [CNIO]). We apologize to those whose work was not cited or mentioned here due to space constraints. The research was funded by NIH grants P01 CA114046, P01 CA025874, P30 CA010815, and R01 CA047159 and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Foundation. The support for Shared Resources used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 (to the Wistar Institute). NR 37 TC 7 Z9 7 U1 2 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 MAY PY 2016 VL 126 IS 5 BP 1834 EP 1856 DI 10.1172/JCI82661 PG 23 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DK8MX UT WOS:000375182100021 PM 27043285 ER PT J AU Brecher, SM AF Brecher, Stephen M. TI Complicated Urinary Tract Infections: What's a Lab To Do? SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material ID ADULT FEMALE BLADDER; DIAGNOSIS AB The article by Price et al. in this issue (T. K. Price et al., J Clin Microbiol 54:1216-1222, 2016, http://dx.doi.org/10.1128/JCM.00044-16) advocates for the use of a larger inoculum when culturing urine obtained by "in-and-out" catheterization in a selected female population. Their findings and the resulting challenges will afford clinical microbiologists and specialty physicians an opportunity to review what will or should be done with the additional microbiological culture data. C1 [Brecher, Stephen M.] VA Boston HealthCare Syst, Dept Pathol & Lab Med, West Roxbury, MA USA. [Brecher, Stephen M.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. RP Brecher, SM (reprint author), VA Boston HealthCare Syst, Dept Pathol & Lab Med, West Roxbury, MA USA.; Brecher, SM (reprint author), Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. EM stephen.brecher@va.gov NR 8 TC 0 Z9 0 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAY PY 2016 VL 54 IS 5 BP 1189 EP 1190 DI 10.1128/JCM.00370-16 PG 2 WC Microbiology SC Microbiology GA DK5JH UT WOS:000374955700005 PM 26962089 ER PT J AU Zhao, FM AF Zhao, Fengmin TI Surrogate End Points and Their Validation in Oncology Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PROGRESSION-FREE SURVIVAL; METASTATIC BREAST-CANCER; CELL LUNG-CANCER; COLORECTAL-CANCER; TUMOR RESPONSE; THERAPIES; CRITERIA; LEVEL C1 [Zhao, Fengmin] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Zhao, FM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 20 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2016 VL 34 IS 13 BP 1436 EP + DI 10.1200/JCO.2016.66.4581 PG 3 WC Oncology SC Oncology GA DK6SM UT WOS:000375055500006 PM 26951314 ER PT J AU Ng, AK Dabaja, BS Hoppe, RT Illidge, T Yahalom, J AF Ng, Andrea K. Dabaja, Bouthaina Shbib Hoppe, Richard T. Illidge, Timothy Yahalom, Joachim TI Re-Examining the Role of Radiation Therapy for Diffuse Large B-Cell Lymphoma in the Modern Era SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID NON-HODGKINS-LYMPHOMA; LOCALIZED AGGRESSIVE LYMPHOMA; CHOP PLUS RADIOTHERAPY; ELDERLY-PATIENTS; ONCOLOGY-GROUP; TREATMENT SELECTION; 2ND MALIGNANCIES; DOSE GUIDELINES; OUTCOMES; RISK C1 [Ng, Andrea K.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Dabaja, Bouthaina Shbib] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hoppe, Richard T.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Illidge, Timothy] Univ Manchester, Manchester Acad Hlth Sci Ctr, Christie Natl Hlth Serv Fdn Trust, Manchester, Lancs, England. [Yahalom, Joachim] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Ng, AK (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. NR 37 TC 3 Z9 3 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2016 VL 34 IS 13 BP 1443 EP + DI 10.1200/JCO.2015.64.9418 PG 6 WC Oncology SC Oncology GA DK6SM UT WOS:000375055500008 PM 26903576 ER PT J AU Tung, N Lin, NU Kidd, J Allen, BA Singh, N Wenstrup, RJ Hartman, AR Winer, EP Garber, JE AF Tung, Nadine Lin, Nancy U. Kidd, John Allen, Brian A. Singh, Nanda Wenstrup, Richard J. Hartman, Anne-Renee Winer, Eric P. Garber, Judy E. TI Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OVARIAN-CANCER; CONFER SUSCEPTIBILITY; SEQUENCING PANEL; RAD51C MUTATIONS; BARD1 MUTATIONS; BRCA2 GENES; RISK; FAMILIES; CARRIERS; POPULATION AB Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2. (C) 2016 by American Society of Clinical Oncology C1 [Tung, Nadine] Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. [Lin, Nancy U.; Winer, Eric P.; Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tung, Nadine; Lin, Nancy U.; Winer, Eric P.; Garber, Judy E.] Harvard Univ, Sch Med, Boston, MA USA. [Kidd, John; Allen, Brian A.; Singh, Nanda; Wenstrup, Richard J.; Hartman, Anne-Renee] Myriad Genet Labs Inc, Salt Lake City, UT USA. RP Tung, N (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM ntung@bidmc.harvard.edu FU DanaFarber/Harvard Cancer Center Breast Specialized Program of Research Excellence (SPORE) [P50CA168504]; Susan F. Smith Center for Women's Cancers Executive Council at Dana-Farber Cancer Institute; Myriad Genetics Laboratories, Inc. FX Supported by grants from the Dana-Farber/Harvard Cancer Center Breast Specialized Program of Research Excellence (SPORE) (P50CA168504), the Susan F. Smith Center for Women's Cancers Executive Council at Dana-Farber Cancer Institute, and Myriad Genetics Laboratories, Inc. Myriad also conducted all germline blood testing free of charge for this retrospective study using the MyRisk assay. NR 51 TC 13 Z9 13 U1 6 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 MAY 1 PY 2016 VL 34 IS 13 BP 1460 EP + DI 10.1200/JCO.2015.65.0747 PG 15 WC Oncology SC Oncology GA DK6SM UT WOS:000375055500011 PM 26976419 ER PT J AU Hodi, FS Hwu, WJ Kefford, R Weber, JS Daud, A Hamid, O Patnaik, A Ribas, A Robert, C Gangadhar, TC Joshua, AM Hersey, P Dronca, R Joseph, R Hille, D Xue, DH Li, XN Kang, SP Ebbinghaus, S Perrone, A Wolchok, JD AF Hodi, F. Stephen Hwu, Wen-Jen Kefford, Richard Weber, Jeffrey S. Daud, Adil Hamid, Omid Patnaik, Amita Ribas, Antoni Robert, Caroline Gangadhar, Tara C. Joshua, Anthony M. Hersey, Peter Dronca, Roxana Joseph, Richard Hille, Darcy Xue, Dahai Li, Xiaoyun Nicole Kang, S. Peter Ebbinghaus, Scot Perrone, Andrea Wolchok, Jedd D. TI Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOLID TUMORS; PHASE-II; T-CELLS; IPILIMUMAB; GUIDELINES; SAFETY; PD-1 AB Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase lb KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with >= 28 weeks of imaging. Pseudoprogression was defined as >= 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. Results Of the 655 patients with melanoma enrolled, 327 had> 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived >= 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). Conclusion Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment. (C) 2016 by American Society of Clinical Oncology C1 [Hodi, F. Stephen] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Hwu, Wen-Jen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Patnaik, Amita] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Kefford, Richard] Westmead Hosp, Melanoma Inst Australia, Sydney, NSW, Australia. [Kefford, Richard] Macquarie Univ, Sydney, NSW 2109, Australia. [Hersey, Peter] Univ Sydney, Sydney, NSW 2006, Australia. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Joseph, Richard] Mayo Clin, Jacksonville, FL 32224 USA. [Daud, Adil] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Ribas, Antoni] Univ Calif Los Angeles, Los Angeles, CA USA. [Robert, Caroline] Gustave Roussy, Villejuif, France. [Robert, Caroline] Univ Paris 11, Villejuif, France. [Gangadhar, Tara C.] Abramson Canc Ctr, Philadelphia, PA USA. [Joshua, Anthony M.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Dronca, Roxana] Mayo Clin, Rochester, MN USA. [Hille, Darcy; Xue, Dahai; Li, Xiaoyun Nicole; Kang, S. Peter; Ebbinghaus, Scot; Perrone, Andrea] Merck, Kenilworth, NJ USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM stephen_hodi@dfci.harvard.edu FU Merck & Co, Kenilworth, NJ FX Supported by Merck & Co, Kenilworth, NJ. NR 22 TC 32 Z9 32 U1 9 U2 18 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 MAY 1 PY 2016 VL 34 IS 13 BP 1510 EP + DI 10.1200/JCO.2015.64.0391 PG 11 WC Oncology SC Oncology GA DK6SM UT WOS:000375055500017 PM 26951310 ER PT J AU Dimopoulos, MA Sonneveld, P Leung, N Merlini, G Ludwig, H Kastritis, E Goldschmidt, H Joshua, D Orlowski, RZ Powles, R Vesole, DH Garderet, L Einsele, H Palumbo, A Cavo, M Richardson, PG Moreau, P San Miguel, J Rajkumar, SV Durie, BGM Terpos, E AF Dimopoulos, Meletios A. Sonneveld, Pieter Leung, Nelson Merlini, Giampaolo Ludwig, Heinz Kastritis, Efstathios Goldschmidt, Hartmut Joshua, Douglas Orlowski, Robert Z. Powles, Raymond Vesole, David H. Garderet, Laurent Einsele, Hermann Palumbo, Antonio Cavo, Michele Richardson, Paul G. Moreau, Philippe San Miguel, Jesus Rajkumar, S. Vincent Durie, Brian G. M. Terpos, Evangelos TI International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID REFRACTORY MULTIPLE-MYELOMA; ACUTE KIDNEY INJURY; GLOMERULAR-FILTRATION-RATE; STEM-CELL TRANSPLANTATION; GROUP CONSENSUS STATEMENT; BORTEZOMIB-BASED REGIMENS; HIGH CUTOFF HEMODIALYSIS; LIGHT-CHAIN; MONOCLONAL GAMMOPATHY; CAST NEPHROPATHY AB Purpose The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma-related renal impairment (RI). Methods Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m(2) to 140 mg/m(2)) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A). (C) 2016 by American Society of Clinical Oncology C1 [Dimopoulos, Meletios A.; Kastritis, Efstathios; Terpos, Evangelos] Univ Athens, Athens 11528, Greece. [Sonneveld, Pieter] Erasmus Univ, Med Ctr Rotterdam, Rotterdam, Netherlands. [Leung, Nelson; Rajkumar, S. Vincent] Mayo Clin, Rochester, MN USA. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Vesole, David H.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Durie, Brian G. M.] Samuel Oschin Canc Ctr, Los Angeles, CA USA. [Merlini, Giampaolo] Policlin San Matteo, Inst Sci, I-27100 Pavia, Italy. [Merlini, Giampaolo] Univ Pavia, Via Palestro 3, I-27100 Pavia, Italy. [Palumbo, Antonio] Univ Turin, Azienda Osped Univ Citta Salute & Sci Torino, Turin, Italy. [Cavo, Michele] Univ Bologna, Sch Med, S Orsolas Univ Hosp, Bologna, Italy. [Ludwig, Heinz] Wilhelminenspital Stadt Wien, Vienna, Austria. [Goldschmidt, Hartmut] Univ Heidelberg Hosp, Heidelberg, Germany. [Goldschmidt, Hartmut] Natl Ctr Tumor Dis Heidelberg, Heidelberg, Germany. [Einsele, Hermann] Univ Wurzburg, Med Ctr, D-97070 Wurzburg, Germany. [Joshua, Douglas] Univ Sydney, Sch Med, Royal Prince Alfred Hosp, Sydney, NSW 2006, Australia. [Powles, Raymond] Canc Ctr London, London, England. [Garderet, Laurent] St Antoine Hosp, Paris, France. [Garderet, Laurent] Univ Paris 06, Paris, France. [Moreau, Philippe] Univ Hosp Hotel Dieu, Nantes, France. [San Miguel, Jesus] Univ Navarra Clin, CIMA, Navarra, Spain. RP Dimopoulos, MA (reprint author), Univ Athens, Sch Med, Dept Clin Therapeut, 80 Vas Sofias Ave, Athens 11528, Greece. EM mdimop@med.uoa.gr RI richard, chrystelle/K-8595-2015 FU Janssen Pharmaceuticals; Celgene; Amgen; Skyline Diagnostics; Takeda Pharmaceuticals; Chugai Pharma; Novartis; Bristol-Myers Squibb; Millennium Pharmaceuticals; Array BioPharma; Spectrum Pharmaceuticals; Karus Therapeutics; Onyx Pharmaceuticals; Janssen-Cilag; Genesis Pharmaceuticals FX Janssen Pharmaceuticals, Janssen Pharmaceuticals (Inst), Celgene, Celgene (Inst), Amgen, Amgen (Inst), Skyline Diagnostics, Skyline Diagnostics (Inst); Takeda Pharmaceuticals (Inst); Celgene (Inst), Janssen Pharmaceuticals (Inst), Chugai Pharma (Inst), Novartis (Inst), Bristol-Myers Squibb (Inst), Millennium Pharmaceuticals; Array BioPharma, Celgene, Bristol-Myers Squibb, Millennium Pharmaceuticals, Spectrum Pharmaceuticals, Karus Therapeutics, Onyx Pharmaceuticals; Celgene, Millennium Pharmaceuticals; Amgen (Inst), Janssen-Cilag (Inst), Genesis Pharmaceuticals (Inst) NR 101 TC 11 Z9 11 U1 0 U2 4 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 MAY 1 PY 2016 VL 34 IS 13 BP 1544 EP + DI 10.1200/JCO.2015.65.0044 PG 20 WC Oncology SC Oncology GA DK6SM UT WOS:000375055500021 PM 26976420 ER PT J AU Teles, R Benecha, HK Preisser, JS Moss, K Starr, JR Corby, P Genco, R Garcia, N Giannobile, WV Jared, H Torresyap, G Salazar, E Moya, J Howard, C Schifferle, R Falkner, KL Gillespie, J Dixon, D Cugini, M AF Teles, Ricardo Benecha, Habtamu K. Preisser, John S. Moss, Kevin Starr, Jacqueline R. Corby, Patricia Genco, Robert Garcia, Nathalia Giannobile, William V. Jared, Heather Torresyap, Gay Salazar, Elida Moya, Julie Howard, Cynthia Schifferle, Robert Falkner, Karen L. Gillespie, Jane Dixon, Debra Cugini, MaryAnn TI Modelling changes in clinical attachment loss to classify periodontal disease progression SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE clinical attachment loss; disease progression; linear mixed models; periodontal disease ID ADULT PERIODONTITIS; LEVEL MEASUREMENTS; LONGITUDINAL DATA; RELIABILITY; PATTERNS AB Aim: The goal of this study was to identify progressing periodontal sites by applying linear mixed models (LMM) to longitudinal measurements of clinical attachment loss (CAL). Methods: Ninety-three periodontally healthy and 236 periodontitis subjects had their CAL measured bi-monthly for 12months. The proportions of sites demonstrating increases in CAL from baseline above specified thresholds were calculated for each visit. The proportions of sites reversing from the progressing state were also computed. LMM were fitted for each tooth site and the predicted CAL levels used to categorize sites regarding progression or regression. The threshold for progression was established based on the model-estimated error in predictions. Results: Over 12 months, 21.2%, 2.8% and 0.3% of sites progressed, according to thresholds of 1, 2 and 3mm of CAL increase. However, on average, 42.0%, 64.4% and 77.7% of progressing sites for the different thresholds reversed in subsequent visits. Conversely, 97.1%, 76.9% and 23.1% of sites classified as progressing using LMM had observed CAL increases above 1, 2 and 3mm after 12months, whereas mean rates of reversal were 10.6%, 30.2% and 53.0% respectively. Conclusion: LMM accounted for several sources of error in longitudinal CAL measurement, providing an improved method for classifying progressing sites. C1 [Teles, Ricardo] Univ N Carolina, Sch Dent, Dept Periodontol, Koury Hlth Sci Bldg,385 S Columbia St,Room 3506, Chapel Hill, NC 27599 USA. [Teles, Ricardo; Starr, Jacqueline R.; Torresyap, Gay; Salazar, Elida; Cugini, MaryAnn] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Benecha, Habtamu K.; Preisser, John S.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA. [Moss, Kevin] Univ N Carolina, Sch Dent, Dept Dent Ecol, Chapel Hill, NC 27599 USA. [Starr, Jacqueline R.] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, 188 Longwood Ave, Boston, MA 02115 USA. [Corby, Patricia; Moya, Julie; Howard, Cynthia] NYU, Coll Dent, Bluestone Ctr Clin Res, New York, NY USA. [Genco, Robert; Schifferle, Robert; Falkner, Karen L.] SUNY Buffalo, Sch Dent Med, Dept Oral Biol, Buffalo, NY 14260 USA. [Garcia, Nathalia; Gillespie, Jane; Dixon, Debra] So Illinois Univ, Sch Dent Med, Sect Periodont, Dept Appl Dent Med, Alton, IL USA. [Giannobile, William V.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA. [Giannobile, William V.] Univ Michigan, Sch Dent, Michigan Ctr Oral Hlth Res, Ann Arbor, MI 48109 USA. [Jared, Heather] Rho Inc, Contract Res Org, Chapel Hill, NC USA. RP Teles, R (reprint author), Univ N Carolina, Sch Dent, Dept Periodontol, Koury Hlth Sci Bldg,385 S Columbia St,Room 3506, Chapel Hill, NC 27599 USA. EM rteles@email.unc.edu OI Giannobile, William/0000-0002-7102-9746 FU National Institute of Dental and Craniofacial Research [DE021127-01] FX This study was supported by research grant DE021127-01 from the National Institute of Dental and Craniofacial Research. NR 25 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2016 VL 43 IS 5 BP 426 EP 434 DI 10.1111/jcpe.12539 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DK5VW UT WOS:000374990100005 PM 26935472 ER PT J AU Pancer, BA Kott, D Sugai, JV Panagakos, FS Braun, TM Teles, RP Giannobile, WV Kinney, JS AF Pancer, Brooke A. Kott, Diana Sugai, James V. Panagakos, Fotinos S. Braun, Thomas M. Teles, Ricardo P. Giannobile, William V. Kinney, Janet S. TI Effects of triclosan on host response and microbial biomarkers during experimental gingivitis SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE anti-inflammatory agents; bacteria; dental plaque; microbiology; dentifrices; gingivitis; inflammation mediators/analysis ID CREVICULAR FLUID; PERIODONTAL-DISEASE; PLAQUE; INTERLEUKIN-1-BETA; INFLAMMATION; PROGRESSION; TOOTHPASTE; DENTIFRICE; RESOLUTION; BIOFILM AB Aim: This exploratory randomized, controlled clinical trial sought to evaluate anti-inflammatory and -microbial effects of triclosan during experimental gingivitis as assessed by host response biomarkers and biofilm microbial pathogens. Materials and Methods: Thirty participants were randomized to triclosan or control dentifrice groups who ceased homecare for 21days in an experimental gingivitis (EG) protocol. Plaque and gingival indices and saliva, plaque, and gingival crevicular fluid (GCF) were assessed/collected at days 0, 14, 21 and 35. Levels and proportions of 40 bacterial species from plaque samples were determined using checkerboard DNA-DNA hybridization. Ten biomarkers associated with inflammation, matrix degradation, and host protection were measured from GCF and saliva and analysed using a multiplex array. Participants were stratified as "high" or "low" responders based on gingival index and GCF biomarkers and bacterial biofilm were combined to generate receiver operating characteristic curves and predict gingivitis susceptibility. Results: No differences in mean PI and GI values were observed between groups and non-significant trends of reduction of host response biomarkers with triclosan treatment. Triclosan significantly reduced levels of A. actinomycetemcomitans and P. gingivalis during induction of gingivitis. Conclusions: Triclosan reduced microbial levels during gingivitis development (ClinicalTrials.gov NCT01799226). C1 [Pancer, Brooke A.; Kott, Diana; Sugai, James V.; Giannobile, William V.; Kinney, Janet S.] Univ Michigan, Dept Periodont & Oral Med, Michigan Ctr Oral Hlth Res, Ann Arbor, MI 48109 USA. [Panagakos, Fotinos S.] Colgate Palmol Technol Ctr, Piscataway, NJ USA. [Braun, Thomas M.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Teles, Ricardo P.] Univ N Carolina, Sch Dent, Dept Periodontol, Chapel Hill, NC USA. [Teles, Ricardo P.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. RP Kinney, JS (reprint author), Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Div Dent Hyg, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. EM kinneyj@umich.edu OI Giannobile, William/0000-0002-7102-9746 FU Colgate-Palmolive Company (Piscataway, NJ); National Institute of Health FX This work was supported by Colgate-Palmolive Company (Piscataway, NJ) and the National Institute of Health. Amy Collins and Erin Heffez (Giannobile Lab, University of Michigan, School of Dentistry, Ann Arbor, Michigan), Janet Riggs, Sara Wesley, Tina Ziba, Tina Huffman, Hily'e Pittman, Elizabeth Easter, and Anna Galloro (Michigan Center for Oral Health Research). NR 45 TC 0 Z9 0 U1 1 U2 3 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 MAY PY 2016 VL 43 IS 5 BP 435 EP 444 DI 10.1111/jcpe.12519 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DK5VW UT WOS:000374990100006 PM 26820239 ER PT J AU Szkudlinska, MA von Frankenberg, AD Utzschneider, KM AF Szkudlinska, Magdalena A. von Frankenberg, Anize D. Utzschneider, Kristina M. TI The antioxidant N-Acetylcysteine does not improve glucose tolerance or beta-cell function in type 2 diabetes SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE N-Acetylcysteine; beta-cell function; Antioxidant; Oxidative stress; Supplement ID CHRONIC OXIDATIVE STRESS; ENDOTHELIAL ACTIVATION; TOXICITY; GLUTATHIONE; DYSFUNCTION; MECHANISM; MELLITUS; CYSTEINE AB Hyperglycemia induces oxidative stress and thereby may exacerbate beta-cell dysfunction in type 2 diabetes (T2DM). Notably, glutathione (GSH), synthesized from N-Acetylcysteine (NAC), neutralizes reactive oxygen species within cells and is low in individuals with diabetes. Aim: Determine if NAC supplementation improves beta-cell function and glucose tolerance by decreasing oxidative stress in T2DM. Methods: Thirteen subjects (6 M/7 F) with T2DM (duration: 0-13 years, median: 2 years), treated with diet/exercise alone (n = 7) or metformin (n = 6), underwent a 2-h oral glucose tolerance test (OGTT) at baseline, after 2 weeks supplementation with 600 mg NAC orally twice daily, and again after 2 weeks supplementation with 1200 mg NAC twice daily. The following measurements were made: fasting glucose and fructosamine for glycemic control, incremental AUC glucose (0-120 min) for glucose tolerance, and A insulin/Delta, glucose (0-30 min) for the early insulin response to glucose. Fasting erythrocyte GSH and GSSG (oxidized glutathione) levels, plasma thiobarbituric acid reactive substances (TBARS), and urine F2 alpha isoprostanes were measured to assess oxidative status. Results: Subjects were middle aged (mean +/- SEM: 53.9 +/- 32 years), obese (BMI 373 +/- 2.8 kg/m(2)), and relatively well-controlled (HbA1c 6.7 +/- 03%, 50 mmol/mol). Glycemic control, glucose tolerance, insulin release, and oxidative markers did not change with either dose of NAC. Conclusions: Based on the lack of any short-term benefit from NAC supplementation on markers of glucose metabolism, beta-cell response, and oxidative status, it is unlikely to be a valuable therapeutic approach for treatment of type 2 diabetes. Published by Elsevier Inc. C1 [Szkudlinska, Magdalena A.; Utzschneider, Kristina M.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Szkudlinska, Magdalena A.; Utzschneider, Kristina M.] Univ Washington, Seattle, WA 98195 USA. [von Frankenberg, Anize D.] Univ Fed Rio Grande do Sul, Sch Med, Postgrad Endocrinol Program, Porto Alegre, RS, Brazil. RP Szkudlinska, MA (reprint author), VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Seattle, WA USA.; Szkudlinska, MA (reprint author), Univ Washington, Seattle, WA 98195 USA. EM magda3@u.washington.edu; anize.frankenberg@gmail.com; kutzschn@u.washington.edu FU Department of Veteran Affairs; Diabetes Research Center [P30DK017047] FX We are grateful to the study participants for their contribution and time. This study was supported by funding and resources from the Department of Veteran Affairs and the Diabetes Research Center (P30DK017047). The NAC supplement was generously provided free of charge from Twin Labs. NR 25 TC 0 Z9 0 U1 5 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD MAY-JUN PY 2016 VL 30 IS 4 BP 618 EP 622 DI 10.1016/j.jdiacomp.2016.02.003 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK4UQ UT WOS:000374916200010 PM 26922582 ER PT J AU Lopes-Virella, MF Hunt, KJ Baker, NL Virella, G AF Lopes-Virella, Maria F. Hunt, Kelly J. Baker, Nathaniel L. Virella, Gabriel CA VADT Grp Investigators TI High levels of AGE-LDL, and of IgG antibodies reacting with MDA-lysine epitopes expressed by oxLDL and MDA-LDL in circulating immune complexes predict macroalbuminuria in patients with type 2 diabetes SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Nephropathy; Albuminuria; Modified LDL immune complexes; Modified LDL antibodies; AGE- LDL; MDA-LDL ID LOW-DENSITY-LIPOPROTEIN; GLYCATION END-PRODUCTS; EURODIAB PROSPECTIVE COMPLICATIONS; INTIMA-MEDIA THICKNESS; OXIDIZED LDL; CARDIOVASCULAR EVENTS; OXIDATIVE STRESS; GLYCEMIC CONTROL; MODIFIED FORMS; RISK-FACTORS AB Background: Circulating immune complexes (IC) containing modified forms of LDL (mLDL) are strongly pro-inflammatory and when present in high levels are associated with the development of diabetic complications. Objective: We investigated whether levels of oxidized LDL (oxLDL), malondialdehyde-LDL (MDA-LDL) and advanced glycation end products-LDL (AGE-LDL) as well as IgG and IgM antibodies reacting with MDA-lysine epitopes expressed by oxLDL and MDA-LDL isolated from circulating IC were associated with progression to macroalbuminuria in type 2 diabetes (VADT cohort). Methods: Levels of mLDL in IC were measured in 905 patients, a median of two years after entry into the study. Participants were followed for an average of 3.7 years for renal outcomes. Generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, persistent micro-(ACR >= 30), incident micro-(ACR >= 30) and incident macroalbuminuria (ACR >= 300) were the outcomes of interest. Results and conclusions: Patients with macro (n = 78) or non-persistent microalbuminuria (n = 81) at baseline were excluded. Odds ratios for endpoints in relation to high versus low (defined using a median split) biomarker levels are found in Fig. 1. Our study demonstrates that high levels of AGE-LDL as well as of IgG antibodies (but not IgM antibodies) reacting with MDA-LDL lysine epitopes in circulating IC predict the development of macroalbuminuria in patients with type 2 diabetes. These data support the pathogenic role of modified LDL IgG antibodies but not the protective role of modified LDL IgM antibodies. Published by Elsevier Inc. C1 [Lopes-Virella, Maria F.] Med Univ S Carolina, Dept Med & Lab Serv, Charleston, SC 29425 USA. [Lopes-Virella, Maria F.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Hunt, Kelly J.; Baker, Nathaniel L.] Med Univ S Carolina, Dept Publ Hlth Serv, Charleston, SC 29425 USA. [Virella, Gabriel] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. RP Lopes-Virella, MF (reprint author), 114 Doughty St, Charleston, SC 29425 USA. EM virellam@musc.edu FU Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK099177] FX This work was supported in part by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. This work was also supported by a program project funded by the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01-DK099177. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. M. L.-V. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 46 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD MAY-JUN PY 2016 VL 30 IS 4 BP 693 EP 699 DI 10.1016/j.jdiacomp.2016.01.012 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK4UQ UT WOS:000374916200021 PM 26861948 ER PT J AU LaMotte, AD Taft, CT Weatherill, RP Scott, JP Eckhardt, CI AF LaMotte, Adam D. Taft, Casey T. Weatherill, Robin P. Scott, Jillian P. Eckhardt, Christopher I. TI Posttraumatic Stress Disorder Symptoms, Traumatic Reminders, and Partner Aggressive Tendencies Among Veterans SO JOURNAL OF FAMILY VIOLENCE LA English DT Article DE Veteran; PTSD; Intimate partner violence; Aggression; Traumatic reminder ID ADMINISTERED PTSD SCALE; INTIMATE PARTNER; SIMULATED SITUATIONS; ARTICULATED THOUGHTS; COMBAT VETERANS; VIOLENCE; ALCOHOL; PERPETRATION; EMOTION; ANGER AB This study examined whether laboratory exposure to traumatic reminders potentiated the relationship between veterans' posttraumatic stress disorder (PTSD) symptoms and intimate partner aggression (IPA) articulations elicited during an anger-induction task. The sample included 82 male Operation Iraqi Freedom/Operation Enduring Freedom veterans. The Articulated Thoughts in Simulated Situations (ATSS) procedure was used to assess physical IPA articulations (i.e., expressions of physically aggressive intentions toward the partner) and verbal IPA articulations (i.e., statements intended to insult or demean the partner) made during "relationship anger" provoking scenarios. Participants were administered versions of the ATSS both with and without trauma cue presentation. Results indicated that trauma cue exposure potentiated the relationship between veterans' PTSD symptoms and physical IPA articulations, but did not strengthen the significant relationship between PTSD symptoms and verbal IPA articulations. Findings contribute to the literature on veterans' PTSD symptoms and IPA perpetration by highlighting the influence of traumatic reminders. C1 [LaMotte, Adam D.; Taft, Casey T.; Weatherill, Robin P.] VA Boston Healthcare Syst 116B 4, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. [Taft, Casey T.; Weatherill, Robin P.; Scott, Jillian P.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Scott, Jillian P.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA 02130 USA. [Eckhardt, Christopher I.] Purdue Univ, W Lafayette, IN 47907 USA. RP Taft, CT (reprint author), VA Boston Healthcare Syst 116B 4, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA.; Taft, CT (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM casey.taft@va.gov FU Department of Veterans Affairs FX This research was supported by a Department of Veterans Affairs Merit Review grant awarded to Casey T. Taft. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 29 TC 0 Z9 0 U1 5 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7482 EI 1573-2851 J9 J FAM VIOLENCE JI J. Fam. Violence PD MAY PY 2016 VL 31 IS 4 BP 461 EP 466 DI 10.1007/s10896-015-9776-9 PG 6 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA DK5IQ UT WOS:000374954000005 ER PT J AU Deshpande, V Konstantinidis, IT Fernandez-del Castillo, C Hezel, AF Haigis, KM Ting, DT Bardeesy, N Goyal, L Zhu, AX Warshaw, AL Lillemoe, KD Ferrone, CR AF Deshpande, Vikram Konstantinidis, Ioannis T. Fernandez-del Castillo, Carlos Hezel, Aram F. Haigis, Kevin M. Ting, David T. Bardeesy, Nabeel Goyal, Lipika Zhu, Andrew X. Warshaw, Andrew L. Lillemoe, Keith D. Ferrone, Cristina R. TI Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Intra-pancreatic distal bile duct carcinoma; Pancreatic ductal adenocarcinoma; KRAS ID SINGLE-INSTITUTION; 5-YEAR SURVIVORS; CANCER; MUTATIONS; CHOLANGIOCARCINOMA; GEMCITABINE; EXPERIENCE; CISPLATIN; ONCOGENE AB Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials. C1 [Deshpande, Vikram; Haigis, Kevin M.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. [Konstantinidis, Ioannis T.; Fernandez-del Castillo, Carlos; Warshaw, Andrew L.; Lillemoe, Keith D.; Ferrone, Cristina R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hezel, Aram F.; Ting, David T.; Bardeesy, Nabeel; Goyal, Lipika; Zhu, Andrew X.] Massachusetts Gen Hosp, Dept Oncol, Boston, MA 02114 USA. RP Deshpande, V (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM vdeshpande@mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 FU Polsky Foundation; Gruenebaum Foundation FX This research has been supported by the Polsky Foundation and the Gruenebaum Foundation. NR 22 TC 2 Z9 2 U1 0 U2 0 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 MAY PY 2016 VL 20 IS 5 BP 953 EP 959 DI 10.1007/s11605-016-3108-0 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DL2KC UT WOS:000375462500010 PM 26956004 ER PT J AU Gallegos, AM Streltzov, NA Stecker, T AF Gallegos, Autumn M. Streltzov, Nicholas A. Stecker, Tracy TI Improving Treatment Engagement for Returning Operation Enduring Freedom and Operation Iraqi Freedom Veterans With Posttraumatic Stress Disorder, Depression, and Suicidal Ideation SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE OEF/OIF veterans; posttraumatic stress disorder; suicidal ideation; treatment engagement ID MENTAL-HEALTH TREATMENT; AFGHANISTAN; CARE; PREDICTORS; SERVICES; BARRIERS; SAMPLE; PTSD; RISK; WAR AB Posttraumatic stress disorder (PTSD) is associated with increased risk of suicidal ideation among veterans of Operation Enduring Freedom and Operation Iraqi Freedom. This report examined the effectiveness of a brief phone-based cognitive-behavioral intervention on treatment seeking among suicidal and nonsuicidal Operation Enduring Freedom and Operation Iraqi Freedom veterans who screened positive for PTSD. Participants were randomized to the intervention or control conditions. We found that suicidal participants, regardless of condition, were twice as likely to attend treatment as nonsuicidal participants. Participants assigned to the control condition who did not indicate suicidality at baseline were less likely to attend treatment at both the 1- and 6-month follow-up interviews. Qualitative findings of the suicidal participants indicated PTSD and depressive symptoms, low social support, and infrequent positive coping mechanisms. Our finding indicates the effectiveness of an intervention to motivate veterans with PTSD to initiate and remain in treatment. The intervention might be particularly useful prior to experiencing a psychological crisis. C1 [Gallegos, Autumn M.] Univ Rochester, Med Ctr, Dept Psychiat, 300 Crittenden Blvd, Rochester, NY 14642 USA. [Streltzov, Nicholas A.] Geisel Sch Med Dartmouth, Dartmouth Psychiat Res Ctr, Lebanon, NH USA. [Stecker, Tracy] Med Univ S Carolina, Coll Nursing, Charleston, SC 29425 USA. [Stecker, Tracy] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Gallegos, AM (reprint author), Univ Rochester, Med Ctr, Dept Psychiat, 300 Crittenden Blvd, Rochester, NY 14642 USA. EM autumn_gallegos@urmc.rochester.edu FU National Institute of Mental Health [R01 MH086939] FX This research was funded by grant R01 MH086939 from the National Institute of Mental Health. NR 26 TC 0 Z9 0 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3018 EI 1539-736X J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD MAY PY 2016 VL 204 IS 5 BP 339 EP 343 DI 10.1097/NMD.0000000000000489 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DK4LL UT WOS:000374889700002 PM 26894313 ER PT J AU Chandra, RV Leslie-Mazwi, TM Mehta, BP Derdeyn, CP Demchuk, AM Menon, BK Goyal, M Gonzalez, RG Hirsch, JA AF Chandra, Ronil V. Leslie-Mazwi, Thabele M. Mehta, Brijesh P. Derdeyn, Colin P. Demchuk, Andrew M. Menon, Bijoy K. Goyal, Mayank Gonzalez, R. Gilberto Hirsch, Joshua A. TI Does the use of IV tPA in the current era of rapid and predictable recanalization by mechanical embolectomy represent good value? SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review DE Stroke ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN-ACTIVATOR; RANDOMIZED CONTROLLED-TRIAL; INTRAVENOUS T-PA; ENDOVASCULAR THERAPY; CARDIOEMBOLIC STROKE; CLINICAL-OUTCOMES; HEALTH-CARE; THROMBECTOMY; THROMBOLYSIS AB As healthcare delivery in the USA transforms into a model that at its core requires value-based considerations, ischemic stroke is confronted by intersecting forces. Modern techniques allow rapid revascularization in the majority of patients with large vessel occlusions. Dramatic advances in the evidentiary basis for mechanical embolectomy are increasing the number of patients treated with this therapy. A key part of the therapeutic arsenal in many patients treated with interventional techniques has been concurrent intravenous thrombolysis. We consider whether this paradigm warrants change. C1 [Chandra, Ronil V.] Monash Hlth, Monash Imaging, Dept Imaging, Melbourne, Vic, Australia. [Chandra, Ronil V.] Monash Univ, Stroke & Ageing Res Ctr, Dept Med, Melbourne, Vic 3004, Australia. [Leslie-Mazwi, Thabele M.; Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, NeuroEndovasc Program, Boston, MA 02114 USA. [Mehta, Brijesh P.] Mem Neurosci Inst, Hollywood, FL USA. [Derdeyn, Colin P.] Univ Iowa Hosp & Clin, Dept Radiol, Dept Neurol, Iowa City, IA 52242 USA. [Derdeyn, Colin P.] Univ Iowa Hosp & Clin, Dept Neurol Surg, Iowa City, IA 52242 USA. [Demchuk, Andrew M.; Menon, Bijoy K.; Goyal, Mayank] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Demchuk, Andrew M.; Menon, Bijoy K.; Goyal, Mayank] Univ Calgary, Hotchkiss Brain Inst, Dept Radiol, Calgary, AB, Canada. [Demchuk, Andrew M.; Menon, Bijoy K.; Goyal, Mayank] Univ Calgary, Dept Radiol, Calgary, AB, Canada. [Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Neuroradiol Div, Boston, MA 02114 USA. RP Hirsch, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, NeuroEndovasc Program, Boston, MA 02114 USA. EM Hirsch@snisonline.org OI Derdeyn, Colin/0000-0002-5932-2683 NR 53 TC 1 Z9 1 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 MAY PY 2016 VL 8 IS 5 BP 443 EP 446 DI 10.1136/neurintsurg-2015-012231 PG 5 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA DK9SJ UT WOS:000375271300006 PM 26758911 ER PT J AU Gupta, R Xiang, B Ge, SJ Sun, CHJ Yoo, AJ Mehta, BP AF Gupta, Rishi Xiang, Bin Ge, Sijian Sun, Chung-Huan J. Yoo, Albert J. Mehta, Brijesh P. TI Stagnation of treatment times over a decade: results of a pooled analysis from the MERCI registry, MERCI, TREVO, and TREVO 2 trials SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article DE Thrombectomy; Stroke ID ACUTE ISCHEMIC-STROKE; ACUTE MYOCARDIAL-INFARCTION; ENDOVASCULAR THERAPY; INTERVENTIONAL MANAGEMENT; RANDOMIZED-TRIAL; REPERFUSION; THROMBOLYSIS; THROMBECTOMY; OCCLUSIONS; HOSPITALS AB Background There has been a growing interest in improving systems of care for the endovascular treatment of acute ischemic stroke. We analyzed data from previous registries and studies to determine if there has been an improvement in times to reperfusion with increasing experience. Methods We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), MERCI Registry and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), and TREVO 2 trials and assessed times from last known normal to puncture, from hospital arrival to puncture, and procedure duration by year to determine if there has been a reduction in times. Demographic, radiographic, and clinical information were also assessed in a multivariate regression analysis to determine the predictors of good outcomes defined as a modified Rankin Scale score of 0-2 at 3months. Results 1248 patients of mean age 6814years and median NIH Stroke Scale score 18 were analyzed from 2001 to 2011. Procedure times showed a significant improvement while last known normal to puncture times remained static. In multivariate logistic regression analysis, longer last known normal to puncture time and longer procedure duration were associated with a decreased chance of a good outcome (OR 0.84, 95% CI 0.76 to 0.92, p=0.0004 and OR 0.75, 95% CI 0.61 to 0.91, p=0.0040, respectively). Conclusions Despite a reduction in procedure times, there has not been a corresponding improvement in overall last known normal to puncture times over a 10-year period. The current study shows that there are many opportunities to create more efficient endovascular stroke systems of care in trials. C1 [Gupta, Rishi] Wellstar Med Grp Neurosurg, Wellstar Neurosci Network, 61 Whitcher St,Suite 3110, Marietta, GA 30060 USA. [Xiang, Bin] Prospect Analyt, San Jose, CA USA. [Ge, Sijian] Stryker Neurovasc, Fremont, CA USA. [Sun, Chung-Huan J.] Columbia Presbyterian Med Ctr, Dept Neurol, New York, NY 10032 USA. [Yoo, Albert J.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Mehta, Brijesh P.] Mem Hlth Syst, Neurointervent Surg, Hollywood, FL USA. RP Gupta, R (reprint author), Wellstar Med Grp Neurosurg, 61 Whitcher St,Suite 3110, Marietta, GA 30060 USA. EM Rishi.gupta@wellstar.org FU Stryker Neurovascular; Penumbra; Wellstar Health Foundation; National Institutes of Health; Remedy Pharmaceuticals FX RG: Scientific advisory board for Stryker Neurovascular, Covidien, and Rapid Medical; Associate Editor of Journal of Neuroimaging, Journal of NeuroInterventional Surgery, and Interventional Neurology; Royalties from UpToDate; Steering Committee for the DAWN Trial sponsored by Stryker Neurovascular and THERAPY trial sponsored by Penumbra; Grant research funding for ReCCLAIM II from the Wellstar Health Foundation. BX: Funding for statistical support through Stryker Neurovascular. SG: Employee of Stryker Neurovascular. AJY: Research funding from the National Institutes of Health, Penumbra, and Remedy Pharmaceuticals. NR 23 TC 1 Z9 1 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 MAY PY 2016 VL 8 IS 5 BP 453 EP 456 DI 10.1136/neurintsurg-2014-011626 PG 4 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA DK9SJ UT WOS:000375271300008 PM 25805755 ER PT J AU Hirsch, JA Leslie-Mazwi, TM Barr, RM McGinty, G Nicola, GN Patel, AB Manchikanti, L AF Hirsch, Joshua A. Leslie-Mazwi, Thabele M. Barr, Robert M. McGinty, Geraldine Nicola, Gregory N. Patel, Aman B. Manchikanti, Laxmaiah TI The Burwell roadmap SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review DE Economics ID TALE AB In January 2015 the current Secretary of the Department of Health and Human Services (HHS) outlined a bold initiative to shape the delivery of healthcare through a set of strategies aimed at improving the quality of care and reducing the growth of healthcare costs. The strategies include increasing payment incentives tied to higher value care, increasing care coordination and integration, and increasing access to information to guide patients and clinicians. Significantly, the proposal includes specific goals for alternative payment models and value-based payments for the first time in the history of the Medicare program. C1 [Hirsch, Joshua A.; Leslie-Mazwi, Thabele M.; Patel, Aman B.] 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. [Patel, Aman B.; 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 14 TC 7 Z9 7 U1 2 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 MAY PY 2016 VL 8 IS 5 BP 544 EP 546 DI 10.1136/neurintsurg-2015-011706 PG 3 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA DK9SJ UT WOS:000375271300026 PM 25744382 ER PT J AU Hirsch, JA Leslie-Mazwi, TM Barr, RM McGinty, G Nicola, GN Silva, E Manchikanti, L AF Hirsch, Joshua A. Leslie-Mazwi, Thabele M. Barr, Robert M. McGinty, Geraldine Nicola, Gregory N. Silva, Ezequiel, III Manchikanti, Laxmaiah TI The Bundled Payments for Care Improvement Initiative SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review DE Economics AB The Affordable Care Act enters its fifth year firmly entrenched in our national consciousness. One method that has entered the vernacular for achieving cost savings is accountable care. There are other approaches that are less well known. The Bundled Payments for Care Improvement Initiative has the potential to significantly impact neurointerventionalists. We review that initiative here. C1 [Hirsch, Joshua A.; Leslie-Mazwi, Thabele M.] 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. [Silva, Ezequiel, III] South Texas Radiol Grp, San Antonio, TX 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 7 TC 1 Z9 1 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD MAY PY 2016 VL 8 IS 5 BP 547 EP 548 DI 10.1136/neurintsurg-2015-011746 PG 3 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA DK9SJ UT WOS:000375271300027 PM 25829366 ER PT J AU La Fountaine, MF Toda, M Testa, A Bauman, WA AF La Fountaine, Michael F. Toda, Michita Testa, Anthony Bauman, William A. TI Suppression of Serum Prolactin Levels after Sports Concussion with Prompt Resolution Upon Independent Clinical Assessment To Permit Return-to-Play SO JOURNAL OF NEUROTRAUMA LA English DT Article DE adult brain injury; head trauma; hypopituitarism ID TRAUMATIC BRAIN-INJURY; SLEEP; HYPOPITUITARISM; DYSFUNCTION; STATEMENT; SECRETION; HORMONE AB A significant outflow of neurotransmitters and metabolites with associated enhanced cortical excitation occurs after concussive head trauma. Cellular changes in the acute post-injury period cannot be observed directly in humans, and as such, require indirect evidence from systems sufficiently sensitive to central neuronal cellular excitation. Dopamine is a neurotransmitter with numerous targets in the central and peripheral nervous system. Changes to central dopaminergic tone result in reciprocal responses to the level of serum prolactin (PRL). Thus, a concussion may lead to abnormal dopaminergic tone, resulting in dynamic perturbations in the serum PRL concentration. To determine the effect of concussion on serum PRL concentrations, venipuncture was performed in the morning in four male intercollegiate athletes (age, 20 +/- 1 years; height, 71 +/- 5 inches; weight, 174 +/- 21 pounds) within 48 h of concussion and again at 7 and 14 days post-injury. Serum PRL concentrations for each visit were categorized by quartile within the normal range. In all athletes, serum PRL concentrations increased from the lower quartiles in samples obtained closer to the time of injury to the higher quartiles at 14 days post-injury. These serum PRL changes accompanied the resolution of symptoms and the clinical decision to permit return-to-play. It may be postulated that transient augmentation of central dopaminergic tone resulted in inhibition of PRL secretion early after concussion and that disinhibition of PRL release occurred when central dopaminergic tone subsequently returned to baseline levels. This novel observation provides evidence for dopaminergic dysfunction after concussion that may be tracked by determination of serum PRL levels. C1 [La Fountaine, Michael F.] Seton Hall Univ, Sch Hlth & Med Sci, 400 South Orange Ave, S Orange, NJ 07079 USA. [La Fountaine, Michael F.] Seton Hall Univ, Inst Adv Study Rehabil & Sports Sci, S Orange, NJ 07079 USA. [Testa, Anthony] Seton Hall Univ, Dept Athlet, S Orange, NJ 07079 USA. [La Fountaine, Michael F.; Bauman, William A.] James J Peters VA Med Ctr, VA Rehabil Res & Dev Natl Ctr Excellence Med Cons, Bronx, NY USA. [Toda, Michita] Univ Wisconsin, Dept Athlet, Madison, WI USA. [Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. RP La Fountaine, MF (reprint author), Seton Hall Univ, Sch Hlth & Med Sci, 400 South Orange Ave, S Orange, NJ 07079 USA. EM lafounmi@shu.edu NR 20 TC 0 Z9 0 U1 1 U2 1 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 MAY 1 PY 2016 VL 33 IS 9 BP 904 EP 906 DI 10.1089/neu.2015.3968 PG 3 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DK7SA UT WOS:000375124800012 PM 26159360 ER PT J AU Lipkis-Orlando, R Carroll, DL Duffy, ME Weiss, AP Jones, DA AF Lipkis-Orlando, Robin Carroll, Diane L. Duffy, Mary E. Weiss, Anthony P. Jones, Dorothy A. TI Initial Psychometric Evaluation of the Staff Perception of the Disruptive Patient Behavior Scale SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article ID VIOLENCE; ENVIRONMENT; NURSES; CARE AB OBJECTIVE: The aim of this study is to develop and psychometrically test the Staff Perception of Disruptive Patient Behavior (SPDPB) Scale. BACKGROUND: Disruptive patient behaviors impact work safety for nurses in hospitals. There is no standardized approach to capturing staff perceptions of these behaviors. METHOD: A mixed-methods approach was used to develop and psychometrically evaluate the SPDPB Scale. Items were generated from a survey completed by 770 healthcare providers. A prototype 66-item instrument was developed and content validity was obtained. Evaluation of the psychometric properties of the SPDPB Scale was completed with 558 nurses. Evaluation included internal consistency reliability, principal components analysis, and internal consistency reliability derived subscales to refine the final scale. RESULTS: The SPDPB Scale is a multidimensional measure of perceptions of disruptive patient behaviors. The analysis identified 6 components explaining 54.1% of the variance. The final scale contained 65 items. CONCLUSION: This scale demonstrated psychometric adequacy and can be recommended to measure staff perceptions of disruptive patient behavior. C1 [Lipkis-Orlando, Robin] Massachusetts Gen Hosp, Inst Patient Care, Off Patient Advocacy, Off Qual & Safety, Boston, MA 02114 USA. [Carroll, Diane L.; Duffy, Mary E.] Massachusetts Gen Hosp, Inst Patient Care, Munn Ctr Nursing Res, 125 Nashu St, Boston, MA 02114 USA. [Jones, Dorothy A.] Boston Coll, Chestnut Hill, MA 02167 USA. [Weiss, Anthony P.] SUNY Upstate Med Univ, Med Affairs, Syracuse, NY 13210 USA. RP Carroll, DL (reprint author), Massachusetts Gen Hosp, Inst Patient Care, Munn Ctr Nursing Res, 125 Nashu St, Boston, MA 02114 USA. EM dcarroll3@mgh.harvard.edu NR 25 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0002-0443 EI 1539-0721 J9 J NURS ADMIN JI J. Nurs. Adm. PD MAY PY 2016 VL 46 IS 5 BP 250 EP 256 DI 10.1097/NNA.0000000000000339 PG 7 WC Nursing SC Nursing GA DK8BF UT WOS:000375151100006 PM 27093182 ER PT J AU Von Keudell, A Kachooei, AR Moradi, A Jupiter, JB AF Von Keudell, Arvind Kachooei, Amir R. Moradi, Ali Jupiter, Jesse B. TI Outcome of Surgical Fixation of Lateral Column Distal Humerus Fractures SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE distal humerus fractures; lateral column; outcome ID ADULTS AB Objective:The purpose of this study was to report the long-term outcome and complications of surgically fixated lateral unicondylar distal humerus fractures.Design:Retrospective Review.Setting:Two level 1 Trauma Centers, Massachusetts General Hospital and Brigham and Women's Hospital.Patients/Participants:Between 2002 and 2014, 24 patients treated with open reduction and internal fixation for lateral unicondylar distal humerus fractures (OTA/AO type B1 fractures) were retrospectively reviewed.Intervention:Open reduction and internal fixation.Main Outcome Measurements:Union rates, early complications, functional outcome, and the range of elbow motion were evaluated. Disabilities of the arm, shoulder, and hand, Mayo elbow Performance Index, satisfaction, pain scale, and American Shoulder and Elbow Surgeons.Results:The mean age of patients was 46 23 years at the time of surgery. The average final flexion/extension arc of motion was 108 degrees. Reoperations were performed in 9 of 24 elbows after an average 21 31 months. Twenty of the 24 patients were available for the clinical follow-up at an average of 70 months (range: 16-144 months). Disabilities of the arm, shoulder, and hand averaged at 10.8 +/- 11.7 points, satisfaction at 9.5 +/- 1.2, American Shoulder and Elbow Surgeons score at 88.5 +/- 13.3 points at final follow-up. Based on the functional classification proposed by Jupiter, 16 demonstrated good to excellent results, 2 fair and 2 poor result.Conclusions:Outcome of open reduction and internal fixation of isolated lateral column distal humerus fractures can result in high union rates with acceptable outcome scores and high patient satisfaction despite a high reoperation rate.Level of Evidence:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. C1 [Von Keudell, Arvind; Kachooei, Amir R.; Moradi, Ali; Jupiter, Jesse B.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Von Keudell, A (reprint author), Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Dept Orthopaed Surg, Yawkey Ctr Outpatient Care, 55 Fruit St,YAW-2-2C, Boston, MA 02114 USA. EM avonkeudell@mgh.harvard.edu FU AO North America FX A. Von Keudell received funding from AO North America. The remaining authors report no conflict of interest. NR 18 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD MAY PY 2016 VL 30 IS 5 BP 245 EP 250 DI 10.1097/BOT.0000000000000496 PG 6 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA DK3QT UT WOS:000374833200015 PM 26709815 ER PT J AU Mellema, JJ Doornberg, JN Molenaars, RJ Ring, D Kloen, P AF Mellema, Jos J. Doornberg, Job N. Molenaars, Rik J. Ring, David Kloen, Peter CA Traumaplatform Study Collaborative TI Tibial Plateau Fracture Characteristics: Reliability and Diagnostic Accuracy SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE tibial plateau; fracture characteristics; computed tomography; interobserver reliability; diagnostic accuracy ID 3-DIMENSIONAL COMPUTED-TOMOGRAPHY; INTEROBSERVER RELIABILITY; CLASSIFICATION SYSTEMS; BICONDYLAR FRACTURES; TUBERCLE FRACTURES; POSTERIOR APPROACH; HUMERAL FRACTURES; HIGH AGREEMENT; LOW KAPPA; CT AB Objectives: The purpose of this study was to assess the interobserver reliability and diagnostic accuracy for 2-dimensional (2D) and 3-dimensional (3D) computed tomography (CT)-based evaluation of tibial plateau fracture characteristics. We hypothesized that recognition of specific tibial plateau fracture characteristics is equally reliable and accurate in 2DCT and 2D- and 3DCT. Methods: Eighty-one orthopedic trauma surgeons and residents were randomized to either 2DCT or 2D- and 3DCT evaluation of 15 complex tibial plateau fractures using web-based platforms to recognize 4 tibial plateau fracture characteristics: (1) a posteromedial component, (2) a lateral component, (3) a tibial tubercle component, and (4) a tibial spine (central) component. Interobserver reliability was evaluated by Siegel and Castellan's multirater kappa measure and kappa values were interpreted according to the categorical rating by Landis and Koch. Diagnostic accuracy was calculated according to standard formulas. Results: Interobserver reliability of tibial plateau fracture characteristics ranged from "fair" to "substantial". The addition of 3DCT reconstructions did not improve agreement between observers or diagnostic accuracy, because kappa values and diagnostic accuracy were significantly better for evaluation of tibial plateau fractures using 2DCT alone. Diagnostic accuracy of fracture characteristics ranged from 70% to 89% and was better for more frequently encountered components (ie, the posteromedial and lateral component). Conclusions: The recognition of tibial plateau fracture characteristics prove accurate and reliable on CT-based evaluation in this study and may be useful besides current classification systems, which do not account for all fracture components, in daily practice to help clinical decision making. Further research is needed to evaluate whether the use of distinct fracture components helps preoperative planning of surgical approach and specific fixation techniques. C1 [Mellema, Jos J.; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Doornberg, Job N.; Molenaars, Rik J.; Kloen, Peter] Univ Amsterdam, Acad Med Ctr, Dept Orthoped Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Mellema, JJ (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Dept Orthoped Surg, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM josjmellema@gmail.com NR 44 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD MAY PY 2016 VL 30 IS 5 BP E144 EP E151 DI 10.1097/BOT.0000000000000511 PG 8 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA DK3QT UT WOS:000374833200001 PM 27101164 ER PT J AU Mansbach, JM Clark, S Teach, SJ Gern, JE Piedra, PA Sullivan, AF Espinola, JA Camargo, CA AF Mansbach, Jonathan M. Clark, Sunday Teach, Stephen J. Gern, James E. Piedra, Pedro A. Sullivan, Ashley F. Espinola, Janice A. Camargo, Carlos A., Jr. TI Children Hospitalized with Rhinovirus Bronchiolitis Have Asthma-Like Characteristics SO JOURNAL OF PEDIATRICS LA English DT Article ID LENGTH-OF-STAY; VIRAL-ETIOLOGY; PROSPECTIVE MULTICENTER; EMERGENCY-DEPARTMENT AB Children with bronchiolitis often are considered a homogeneous group. However, in a multicenter, prospective study of 2207 young children hospitalized for bronchiolitis, we found that children with respiratory syncytial virus detected differ from those with rhinovirus detected; the latter patients resemble older children with asthma, including more frequent treatment with corticosteroids. C1 [Mansbach, Jonathan M.] Harvard Univ, Sch Med, Dept Med, Boston Childrens Hosp, Boston, MA USA. [Clark, Sunday] Weill Cornell Med Coll, Dept Emergency Med, New York, NY USA. [Teach, Stephen J.] George Washington Univ, Dept Pediat, Childrens Natl Hlth Syst, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Gern, James E.] Univ Wisconsin, Dept Pediat & Med, Sch Med & Publ Hlth, Madison, WI USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Sullivan, Ashley F.; Espinola, Janice A.; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Mansbach, JM (reprint author), Harvard Univ, Sch Med, Dept Med, Boston Childrens Hosp, Boston, MA USA. FU National Institutes of Health [U01 AI-67693] FX Supported by the National Institutes of Health (U01 AI-67693). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. J.M. and P.P. served as consultants for Regneron in 2014. The other authors declare no conflicts of interest. NR 10 TC 2 Z9 2 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2016 VL 172 BP 202 EP + DI 10.1016/j.jpeds.2016.01.041 PG 4 WC Pediatrics SC Pediatrics GA DK8WP UT WOS:000375209600035 PM 26875009 ER PT J AU Amr, G Boulouis, G Bricout, N Modine, T Fayad, G Aguettaz, P Koussa, M AF Amr, Gilles Boulouis, Gregoire Bricout, Nicolas Modine, Thomas Fayad, Georges Aguettaz, Pierre Koussa, Mohamad TI Stroke Presentation of Acute Type A Aortic Dissection with 100% Perfusion-Weighted Imaging-Diffusion-Weighted Imaging Mismatch: A Call for Urgent Action SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Aortic dissection; ischemic stroke; MRI; perfusion-diffusion mismatch ID NEUROLOGICAL SYMPTOMS AB Background and Purpose: Acute stroke in the setting of acute type A aortic dissection is not rare and may contraindicate immediate surgery. Evaluating irreversible brain damage is critical in this setting and magnetic resonance imaging is a key determinant in the decision of selecting surgical over medical treatment for these patients. Summary of Cases: We report herein 2 cases assessed at a tertiary care center for acute stroke. The initial diagnosis workup revealed cerebral hemispheric severe hypoperfusion without any brain infarction. The absence of ischemic lesions prompted surgical repair, despite the severity of clinical symptoms. Both patients demonstrated complete neurological recovery and neuroimaging showed no persistent sequel. Conclusion: Acute type A aortic dissection is an important differential diagnosis in the causative workup for stroke. Brain hypoperfusion alone should not be a contraindication for urgent surgical treatment, regardless of initial clinical neurological severity. (C) 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. C1 [Amr, Gilles; Modine, Thomas; Fayad, Georges; Koussa, Mohamad] CHU Lille, Hop Cardiol, Serv Chirurg Cardiovasc, F-59037 Lille, France. [Boulouis, Gregoire; Aguettaz, Pierre] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Stroke Res, Boston, MA USA. [Bricout, Nicolas; Aguettaz, Pierre] Univ Lille Nord de France, CHRU Lille, Hop Roger Salengro, Dept Neuroradiol, Lille, France. [Aguettaz, Pierre] Hop Prive Clairval, Serv Neuroradiol Intervent, Marseille, France. RP Boulouis, G (reprint author), Ctr Stroke Res, 175 Cambridge St, Boston, MA 02114 USA. EM gregoireboulouis@gmail.com OI Boulouis, Gregoire/0000-0001-8422-9205 NR 10 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD MAY PY 2016 VL 25 IS 5 BP 1280 EP 1283 DI 10.1016/j.jstrokecerebrovasdis.2016.02.012 PG 4 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DK7YW UT WOS:000375144200043 PM 26965469 ER PT J AU Waltz, P Carchman, E Gomez, H Zuckerbraun, B AF Waltz, Paul Carchman, Evie Gomez, Hernando Zuckerbraun, Brian TI Sepsis results in an altered renal metabolic and osmolyte profile SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Sepsis; CLP; Acute kidney injury; Metabolomics ID ACUTE KIDNEY INJURY; EPIDEMIOLOGY; MULTICENTER; DYSFUNCTION; UREA AB Background: Sepsis remains a major health-care burden and source of morbidity and mortality. Acute kidney injury and failure frequently accompanies severe sepsis and contributes to this burden. Despite a great deal of research, the exact mechanisms underlying renal failure in sepsis are poorly understood. This study aims to further understand metabolic changes in renal tissue during sepsis. Materials and methods: Experimental sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Serum and organs were harvested 8 h after CLP. Markers of renal function including serum creatinine, blood urea nitrogen, and cystatin C were measured. Whole kidneys were analyzed for a global biochemical profile via liquid chromatography/tandem mass spectrometry by Metabolon. Results: CLP induced renal injury as evidenced by elevated serum creatinine, blood urea nitrogen, and cystatin C. Global energetic profile in sepsis showed an increase in glycolytic intermediates with decreased flux through the tricarboxylic acid (TCA) cycle. Multiple inflammatory markers were elevated in response to CLP. Levels of osmotic regulators varied, with an overall increase in pinitol, urea, and taurine in response to CLP. Conclusions: CLP resulted in dramatic changes in the renal macromolecular milieu. There appears to be an increased dependence on glycolysis and diminished flush through the TCA cycle. In addition, changes in renal osmolytes including pinitol, urea, and taurine were observed, perhaps uncovering an additional change with implications on renal function during sepsis. Published by Elsevier Inc. C1 [Waltz, Paul; Carchman, Evie; Zuckerbraun, Brian] Univ Pittsburgh, Dept Surg, F1267PUH,200 Lothrop St, Pittsburgh, PA 15213 USA. [Gomez, Hernando] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Zuckerbraun, Brian] VA Pittsburgh Healthcare Syst, Univ Dr C, Pittsburgh, PA USA. RP Zuckerbraun, B (reprint author), Univ Pittsburgh, Dept Surg, F1267PUH,200 Lothrop St, Pittsburgh, PA 15213 USA. EM zuckerbraunbs@upmc.edu FU NIH [GM113816] FX This work was funded by NIH grant GM113816. NR 14 TC 2 Z9 2 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD MAY 1 PY 2016 VL 202 IS 1 BP 8 EP 12 DI 10.1016/j.jss.2015.12.011 PG 5 WC Surgery SC Surgery GA DK5OR UT WOS:000374969800002 PM 27083942 ER PT J AU Scahill, L Jeon, S Boorin, SJ McDougle, CJ Aman, MG Dziura, J McCracken, JT Caprio, S Arnold, LE Nicol, G Deng, YH Challa, SA Vitiello, B AF Scahill, Lawrence Jeon, Sangchoon Boorin, Susan J. McDougle, Christopher J. Aman, Michael G. Dziura, James McCracken, James T. Caprio, Sonia Arnold, L. Eugene Nicol, Ginger Deng, Yanhong Challa, Saankari A. Vitiello, Benedetto TI Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE autism spectrum disorder; risperidone; weight gain; metabolic syndrome; insulin resistance ID PERVASIVE DEVELOPMENTAL DISORDERS; ABERRANT BEHAVIOR CHECKLIST; RANDOMIZED CLINICAL-TRIAL; CARDIOVASCULAR RISK; CARDIOMETABOLIC RISK; INSULIN-RESISTANCE; GLUCOSE-TOLERANCE; CHOLESTEROL RATIO; OBESE CHILDREN; ADOLESCENTS AB Objective: We examine weight gain and metabolic consequences of risperidone monotherapy in children with autism spectrum disorder (ASD). Method: This was a 24-week, multisite, randomized trial of risperidone only versus risperidone plus parent training in 124 children (mean age 6.9 +/- 2.35 years; 105 boys and 19 girls) with ASD and serious behavioral problems. We monitored height, weight, waist circumference, and adverse effects during the trial. Fasting blood samples were obtained before treatment and at week 16. Results: In 97 children with a mean of 22.9 +/- 2.8 weeks of risperidone exposure, there was a 5.4 +/- 3.4 kg weight gain over 24 weeks (p<.0001); waist circumference increased from 60.7 +/- 10.4 cm to 66.8 +/- 11.3 cm (p<.0001). At baseline, 59 of 97 children (60.8%) were classified as having normal weight; by week 24, only 25 of 85 (29.4%) remained in that group. Growth curve analysis showed a significant change in body mass index (BMI) z scores from pretreatment to week 24 (p<.0001). This effect was significantly greater for children with reported increased appetite in the first 8 weeks. From before treatment to week 16, there were significant increases in glucose (p=.02), hemoglobin Alc (p=.01), insulin (p<.0001), homeostatic model assessment insulin resistance (HOMA-IR; p<.001), alanine aminotransferase (p=.01), and leptin (p<.0001). Adiponectin declined (p=.003). At baseline, 7 children met conventional criteria for metabolic syndrome; by week 16, 12 additional children were so classified. Conclusion: Rapid weight gain with risperidone treatment may promote the cascade of biochemical indices associated with insulin resistance and metabolic syndrome. Appetite, weight, waist circumference, liver function tests, blood lipids, and glucose warrant monitoring. C1 [Scahill, Lawrence; Challa, Saankari A.] Emory Univ, Sch Med, Atlanta, GA USA. [Scahill, Lawrence] Marcus Autism Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. [Jeon, Sangchoon; Boorin, Susan J.] Yale Univ, Sch Nursing, West Haven, CT USA. [McDougle, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [McDougle, Christopher J.] Lurie Ctr Autism, Boston, MA USA. [Aman, Michael G.; Arnold, L. Eugene] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Dziura, James; Caprio, Sonia] Yale Univ, Sch Med, New Haven, CT USA. [McCracken, James T.] Univ Calif Los Angeles, Div Child Psychiat, Los Angeles, CA USA. [Nicol, Ginger] Washington Univ, St Louis, MO 63130 USA. [Deng, Yanhong] Yale Univ, New Haven, CT 06520 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Scahill, L (reprint author), Marcus Autism Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. EM lawrence.scahill@emory.edu FU NIMH, Yale [U10MH66764]; NIMH, Indiana University [U10MH66766]; NIMH, Ohio State University [U10MH66768]; Yale CTSA [UL1 RR024139]; IU CTSA [UL1 RR025761]; OSU CTSA [UL1 RR025755]; Atlanta Clinical and Translational Science Institute at Emory University from the National Center for Research Resources [UL1TR000454]; Marcus Foundation; Children's Hospital of Atlanta Trust Fund FX This work was funded by NIMH by the following RUPP grants: Yale, U10MH66764; Indiana University, U10MH66766, Ohio State University, U10MH66768; and Janssen/Johnson and Johnson Pharmaceutical Research and Development provided active risperidone for the study. This publication was also supported by the Yale CTSA UL1 RR024139, IU CTSA UL1 RR025761, OSU CTSA UL1 RR025755, and Atlanta Clinical and Translational Science Institute UL1TR000454 at Emory University from the National Center for Research Resources. Dr. Scahill also received support from the Marcus Foundation and the Children's Hospital of Atlanta Trust Fund. NR 47 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAY PY 2016 VL 55 IS 5 BP 415 EP 423 DI 10.1016/j.jaac.2016.02.016 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DL1AA UT WOS:000375363100014 PM 27126856 ER PT J AU Frydman, GH Bendapudi, PK Marini, RP Vanderburg, CR Tompkins, RG Fox, JG AF Frydman, Galit H. Bendapudi, Pavan K. Marini, Robert P. Vanderburg, Charles R. Tompkins, Ronald G. Fox, James G. TI Coagulation Biomarkers in Healthy Chinese-Origin Rhesus Macaques (Macaca mulatta) SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID P-SELECTIN; D-DIMER; PROTEIN; DISEASE; PLASMA; THROMBOEMBOLISM; ANTITHROMBIN; THROMBOSIS; INFECTION; PATHOLOGY AB Rhesus macaques (Macaca mulatta) are a common model for the study of human biology and disease. To manage coagulopathies in these animals and to study their clotting changes, the ability to measure coagulation biomarkers is necessary Currently, few options for coagulation testing in NHP are commercially available. In this study, assays for 4 coagulation biomarkers-D-dimer, antithrombin III, protein C, and soluble P-selectin were developed and optimized for rhesus macaques. Whole blood was collected from 28 healthy Chinese-origin rhesus macaques (11 male; 17 female) ranging in age from 5 to 20 y. Coagulation biomarkers were measured by using bead-based sandwich ELISA technology The ranges (mean +/- 90% confidence interval) for these biomarkers were: antithrombin III, 124.2 to 133.4 mu g/mL; protein C, 3.2 to 3.6 mu g/mL; D-dimer, 110.3 to 161.3 ng/mL; soluble P-selectin, 0.12 to 0.14 ng/10(6) platelets. These reference values did not differ significantly according to sex or age. These new assays for coagulation biomarkers in rhesus macaques will facilitate the evaluation of in vivo hemostasis. C1 [Frydman, Galit H.; Marini, Robert P.; Fox, James G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Frydman, Galit H.; Marini, Robert P.; Fox, James G.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Frydman, Galit H.; Tompkins, Ronald G.] Massachusetts Gen Hosp, Div Surg Sci & Bioengn, Boston, MA 02114 USA. [Bendapudi, Pavan K.] Massachusetts Gen Hosp, Div Hematol, Boston, MA 02114 USA. [Vanderburg, Charles R.] Massachusetts Gen Hosp, Inst Neurodegenerat Dis, Adv Tissue Resource Ctr, Charlestown, MA USA. [Frydman, Galit H.; Bendapudi, Pavan K.; Vanderburg, Charles R.; Tompkins, Ronald G.] Harvard Univ, Sch Med, Boston, MA USA. RP Frydman, GH (reprint author), MIT, Div Comparat Med, Cambridge, MA 02139 USA.; Frydman, GH (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Frydman, GH (reprint author), Massachusetts Gen Hosp, Div Surg Sci & Bioengn, Boston, MA 02114 USA.; Frydman, GH (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM girydman@mit.edu FU [T32-0D019078-27]; [P30-ES002109]; [P50-GM021700] FX Financial support was provided by grants T32-0D019078-27 (to JGF), P30-ES002109 (to JGF), and P50-GM021700 (to RGT). NR 35 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAY PY 2016 VL 55 IS 3 BP 252 EP 259 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DL3BY UT WOS:000375510400002 PM 27177557 ER PT J AU Brink, JA AF Brink, James A. TI Adding Value Isn't an Option Anymore SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Brink, James A.] Massachusetts Gen Hosp, 55 Fruit St,FND-216, Boston, MA 02114 USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,FND-216, Boston, MA 02114 USA. EM jabrink@partners.org 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAY PY 2016 VL 13 IS 5 BP 487 EP 488 DI 10.1016/j.jacr.2016.02.007 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DL0YE UT WOS:000375357700001 PM 27151263 ER PT J AU Veenstra, CM Vachani, A Ciunci, CA Zafar, HM Epstein, AI Paulson, EC AF Veenstra, Christine M. Vachani, Anil Ciunci, Christine A. Zafar, Hanna M. Epstein, Andrew I. Paulson, E. Carter TI Trends in the Use of F-18-Fluorodeoxyglucose PET Imaging in Surveillance of Non-Small-Cell Lung and Colorectal Cancer SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol DE Positron emission tomographic imaging; surveillance; colorectal cancer; non-small-cell lung cancer; Choosing Wisely; FDG-PET ID MEDICARE BENEFICIARIES; FOLLOW-UP; CLINICAL ONCOLOGY; AMERICAN SOCIETY; TOMOGRAPHY AB Purpose: Surveillance PET after curative-intent treatment of non small-cell lung cancer (NSCLC) or colorectal cancer (CRC) is not clearly supported by available evidence or the Choosing Wisely campaign. However, the frequency of PET imaging during the surveillance period is relatively unknown. Methods: Using Surveillance, Epidemiology, and End Results Medicare data, 65,748 patients aged 66 years or older who were diagnosed with stage I to IIIA NSCLC or stage I to III CRC from 2001 through 2009 and who underwent surgical resection were identified. Trends in "any PET" or "PET-only" use 6 to 18 months postoperatively were assessed. Results: Any PET use more than doubled over the study period. Eleven percent of patients with NSCLC and 4% of those with CRC diagnosed in 2001 received any PET, compared with 25% of patients with NSCLC and 13% of those with CRC in 2009 (P < .001 for both). Higher stage disease was correlated with higher PET utilization and faster growth in use over the study period. PET-only use also increased over the study period, especially in higher stage disease. Fewer than 2% of patients diagnosed with stage IIIA NSCLC in 2001 received PET only, compared with 15% of patients diagnosed in 2009 (P = .014). Similarly, 1% of patients diagnosed with stage III CRC in 2001 received PET only, compared with 8% of patients diagnosed in 2009 (P < .001). Conclusions: PET utilization during the surveillance period increased between 2001 and 2009. Further research is needed to determine the factors driving use of surveillance PET and to examine relationships between PET and patient outcomes. C1 [Veenstra, Christine M.] Univ Michigan, Dept Internal Med, North Ingalls Bldg,3A22,300 North Ingalls, Ann Arbor, MI 48109 USA. [Veenstra, Christine M.] Univ Michigan, Inst Healthcare Policy & Innovat, North Ingalls Bldg,3A22,300 North Ingalls, Ann Arbor, MI 48109 USA. [Vachani, Anil; Ciunci, Christine A.; Epstein, Andrew I.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Zafar, Hanna M.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Zafar, Hanna M.; Epstein, Andrew I.; Paulson, E. Carter] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Vachani, Anil; Epstein, Andrew I.; Paulson, E. Carter] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Paulson, E. Carter] Univ Penn, Div Colon & Rectal Surg, Philadelphia, PA 19104 USA. RP Veenstra, CM (reprint author), Univ Michigan, North Ingalls Bldg,3A22,300 North Ingalls, Ann Arbor, MI 48109 USA. EM cveenstr@med.umich.edu FU NCI NIH HHS [P30 CA016520] NR 13 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAY PY 2016 VL 13 IS 5 BP 491 EP 496 DI 10.1016/j.jacr.2015.11.016 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DL0YE UT WOS:000375357700004 PM 26774883 ER PT J AU Percac-Lima, S Ashburner, JM Shepard, JAO Lennes, IT Rimmelin, DE Atlas, SJ AF Percac-Lima, Sanja Ashburner, Jeffrey M. Shepard, Jo-Anne O. Lennes, Inga T. Rimmelin, Dorothy E. Atlas, Steven J. TI Timeliness of Recommended Follow-Up After an Abnormal Finding on Diagnostic Chest CT in Smokers at High Risk of Developing Lung Cancer SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE CT; pulmonary nodule; smokers; lost to follow-up ID PULMONARY NODULES; FLEISCHNER-SOCIETY; SELECTION CRITERIA; GUIDELINES; MANAGEMENT; TRIAL; SCANS; CARE; TOO AB Purpose: Diagnostic chest CT frequently results in abnormal findings that require follow-up. We assessed the timeliness of follow-up after CT abnormalities were identified in symptomatic smokers at high risk for developing lung cancer. Methods: In an academic primary care network, we identified current smokers aged 55-79 years who received a diagnostic chest CT to evaluate symptoms during 2012. Medical chart abstraction identified radiologist recommendations and follow-up care. The outcome was the proportion of patients who received timely follow-up (within 30 days of recommendation) after an abnormal chest CT. We assessed for predictors of compliance with recommended follow-up. Results: Of 3,257 eligible smokers, 446 (14%) had a chest CT during 2012. We excluded 70 patients who already had lung cancer, died, had imaging done elsewhere, or left the practice. Of the remaining 376 patients, 337 (90%) had abnormal chest CT findings, and 184 (55%) had a specific follow-up recommendation. Among those with recommended follow-up, only 102 of 184 (55%) had timely follow-up. Those who had a CT performed to evaluate pulmonary disease and those receiving care in community health centers were more likely to receive timely follow-up. Of 27 patients newly diagnosed with lung cancer, 18 (67%) had their first oncology visit within 30 days of diagnosis. Conclusions: Among patients undergoing diagnostic chest CTs, most received follow-up for abnormal findings, but it was often delayed. Systems to support patients in obtaining recommended follow-up are needed to ensure that the benefits of lung cancer screening translate into usual clinical practice. C1 [Percac-Lima, Sanja] Massachusetts Gen Hosp, Chelsea HealthCare Ctr, Chelsea, MA USA. [Percac-Lima, Sanja; Ashburner, Jeffrey M.; Atlas, Steven J.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Percac-Lima, Sanja; Shepard, Jo-Anne O.; Lennes, Inga T.; Rimmelin, Dorothy E.; Atlas, Steven J.] Harvard Univ, Sch Med, Boston, MA USA. [Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Lennes, Inga T.] Massachusetts Gen Hosp, Ctr Canc, 50 Staniford St,9th Floor, Boston, MA 02114 USA. RP Percac-Lima, S (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM Spercaclima@mgh.harvard.edu FU American Cancer Society: Cancer Control Career Development Award for Primary Care Physicians [CCCDAA-14-012-01-CCCDA]; Lazarex Cancer Foundation FX Sanja Percac-Lima is in part supported by the American Cancer Society: Cancer Control Career Development Award for Primary Care Physicians, CCCDAA-14-012-01-CCCDA; and Lazarex Cancer Foundation. NR 23 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAY PY 2016 VL 13 IS 5 BP 497 EP 504 DI 10.1016/j.jacr.2016.01.007 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DL0YE UT WOS:000375357700005 PM 26924163 ER PT J AU Swan, JS Pandharipande, PV Salazar, GM AF Swan, J. Shannon Pandharipande, Pari V. Salazar, Gloria M. TI Developing a Patient-Centered Radiology Process Model SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Patient-centered care; radiology process; quality of life ID TESTING MORBIDITIES INDEX; PROCESS UTILITY; CARE; MULTIATTRIBUTE; PREFERENCES; SYSTEM AB Purpose: There has been increasing interest in the process of care that patients experience. To keep step with the rest of medicine, our specialty should be designing metrics that assess the overall experience of patients seeking care in radiology departments. A recent memo from the ACR chair calls for more work in this area. The aim of this study was to develop a patient-centered model for the experience of radiologic care, which may be helpful in addressing this need. Methods: Using principles of multiattribute utility theory and psychometric theory as well as recent literature, a model was developed for a patient-centered index that could be used in radiology facilities. Results: A model was developed that concisely incorporates patient-centeredness of both radiologists and staff members (communication with patient and referrers, competence, and pain control) as well as patient- and process-related issues such as costs, procedural morbidity, access to care, appointment duration, waiting, timing of appointments, cleanliness of facility, and coordination with clinical services. The overall radiology process model was constructed as a set of nested models, which allow more integrated detail within the domains of patient experience. Conclusions: This model and others like it may help the ACR develop quality metrics to reasonably quantify the patient experience. C1 [Swan, J. Shannon; Pandharipande, Pari V.] Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Swan, J. Shannon; Pandharipande, Pari V.; Salazar, Gloria M.] Harvard Univ, Sch Med, Boston, MA USA. [Salazar, Gloria M.] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. RP Swan, JS (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM jsswan@mgh.harvard.edu FU American Cancer Society [PEP-14-206-01-PCSM]; Medical Imaging and Technology Alliance FX Dr Swan receives funding from the American Cancer Society (PEP-14-206-01-PCSM). Dr Pandharipande receives funding from the Medical Imaging and Technology Alliance. The authors have no conflicts of interest related to the material discussed in this article. NR 35 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAY PY 2016 VL 13 IS 5 BP 510 EP 516 DI 10.1016/j.jacr.2015.11.022 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DL0YE UT WOS:000375357700007 PM 26833030 ER PT J AU Molina, G Jiang, W Edmondson, L Gibbons, L Huang, LC Kiang, MV Haynes, AB Gawande, AA Berry, WR Singer, SJ AF Molina, George Jiang, Wei Edmondson, Lizabeth Gibbons, Lorri Huang, Lyen C. Kiang, Mathew V. Haynes, Alex B. Gawande, Atul A. Berry, William R. Singer, Sara J. TI Implementation of the Surgical Safety Checklist in South Carolina Hospitals Is Associated with Improvement in Perceived Perioperative Safety SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID OPERATING-ROOM DELAYS; PATIENT SAFETY; COMMUNICATION; MORTALITY; MORBIDITY; TEAMWORK; SURGERY; IMPACT; PERFORMANCE; BRIEFINGS AB BACKGROUND: Previous research suggests that surgical safety checklists (SSCs) are associated with reductions in postoperative morbidity and mortality as well as improvement in teamwork and communication. These findings stem from evaluations of individual or small groups of hospitals. Studies with more hospitals have assessed the relationship of checklists with teamwork at a single point in time. The objective of this study was to evaluate the impact of a large-scale implementation of SSCs on staff perceptions of perioperative safety in the operating room. STUDY DESIGN: As part of the Safe Surgery 2015 initiative to implement SSCs in South Carolina hospitals, we administered a validated survey designed to measure perception of multiple dimensions of perioperative safety among clinical operating room personnel before and after implementation of an SSC. RESULTS: Thirteen hospitals administered baseline and follow-up surveys, separated by 1 to 2 years. Response rates were 48.4% at baseline (929 of 1,921) and 42.7% (815 of 1,909) at follow-up. Results suggest improvement in all of the 5 dimensions of teamwork (relative percent improvement ranged from +2.9% for coordination to +11.9% for communication). These were significant after adjusting for respondent characteristics, hospital fixed-effects, multiple comparisons, and clustering robust standard errors by hospital (all p < 0.05). More than half of respondents (54.1%) said their surgical teams always used checklists effectively; 73.6% said checklists had averted problems or complications. CONCLUSIONS: A large-scale initiative to implement SSCs is associated with improved staff perceptions of mutual respect, clinical leadership, assertiveness on behalf of safety, team coordination and communication, safe practice, and perceived checklist outcomes. (C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved. C1 [Molina, George; Edmondson, Lizabeth; Haynes, Alex B.; Gawande, Atul A.; Berry, William R.; Singer, Sara J.] Brigham & Womens Hosp, Ariadne Labs, 75 Francis St, Boston, MA 02115 USA. [Molina, George; Edmondson, Lizabeth; Haynes, Alex B.; Gawande, Atul A.; Berry, William R.; Singer, Sara J.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Molina, George; Haynes, Alex B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Singer, Sara J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Jiang, Wei] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, 75 Francis St, Boston, MA 02115 USA. [Kiang, Mathew V.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Huang, Lyen C.; Singer, Sara J.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. [Gibbons, Lorri] South Carolina Hosp Assoc, Columbia, SC USA. RP Singer, SJ (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ssinger@hsph.harvard.edu FU AHRQ [R18:HS019631-01] FX Supported by a grant from AHRQ (R18:HS019631-01). NR 39 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD MAY PY 2016 VL 222 IS 5 BP 725 EP + DI 10.1016/j.jamcollsurg.2015.12.052 PG 17 WC Surgery SC Surgery GA DK7UD UT WOS:000375130300006 PM 27049781 ER PT J AU Berian, JR Paruch, JL Cohen, ME Merkow, RP Dahlke, AR Ko, CY Bilimoria, KY AF Berian, Julia R. Paruch, Jennifer L. Cohen, Mark E. Merkow, Ryan P. Dahlke, Allison R. Ko, Clifford Y. Bilimoria, Karl Y. TI Does Performance Vary Within the Same Hospital When Separately Examining Different Patient Subgroups? SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; SURGICAL QUALITY; AMERICAN-COLLEGE; SURGERY; OUTCOMES; CANCER; RISK; MORTALITY; NSQIP; DISPARITIES AB BACKGROUND: Surgical quality programs, such as the American College of Surgeons NSQIP, provide reports based on specialty or procedure, with patients aggregated together. It is unknown whether hospital performance differs by patient subgroup (eg cancer vs noncancer patients), masking opportunities for improvement. Our objectives were to determine whether performance differs within a given hospital for 6 contrasting patient subgroups and to identify the percentage of hospitals with greater than chance differences in performance. STUDY DESIGN: Using the American College of Surgeons NSQIP data, adults undergoing lung resection, esophagectomy, hepatectomy, pancreatectomy, colectomy, and proctectomy (2005 through 2012) were divided into 6 contrasting subgroups (elderly vs nonelderly, white vs nonwhite, obese vs nonobese, renal insufficiency vs normal renal function, cancer vs noncancer, emergency vs nonemergency). The main end point was serious morbidity or mortality. Observed to expected ratios were constructed using hierarchical models and compared using paired t-tests (eg observed to expected for cancer cases compared with noncancer). Variation in performance differences was assessed using a randomization test and z-tests for proportions. RESULTS: From 433 hospitals, 221,518 patients were included. Overall quality differed for elderly vs nonelderly, renal insufficiency vs normal renal function patients, cancer vs noncancer, and emergency vs nonemergency (p < 0.05). Variation in within-hospital performance differences exceeded chance expectations for renal insufficiency vs normal renal function in 31.1% of hospitals, cancer vs noncancer in 40.8%, and emergency vs nonemergency patients in 55.4% (p < 0.001). CONCLUSIONS: Hospital performance within a given hospital varies by patient subgroup. Quality programs can consider separate reports for these subgroups to identify opportunities for quality improvement. (C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved. C1 [Berian, Julia R.; Paruch, Jennifer L.; Cohen, Mark E.; Merkow, Ryan P.; Ko, Clifford Y.; Bilimoria, Karl Y.] Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. [Berian, Julia R.; Paruch, Jennifer L.; Merkow, Ryan P.] Univ Chicago, Med Ctr, Dept Surg, Chicago, IL 60637 USA. [Berian, Julia R.; Merkow, Ryan P.; Dahlke, Allison R.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Surg Outcomes & Qual Improvement, Dept Surg, Chicago, IL 60611 USA. [Berian, Julia R.; Merkow, Ryan P.; Dahlke, Allison R.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Northwestern Inst Comparat Effectiveness Res Onco, Chicago, IL 60611 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Berian, JR (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM jberian@facs.org FU Agency for Healthcare Research and Quality [R21 HS21857-01]; American Cancer Society [280521]; American College of Surgeons Clinical Scholars in Residence Program, University of Chicago Medical Center, Northwestern University; John A Hartford Foundation; American College of Surgeons, the University of Chicago, Northwestern University; Genentech FX This work was supported in part by the Agency for Healthcare Research and Quality (R21 HS21857-01; Principal Investigator: Dr Bilimoria) and American Cancer Society (280521; Principal Investigator: Dr Bilimoria). Dr Berian's fellowship position at the American College of Surgeons as a Clinical Scholar in Residence is supported by the American College of Surgeons Clinical Scholars in Residence Program, University of Chicago Medical Center, Northwestern University, and a grant from the John A Hartford Foundation. Dr Paruch's American College of Surgeons Clinical Scholars in Residence fellowship was supported by the American College of Surgeons, the University of Chicago, Northwestern University, and an unrestricted educational grant from Genentech, which had no input on the selection of the recipient, research topic, research direction, or the content of any resulting report, presentation, or publication. NR 27 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 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD MAY PY 2016 VL 222 IS 5 BP 790 EP + DI 10.1016/j.jamcollsurg.2016.01.057 PG 9 WC Surgery SC Surgery GA DK7UD UT WOS:000375130300012 PM 27016904 ER PT J AU Bertrand, PB Levine, RA Isselbacher, EM Vandervoort, PM AF Bertrand, Philippe B. Levine, Robert A. Isselbacher, Eric M. Vandervoort, Pieter M. TI Fact or Artifact in Two-Dimensional Echocardiography: Avoiding Misdiagnosis and Missed Diagnosis SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Review DE Echocardiography; Ultrasound physics; Artifacts ID LEFT ATRIAL APPENDAGE; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; AORTIC DISSECTION; FIGURE-OF-8 ARTIFACT; MIRROR-IMAGE; DOPPLER ARTIFACTS; ASCENDING AORTA; LOBE ARTIFACTS; ULTRASOUND; COLOR AB Two-dimensional transthoracic echocardiography is the most widely used noninvasive imaging modality for the evaluation and diagnosis of cardiac pathology. However, because of the physical properties of ultrasound waves and specifics in ultrasound image reconstruction, cardiologists are often confronted with ultrasound image artifacts. It is particularly important to recognize such artifacts in order to avoid misdiagnosis of conditions ranging from aortic dissection to thrombosis and endocarditis. This overview article summarizes the most common image artifacts encountered in routine clinical practice, along with explanations of their physical mechanisms and guidance in avoiding their misinterpretation. C1 [Bertrand, Philippe B.; Vandervoort, Pieter M.] Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium. [Bertrand, Philippe B.; Vandervoort, Pieter M.] Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium. [Levine, Robert A.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. RP Vandervoort, PM (reprint author), Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium. EM pieter.vandervoort@zol.be FU Research Foundation Flanders (FWO) [11N7214N]; National Institutes of Health (Bethesda, MD) [R01 HL109506]; Leducq Foundation (Paris, France) [07CVD04] FX Funding was provided in part by the Research Foundation Flanders (FWO), 11N7214N (P.B.B.), and by grant R01 HL109506, National Institutes of Health (Bethesda, MD) (R.A.L.) and grant 07CVD04 of the Leducq Foundation (Paris, France). NR 51 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD MAY PY 2016 VL 29 IS 5 BP 381 EP 391 DI 10.1016/j.echo.2016.01.009 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK7XE UT WOS:000375139300004 PM 26969139 ER PT J AU Tsao, AS Scagliotti, GV Bunn, PA Carbone, DP Warren, GW Bai, CX de Koning, HJ Yousaf-Khan, AU McWilliams, A Tsao, MS Adusumilli, PS Rami-Porta, R Asamura, H Van Schil, PE Darling, GE Ramalingam, SS Gomez, DR Rosenzweig, KE Zimmermann, S Peters, S Ignatius, SH Reungwetwattana, T Janne, PA Mok, TS Wakelee, HA Pirker, R Mazieres, J Brahmer, JR Zhou, Y Herbst, RS Papadimitrakopoulou, VA Redman, MW Wynes, MW Gandara, DR Kelly, RJ Hirsch, FR Pass, HI AF Tsao, Anne S. Scagliotti, Giorgio V. Bunn, Paul A., Jr. Carbone, David P. Warren, Graham W. Bai, Chunxue de Koning, Harry J. Yousaf-Khan, A. Uraujh McWilliams, Annette Tsao, Ming Sound Adusumilli, Prasad S. Rami-Porta, Ramon Asamura, Hisao Van Schil, Paul E. Darling, Gail E. Ramalingam, Suresh S. Gomez, Daniel R. Rosenzweig, Kenneth E. Zimmermann, Stefan Peters, Solange Ignatius, Sai-Hong Reungwetwattana, Thanyanan Jaenne, Pasi A. Mok, Tony S. Wakelee, Heather A. Pirker, Robert Mazieres, Julien Brahmer, Julie R. Zhou, Yang Herbst, Roy S. Papadimitrakopoulou, Vassiliki A. Redman, Mary W. Wynes, Murry W. Gandara, David R. Kelly, Ronan J. Hirsch, Fred R. Pass, Harvey I. TI Scientific Advances in Lung Cancer 2015 SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Lung cancer; Smoking cessation; Cancer prevention; Targeted therapy; Immunotherapy; Screening; Pathology; Staging; Surgery; Adjuvant chemotherapy; Radiotherapy; Gene mutations; Master protocols; Biomarkers; Value of therapy ID RESPIRATORY SOCIETY CLASSIFICATION; PREVIOUSLY TREATED PATIENTS; BODY RADIATION-THERAPY; ALK-POSITIVE NSCLC; PHASE-III TRIAL; MUTATION CONFERS RESISTANCE; VINORELBINE PLUS CISPLATIN; STAGING PROJECT PROPOSALS; HARBORING BRAF MUTATIONS; FORTHCOMING 8TH EDITION AB Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. C1 [Tsao, Anne S.; Papadimitrakopoulou, Vassiliki A.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Scagliotti, Giorgio V.] Univ Turin, San Luigi Hosp, Orbassano, Italy. [Bunn, Paul A., Jr.; Hirsch, Fred R.] Univ Colorado, Ctr Canc, Div Med Oncol, Aurora, CO USA. [Carbone, David P.] Ohio State Univ, Div Med Oncol, Columbus, OH 43210 USA. [Warren, Graham W.] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Dept Radiat Oncol, Charleston, SC 29425 USA. [Bai, Chunxue] Fudan Univ, Zhongshan Hosp, Dept Pulm Med, Shanghai Resp Res Inst, Wuhan, Peoples R China. [de Koning, Harry J.; Yousaf-Khan, A. Uraujh] Univ Med Ctr Rotterdam, Erasmus Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands. [McWilliams, Annette] Fiona Stanley Hosp, Murdoch, WA, Australia. [McWilliams, Annette] Univ Western Australia, Perth, WA 6009, Australia. [Tsao, Ming Sound] Univ Hlth Network, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Tsao, Ming Sound] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Adusumilli, Prasad S.] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Serv, 1275 York Ave, New York, NY 10021 USA. [Adusumilli, Prasad S.] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, 1275 York Ave, New York, NY 10021 USA. [Rami-Porta, Ramon] Univ Barcelona, Hosp Univ Mutua Terrassa, Dept Thorac Surg, E-08007 Barcelona, Spain. [Rami-Porta, Ramon] Ctr Invest Biomed Red Enfermedades Resp CIBERES, Lung Canc Grp, Barcelona, Spain. [Asamura, Hisao] Keio Univ, Sch Med, Div Thorac Surg, Tokyo, Japan. [Van Schil, Paul E.] Univ Antwerp Hosp, Dept Thorac & Vasc Surg, Antwerp, Belgium. [Darling, Gail E.] Univ Toronto, Div Thorac Surg, Toronto, ON, Canada. [Ramalingam, Suresh S.] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA. [Gomez, Daniel R.] Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, Dept Radiat Oncol, Houston, TX 77030 USA. [Rosenzweig, Kenneth E.] Icahn Sch Med Mt Sinai, Dept Radiat Oncol, New York, NY 10029 USA. [Zimmermann, Stefan] HFR Fribourg, Dept Oncol, Fribourg, Switzerland. [Peters, Solange] Univ Lausanne, Dept Oncol, Lausanne, Switzerland. [Ignatius, Sai-Hong] Univ Calif Irvine, Sch Med, Dept Med, Chao Family Comprehens Canc Ctr,Div Hematol Oncol, Orange, CA 92668 USA. [Reungwetwattana, Thanyanan] Mahidol Univ, Ramathibodi Hosp, Fac Med, Div Med Oncol,Dept Med, Bangkok 10400, Thailand. [Jaenne, Pasi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Mok, Tony S.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. [Wakelee, Heather A.] Stanford Univ, Dept Med, Sch Med, Div Oncol, Stanford, CA 94305 USA. [Pirker, Robert] Med Univ Vienna, Dept Med 1, Vienna, Austria. [Mazieres, Julien] Univ Toulouse 3, Larrey Hosp, F-31062 Toulouse, France. [Brahmer, Julie R.] Johns Hopkins, Johns Hopkins Kimmel Canc Ctr, Baltimore, MD USA. [Zhou, Yang] Yale Univ, Sch Med, Yale Comprehens Canc Ctr, New Haven, CT 06504 USA. [Herbst, Roy S.] Yale Canc Ctr, New Haven, CT USA. [Herbst, Roy S.] Yale New Haven, Smilow Canc Hosp, New Haven, CT USA. [Redman, Mary W.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div Seattle, 1124 Columbia St, Seattle, WA 98104 USA. [Wynes, Murry W.] Int Assoc Study Lung Canc, Aurora, CO USA. [Gandara, David R.] UC Davis Comprehens Canc Ctr, Thorac Oncol Program, Sacramento, CA USA. [Kelly, Ronan J.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Pass, Harvey I.] NYU, Langone Med Ctr, Dept Cardiothorac Surg, New York, NY USA. RP Hirsch, FR (reprint author), Univ Colorado, Ctr Canc, Div Med Oncol, Aurora, CO USA. OI Van Schil, Paul/0000-0002-1962-8821; MAZIERES, JULIEN/0000-0002-5921-7613 FU NCI NIH HHS [P30 CA016672] NR 253 TC 16 Z9 16 U1 8 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD MAY PY 2016 VL 11 IS 5 BP 613 EP 638 DI 10.1016/j.jtho.2016.03.012 PG 26 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DL1DN UT WOS:000375372500001 PM 27013409 ER PT J AU Janne, PA Shaw, AT Camidge, DR Giaccone, G Shreeve, SM Tang, YY Goldberg, Z Martini, JF Xu, HP James, LR Solomon, BJ AF Janne, Pasi A. Shaw, Alice T. Camidge, D. Ross Giaccone, Giuseppe Shreeve, S. Martin Tang, Yiyun Goldberg, Zelanna Martini, Jean-Francois Xu, Huiping James, Leonard R. Solomon, Benjamin J. TI Combined Pan-HER and ALK/ROS1/MET Inhibition with Dacomitinib and Crizotinib in Advanced Non-Small Cell Lung Cancer: Results of a Phase I Study SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Non-small cell; Dacomitinib; Crizotinib; EGFR TKI resistance; Biomarkers ID RECEPTOR GENE-MUTATIONS; ACQUIRED-RESISTANCE; EGFR INHIBITOR; DOUBLE-BLIND; GEFITINIB; ERLOTINIB; AMPLIFICATION; NSCLC; TRIAL; CHEMOTHERAPY AB Introduction: This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non-small cell lung cancer. Methods: Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose; secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers. Results: Seventy patients were treated in the dose escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths; none were considered treatment related. One patient (1%) had a partial response; 46% had stable disease. Most of the tumor samples analyzed had activating epidermal growth factor receptor gene (EGFR) mutations (18 of 20 [90%]); 50% (10 of 20) had a concurrent resistance mutation. Only one sample showed MMNG HOS Transforming gene (MET) amplification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity. Conclusion: The combination of dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non-small cell lung cancer and was associated with substantial toxicity. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. C1 [Janne, Pasi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 44 Binney St, Boston, MA 02115 USA. [Janne, Pasi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, 44 Binney St, Boston, MA 02115 USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Camidge, D. Ross] Univ Colorado Denver, Denver, CO USA. [Giaccone, Giuseppe] Georgetown Univ, Washington, DC USA. [Shreeve, S. Martin; Tang, Yiyun; Goldberg, Zelanna; Martini, Jean-Francois; Xu, Huiping] Pfizer Oncol, La Jolla, CA USA. [James, Leonard R.] Pfizer Oncol, New York, NY USA. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,LC4114, Boston, MA 02215 USA. EM pasi_janne@dfci.harvard.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 45 TC 5 Z9 5 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD MAY PY 2016 VL 11 IS 5 BP 737 EP 747 DI 10.1016/j.jtho.2016.01.022 PG 11 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DL1DN UT WOS:000375372500011 PM 26899759 ER PT J AU Misono, AS Mueller, PR Hirsch, JA Sheridan, RM Siddiqi, AU Liu, RW AF Misono, Alexander S. Mueller, Peter R. Hirsch, Joshua A. Sheridan, Robert M. Siddiqi, Assad U. Liu, Raymond W. TI Revenue Potential for Inpatient IR Consultation Services: A Financial Model SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID INTERVENTIONAL RADIOLOGY AB Purpose: Interventional radiology (IR) has historically failed to fully capture the value of evaluation and management services in the inpatient setting. Understanding financial benefits of a formally incorporated billing discipline may yield meaningful insights for interventional practices. Materials and Methods: A revenue modeling tool was created deploying standard financial modeling techniques, including sensitivity and scenario analyses. Sensitivity analysis calculates revenue fluctuation related to dynamic adjustment of discrete variables. In scenario analysis, possible future scenarios as well as revenue potential of different-size clinical practices are modeled. Results: Assuming a hypothetical inpatient IR consultation service with a daily patient census of 35 patients and two new consults per day, the model estimates annual charges of $2.3 million and collected revenue of $390,000. Revenues are most sensitive to provider billing documentation rates and patient volume. A range of realistic scenarios-from cautious to optimistic results in a range of annual charges of $1.8 million to $2.7 million and a collected revenue range of $241,000 to $601,000. Even a small practice with a daily patient census of 5 and 0.20 new consults per day may expect annual charges of $320,000 and collected revenue of $55,000. Conclusions: A financial revenue modeling tool is a powerful adjunct in understanding economics of an inpatient IR consultation service. Sensitivity and scenario analyses demonstrate a wide range of revenue potential and uncover levers for financial optimization. C1 [Misono, Alexander S.; Mueller, Peter R.; Hirsch, Joshua A.; Sheridan, Robert M.; Siddiqi, Assad U.; Liu, Raymond W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,Gray 2, Boston, MA 02114 USA. [Mueller, Peter R.; Hirsch, Joshua A.; Liu, Raymond W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Intervent Radiol, 55 Fruit St,Gray 2, Boston, MA 02114 USA. RP Misono, AS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,Gray 2, Boston, MA 02114 USA. EM amisono@mgh.harvard.edu NR 19 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 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAY PY 2016 VL 27 IS 5 BP 658 EP 664 DI 10.1016/j.jvir.2016.01.144 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DL1DR UT WOS:000375372900008 PM 27080010 ER PT J AU Deery, SE Lancaster, RT Baril, DT Indes, JE Bertges, DJ Conrad, MF Cambria, RP Patel, VI AF Deery, Sarah E. Lancaster, Robert T. Baril, Donald T. Indes, Jeffrey E. Bertges, Daniel J. Conrad, Mark F. Cambria, Richard P. Patel, Virendra I. TI Contemporary outcomes of open complex abdominal aortic aneurysm repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID OPEN SURGICAL REPAIR; JUXTARENAL ANEURYSM; EXPERIENCE; ERA AB Objective: The recent commercial availability of fenestrated stent grafts is likely to result in increasing endovascular repair of complex (juxtarenal and suprarenal) abdominal aortic aneurysms (cAAAs). Whereas most studies providing bench-marking for outcomes after open repair have been from high-volume centers, we sought to evaluate outcomes after elective open cAAA repair vs infrarenal AAA repair at a regional level. Methods: We used the Vascular Study Group of New England registry, which recorded 1875 open AAA repairs in New England from 2003 to 2011. Data from 14 hospitals performing both AAA and cAAA repair were used to assess the impact of clinical and technical factors on outcomes of cAAA repair. Results: There were 443 patients who had elective cAAA repair as defined by use of a suprarenal (n = 340; 77%) or supraceliac (n = 103; 23%) clamp, with median survival follow-up of 35 months (interquartile range, 47 months). Compared with AAA repair, patients undergoing cAAA repair were more likely to be female; to have hypertension, congestive heart failure, or chronic obstructive pulmonary disease; and to have a higher baseline creatinine concentration. cAAA cases were repaired through a retroperitoneal incision in 40% of cases, with hypothermic renal perfusion use in 15%, mannitol in 73%, and renal bypass in 13%, with wide variability in the application of these adjuncts. Complex aneurysm repair vs routine AAA repair was associated with a higher independent risk of 30-day mortality (3.6% vs 1.2%; P = .002), respiratory complications (19% vs 10%; P < .001), and renal complications (21% vs 8.7%; P < .001). Among all patients, the only independent clinical or technical predictors of 30-day mortality were preoperative coronary artery disease (odds ratio = OR], 2.5; 95% confidence interval = CI], 1.1-5.4; P = .02) and amount of intraoperative blood transfusion (OR, 2.8; 95% CI, 1.3-6.2; P = .01). In the subgroup undergoing cAAA repair, there were no predictors of operative mortality. Renal or visceral ischemia time was the only technical factor during cAAA repair that independently predicted cardiac (OR, 1.01; 95% CI, 1.00-1.03; P = .04), respiratory (OR, 1.03; 95% CI, 1.01 -1.04; P < .001), and renal (OR, 1.03; 95% CI, 1.02-1.05; P < .001) complications. Long-term survival for cAAA patients was 91% 6 1% at 1 year and 71% 6 3% at 5 years and not different from that of patients undergoing infrarenal AAA repair. Risk-adjusted predictors of late mortality after cAAA repair included age (hazard ratio = HR], 1.08; 95% CI, 1.04-1.11; P < .001), chronic obstructive pulmonary disease (HR, 1.9; 95% CI, 1.2-3.0; P = .008), and preoperative creatinine concentration (per mg/dL; HR, 1.8; 95% CI, 1.05-2.9; P = .03). Conclusions: These data highlight excellent operative outcomes for open cAAA repair across the New England region despite significant variation in operative conduct across hospitals. Patients tolerating cAAA repair have durable long-term survival. C1 [Deery, Sarah E.; Lancaster, Robert T.; Conrad, Mark F.; Cambria, Richard P.; Patel, Virendra I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA USA. [Baril, Donald T.] Univ Pittsburgh, Med Ctr, Div Vasc Surg, Pittsburgh, PA USA. [Indes, Jeffrey E.] Yale Univ, Med Ctr, Vasc Surg Sect, New Haven, CT USA. [Bertges, Daniel J.] Univ Vermont, Coll Med, Div Vasc Surg, Burlington, VT USA. RP Patel, VI (reprint author), Massachusetts Gen Hosp, 15 Parkman St,Wang ACC 440, Boston, MA 02114 USA. EM vpatel4@partners.org NR 29 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAY PY 2016 VL 63 IS 5 BP 1195 EP 1200 DI 10.1016/j.jvs.2015.12.038 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DK8YN UT WOS:000375216000010 PM 27109792 ER PT J AU Jones, DW Goodney, PP Conrad, MF Nolan, BW Rzucidlo, EM Powell, RJ Cronenwett, JL Stone, DH AF Jones, Douglas W. Goodney, Philip P. Conrad, Mark F. Nolan, Brian W. Rzucidlo, Eva M. Powell, Richard J. Cronenwett, Jack L. Stone, David H. TI Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID PERIPHERAL ARTERIAL-SURGERY; VASCULAR STUDY-GROUP; NEW-ENGLAND; CLOPIDOGREL; COMPLICATIONS; PREDICTORS; STENOSIS; ASPIRIN; EMBOLI AB Objective: Controversy persists regarding the perioperative management of clopidogrel among patients undergoing carotid endarterectomy (CEA). This study examined the effect of preoperative dual antiplatelet therapy (aspirin and clopidogrel) on in-hospital CEA outcomes. Methods: Patients undergoing CEA in the Vascular Quality Initiative were analyzed (2003-2014). Patients on clopidogrel and aspirin (dual therapy) were compared with patients taking aspirin alone preoperatively. Study outcomes included reoperation for bleeding and thrombotic complications defined as transient ischemic attack (TIA), stroke, or myocardial infarction. Secondary outcomes were in-hospital death and composite stroke/death. Univariate andmultivariable analyses assessed differences in demographics and operative factors. Propensity score-matched cohorts were derived to control for subgroup heterogeneity. Results: Of 28,683 CEAs, 21,624 patients (75%) were on aspirin and 7059 (25%) were on dual therapy. Patients on dual therapy were more likely to have multiple comorbidities, including coronary artery disease (P < .001), congestive heart failure (P < .001), and diabetes (P < .001). Patients on dual therapy were also more likely to have a drain placed (P < .001) and receive protamine during CEA (P < .001). Multivariable analysis showed that dual therapy was independently associated with increased reoperation for bleeding (odds ratio = [OR], 1.71; 95% confidence interval = [CI], 1.20-2.42; P = .003) but was protective against TIA or stroke (OR, 0.61; 95% CI, 0.43-0.87; P = .007), stroke (OR, 0.63; 95% CI, 0.41-0.97; P = .03), and stroke/death (OR, 0.66; 95% CI, 0.44-0.98; P = .04). Propensity score matching yielded two groups of 4548 patients and showed that patients on dual therapy were more likely to require reoperation for bleeding (1.3% vs 0.7%; P = .004) but less likely to suffer TIA or stroke (0.9% vs 1.6%; P = .002), stroke (0.6% vs 1.0%; P = .04), or stroke/death (0.7% vs 1.2%; P = .03). Within the propensity score-matched groups, patients on dual therapy had increased rates of reoperation for bleeding regardless of carotid symptom status. However, asymptomatic patients on dual therapy demonstrated reduced rates of TIA or stroke (0.6% vs 1.5%; P < .001), stroke (0.4% vs 0.9%; P = .01), and composite stroke/death (0.5% vs 1.0%; P = .02). Among propensity score-matched patients with symptomatic carotid disease, these differences were not statistically significant. Conclusions: Preoperative dual antiplatelet therapy was associated with a 40% risk reduction for neurologic events but also incurred a significant increased risk of reoperation for bleeding after CEA. Given its observed overall neurologic protective effect, continued dual antiplatelet therapy throughout the perioperative period is justified. Initiating dual therapy in all patients undergoing CEA may lead to decreased neurologic complication rates. C1 [Jones, Douglas W.] Beth Israel Deaconess Med Ctr, Dept Vasc & Endovasc Surg, Boston, MA 02215 USA. [Conrad, Mark F.] Massachusetts Gen Hosp, Dept Vasc & Endovasc Surg, Boston, MA 02114 USA. [Goodney, Philip P.; Nolan, Brian W.; Rzucidlo, Eva M.; Powell, Richard J.; Cronenwett, Jack L.; Stone, David H.] Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Lebanon, NH 03766 USA. [Goodney, Philip P.; Nolan, Brian W.; Cronenwett, Jack L.] Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. RP Stone, DH (reprint author), Dept Vasc Surg, 1 Med Ctr Dr, Lebanon, NH 03766 USA. EM david.h.stone@hitchcock.org FU FDA HHS [U01 FD005478]; NHLBI NIH HHS [K08 HL105676]; NIA NIH HHS [U01 AG046830] NR 20 TC 4 Z9 5 U1 1 U2 4 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 MAY PY 2016 VL 63 IS 5 BP 1262 EP 1270 DI 10.1016/j.jvs.2015.12.020 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DK8YN UT WOS:000375216000019 PM 26947237 ER PT J AU Sharath, SE Kougias, P Pisimisis, G Barshes, NR AF Sharath, Sherene E. Kougias, Panos Pisimisis, George Barshes, Neal R. TI The impact of clinical, psychological, behavioral, social, and environmental factors on self-perceived symptom severity in a male cohort with intermittent claudication SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; WALKING IMPAIRMENT QUESTIONNAIRE; ANKLE-BRACHIAL INDEX; QUALITY-OF-LIFE; LOW-BACK-PAIN; PHYSICAL-ACTIVITY; D PERSONALITY; EXERCISE; VALIDATION; THERAPY AB Objective: To understand the relationship between self-perceived severity of intermittent claudication and various associated nonclinical factors, we examined how correlates in domains of physical activity (ie, clinical, psychological, behavioral, social, and environmental factors) relate to exertional limb symptoms. Methods: A survey was administered to individuals with intermittent claudication during their initial outpatient assessment. The subjects' self-reported exertional limb symptom severity and classic -versus -atypical claudication classification was based on the Walking Impairment Questionnaire (WIQ) and San Diego Claudication Questionnaire (SDCQ), respectively. We evaluated psychosocial and environmental factors, osteoarthritis symptoms, health, behaviors, and beliefs. Logistic and linear regressions identified factors with a strong independent association with total WIQ scores and the SDCQs. Results: A cohort of 102 subjects (99.0% male) was enrolled in the study. The median age was 65 years with a median ankle -brachial index of 0.69. Forty-three subjects (43%) had "typical" claudication per SDCQs. Individuals with atypical claudication were more likely to report higher Aberdeen Clinical Back Pain Questionnaire scores (odds ratio, 1.04; P = .04) and no depressive symptoms (odds ratio, 8.30; P = .03). Exertional limb symptom severity among the entire cohort was significantly associated with increasing osteoarthritis symptoms (P <001), age (P = .02), a reserved personality (P = .008), and the belief that an exercise regimen would not improve symptoms (P = .005), self -perceived levels of boredom (P = .002), and the belief that exercise (P = .002) was the best way to improve symptoms were associated with decreased symptom severity. When restricted to those with atypical pain, significant factors associated with increasing exertional symptom severity included age greater than 60 years (P = .005), osteoarthritis (P = .02), alcohol use (P = .01), belief that exercise would not improve walking (P = .03), and difficulty walking around the neighborhood (P = .02). When restricted to those with classic claudication, significant factors associated with increasing exertional limb symptom severity included frequent pain or aching in the calves while walking or sitting (P = .03 [walking]; P = .01 [sitting]) and occasional morning joint stiffness (P = .007). Exertional limb symptom severity was also associated with high limitations at home (P = .003) and a belief that exercise would not improve walking (P = .005) among those with classic claudication. Conclusions: Symptom severity and type of pain are associated with a number of nonclinical factors. A multidomain approach, as indicated by the models above, would benefit the continuum of care for intermittent claudication, where management is integrated and coordinated among multiple lines of care. C1 [Sharath, Sherene E.] Michael E DeBakey VA Med Ctr, Hlth Serv & Res Dev, Houston, TX USA. [Kougias, Panos; Pisimisis, George; Barshes, Neal R.] Baylor Coll Med, Michael E DeBakey Dept Surg, Div Vasc Surg & Endovasc Therapy, Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd OCL 112, Houston, TX 77030 USA. RP Barshes, NR (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, Div Vasc Surg & Endovasc Therapy, Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd OCL 112, Houston, TX 77030 USA. EM nbarshes@bcm.tmc.edu NR 38 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAY PY 2016 VL 63 IS 5 BP 1296 EP U483 DI 10.1016/j.jvs.2015.11.040 PG 13 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DK8YN UT WOS:000375216000025 PM 26821592 ER PT J AU Cui, J Steele, D Wenger, J Kawai, T Liu, FY Elias, N Watkins, MT Irani, Z AF Cui, Jie Steele, David Wenger, Julia Kawai, Tatsuo Liu, Fengyong Elias, Nahel Watkins, Michael T. Irani, Zubin TI Hemodialysis arteriovenous fistula as first option not necessary in elderly patients SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID VASCULAR ACCESS; UNITED-STATES; ESRD PATIENTS; MORTALITY; OUTCOMES; RISK; PREDICTORS; DIALYSIS; OCTOGENARIANS; COMPLICATIONS AB Objective: Kidney Disease Outcomes Quality Initiative guidelines recommend arteriovenous fistulas as the preferred access for hemodialysis patients. However, this may not hold across all populations of patients, especially the elderly, given their comorbidities and relatively reduced life expectancy. Therefore, we investigated whether fistulas held benefit over arteriovenous grafts as hemodialysis access in elderly patients. Methods: We retrospectively searched a vascular access database to compare the outcomes for 138 fistulas and 44 grafts that were placed in elderly patients (>75 years old) during a 4-year period at a tertiary medical center. Results: The primary failure rate was higher for the fistulas compared with the grafts (odds ratio, 2.89; P = .008), and more fistulas required one or more interventions before their successful use compared with grafts (31% vs 10%, respectively; P =.03). In addition, the time to catheter-free dialysis was longer for fistulas than for grafts (P<.001). However, the primary and secondary patency rates were comparable between the fistulas and grafts and between the different access locations. The all-cause mortality rates were also comparable between the fistula and graft groups. Conclusions: Despite the Fistula First Initiative recommendations, grafts need not be discounted as a first-line hemodialysis access option in select elderly patients. C1 [Cui, Jie; Steele, David; Wenger, Julia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Nephrol, Boston, MA USA. [Kawai, Tatsuo; Elias, Nahel] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp,Div Transplant Surg, Boston, MA 02115 USA. [Watkins, Michael T.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp,Div Vasc & Endovasc Surg, Boston, MA 02115 USA. [Irani, Zubin] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Div Intervent Radiol, Boston, MA 02115 USA. [Liu, Fengyong] Chinese Peoples Liberat Army Gen Hosp, Dept Intervent Radiol, Beijing, Peoples R China. RP Irani, Z (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Intervent Radiol, 55 Fruit St, Boston, MA 02114 USA. EM zirani@mgh.harvard.edu FU American Society of Nephrology; American Society of Diagnostic and Interventional Nephrology FX J.C. was supported by grants from the American Society of Nephrology Ben J. Lipps Research Fellowship grant and American Society of Diagnostic and Interventional Nephrology Fellowship Grant. NR 30 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAY PY 2016 VL 63 IS 5 BP 1326 EP 1332 DI 10.1016/j.jvs.2015.11.036 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DK8YN UT WOS:000375216000029 PM 26776449 ER PT J AU Ankri-Eliahoo, G Weitz, K Cox, TC Tang, GL AF Ankri-Eliahoo, Galit Weitz, Kevin Cox, Timothy C. Tang, Gale L. TI p27(kip1) Knockout enhances collateralization in response to hindlimb ischemia SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID MUSCLE-CELL MIGRATION; SINGLE NUCLEOTIDE POLYMORPHISM; MATRIX METALLOPROTEINASES; THERAPEUTIC ANGIOGENESIS; PROLIFERATION; CONTRACTION; INHIBITORS; GROWTH; MMP-9; CYCLE AB Objective: The natural response to arterial occlusive disease is enlargement of collaterals; however, the molecular factors that control collateralization are not well understood. The gene p27(Kipl) (p27) affects human response to arterial injury. Previous studies have shown that overexpression of p27 inhibits vascular endothelial and vascular smooth muscle cell (VSMC) proliferation and angiogenesis. To test the hypothesis that knockout of p27 would improve collateralization in reaction to ischemia, we performed in vivo and in vitro experiments using p27 knockout (p27(-/-)) and wild-type (wt) mice. Methods: Hindlimb ischemia was induced by left femoral artery ligation in p27(-/-) and wt (C57BL/6) female mice. The mice underwent weekly laser Doppler perfusion imaging of the footpads until sacrifice on postoperative day 28 followed by microcomputed tomography scanning of both hindlimbs VSMCs were isolated from p27 /and wt mice and used in migration and gel contraction assays in the absence and presence of the nonspecific matrix metalloproteinase (M1VIP) inhibitor BB94. MMP-2 and MMP-9 messenger RNA (mRNA) expression was measured by quantitative reverse transcription-polymerase chain reaction in p27 /and wt VSMCs. Results: p27 /mice reperfused more effectively than wt mice by laser Doppler starting from day 7 (ischemic/nonischemic ratio, 0.33 +/- 0.02 vs 0.25 +/- 0.02; P<.05) and continuing through day 28 (0.45 +/- 0.04 vs +/- 0.31 0.04; P<.05). The gracilis collateral diameter was similar for the nonischemic hindlimbs of the p27 /and wt mice, and this collateral pathway increased similarly after ischemia as assessed by microcomputed tomography. However, the p27 /mice significantly enlarged a novel collateral pathway that bridged directly between the femoral artery proximal to the ligation site and the saphenous or popliteal artery distal to the ligation site more than wt mice (158 18.3 vs 82 22 m; P<.001). p27 /VSMCs migrated more (79% 5% vs 56% 6%; P<.05) and caused more gel contraction (18% 5% of the initial area vs 43% 4%; P<.05) than wt cells. Migration and collagen contraction were abolished in p27 /and wt cells by MMP inhibition. p27 /cells expressed significantly more MMP-2 mRNA than wt cells did. Conclusions: Knockout of p27 enhances arterial collateralization in response to hindlimb ischemia through enlargement of a new collateral pathway. In vitro, knockout of p27 increases collagen gel contraction in addition to stimulating VSMC migration. We speculate that p27 may affect collateralization through its role in regulating MMP-2 expression. (J Vasc Surg 2016;63:1351-9.) Clinical Relevance: Atherosclerosis is the leading cause of mortality and morbidity in the United States. _ENREF_2 The adaptive response to the progressive occlusion of arteries is collateralization (arteriogenesis). As many patients with severe atherosclerosis are not good candidates for angioplasty or surgical bypass, therapies directed toward improving collateralization are needed. The molecular pathways controlling collateralization, however, are not well understood. The human response to arterial injury is affected by a genetic polymorphism in the gene CDKNIB (p27K'P1 or p27). We demonstrate that knockout of p27 improves collateralization. Study of the molecular partners of p27 will identify therapeutic candidates to enhance this process for patients. C1 [Ankri-Eliahoo, Galit; Weitz, Kevin; Tang, Gale L.] Univ Washington, Div Vasc Surg, Seattle, WA 98195 USA. [Cox, Timothy C.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Cox, Timothy C.] Seattle Childrens Res Inst, Ctr Dev Biol & Regenerat Med, Seattle, WA USA. [Tang, Gale L.] VA Puget Sound Hlth Care Syst, Dept Surg, Div Vasc Surg, Seattle, WA USA. RP Tang, GL (reprint author), Univ Washington, Dept Surg, Div Vasc Surg, Surg Serv 112, 1660 S Columbian Way, Seattle, WA 98108 USA. EM gtang@uw.edu FU University of Washington Royalty Research Fund FX This work was supported with the facilities and resources of the VA Puget Sound Health Care System, the Seattle Institute for Biomedical and Clinical Research, the University of Washington Royalty Research Fund, the Vascular Cures Foundation, and the Laurel Foundation. NR 29 TC 0 Z9 0 U1 2 U2 2 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 MAY PY 2016 VL 63 IS 5 BP 1351 EP 1359 DI 10.1016/j.jvs.2015.12.047 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DK8YN UT WOS:000375216000032 PM 25701497 ER PT J AU Chou, YY Cuevas, C Carocci, M Stubbs, SH Ma, MH Cureton, DK Chao, LK Evesson, F He, KM Yang, PL Whelan, SP Ross, SR Kirchhausen, T Gaudina, R AF Chou, Yi-ying Cuevas, Christian Carocci, Margot Stubbs, Sarah H. Ma, Minghe Cureton, David K. Chao, Luke Evesson, Frances He, Kangmin Yang, Priscilla L. Whelan, Sean P. Ross, Susan R. Kirchhausen, Tom Gaudina, Raphael TI Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor SO JOURNAL OF VIROLOGY LA English DT Article ID ARGENTINE HEMORRHAGIC-FEVER; GROWTH-FACTOR RECEPTOR; NEW-WORLD ARENAVIRUSES; JUNIN-VIRUS; CELL ENTRY; MEMBRANE-FUSION; ACTIN DYNAMICS; GLIAL-CELLS; RHO GTPASES; VERO CELLS AB Virus entry into cells is a multistep process that often requires the subversion of subcellular machineries. A more complete understanding of these steps is necessary to develop new antiviral strategies. While studying the potential role of the actin network and one of its master regulators, the small GTPase Cdc42, during Junin virus (JUNV) entry, we serendipitously uncovered the small molecule ZCL278, reported to inhibit Cdc42 function as an entry inhibitor for JUNV and for vesicular stomatitis virus, lymphocytic choriomeningitis virus, and dengue virus but not for the nonenveloped poliovirus. Although ZCL278 did not interfere with JUNV attachment to the cell surface or virus particle internalization into host cells, it prevented the release of JUNV ribonucleoprotein cores into the cytosol and decreased pH-mediated viral fusion with host membranes. We also identified SVG-A astroglial cell-derived cells to be highly permissive for JUNV infection and generated new cell lines expressing fluorescently tagged Rab5c or Rab7a or lacking Cdc42 using clustered regularly interspaced short palindromic repeat (CRISPR)-caspase 9 (Cas9) gene-editing strategies. Aided by these tools, we uncovered that perturbations in the actin cytoskeleton or Cdc42 activity minimally affect JUNV entry, suggesting that the inhibitory effect of ZCL278 is not mediated by ZCL278 interfering with the activity of Cdc42. Instead, ZCL278 appears to redistribute viral particles from endosomal to lysosomal compartments. ZCL278 also inhibited JUNV replication in a mouse model, and no toxicity was detected. Together, our data suggest the unexpected antiviral activity of ZCL278 and highlight its potential for use in the development of valuable new tools to study the intracellular trafficking of pathogens. C1 [Chou, Yi-ying; Cureton, David K.; Evesson, Frances; He, Kangmin; Kirchhausen, Tom; Gaudina, Raphael] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Chou, Yi-ying; Ma, Minghe; Cureton, David K.; Evesson, Frances; He, Kangmin; Kirchhausen, Tom; Gaudina, Raphael] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Cuevas, Christian; Ross, Susan R.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Carocci, Margot; Stubbs, Sarah H.; Yang, Priscilla L.; Whelan, Sean P.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Chao, Luke] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kirchhausen, Tom] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Cureton, David K.] Merial Ltd, Athens, GA USA. [Gaudina, Raphael] Inst Rech Malad Virales & Hepat, INSERM, U1110, Strasbourg, France. [Gaudina, Raphael] Univ Strasbourg, Strasbourg, France. RP Kirchhausen, T; Gaudina, R (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA.; Kirchhausen, T; Gaudina, R (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. EM kirchhausen@crystal.harvard.edu; rgaudin@unistra.fr OI Chao, Luke/0000-0002-4849-4148 FU National Institutes of Health [GM075252, U54 AI057159, U54 AI 057168] FX This work was supported by National Institutes of Health grants GM075252 and U54 AI057159 (New England Regional Center of Excellence in Biodefense and Emerging Infectious Diseases [NERCE BEID]) to T.K. and U54 AI 057168 (Mid-Atlantic RCE) to S.R.R. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 68 TC 2 Z9 2 U1 2 U2 5 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 MAY PY 2016 VL 90 IS 9 BP 4494 EP 4510 DI 10.1128/JVI.00103-16 PG 17 WC Virology SC Virology GA DK7SG UT WOS:000375125400022 PM 26912630 ER PT J AU Madani, N Princiotto, AM Easterhoff, D Bradley, T Luo, K Williams, WB Liao, HX Moody, MA Phad, GE Bernat, NV Melillo, B Santra, S Smith, AB Hedestam, GBK Haynes, B Sodroski, J AF Madani, Navid Princiotto, Amy M. Easterhoff, David Bradley, Todd Luo, Kan Williams, Wilton B. Liao, Hua-Xin Moody, M. Anthony Phad, Ganesh E. Bernat, Nestor Vazquez Melillo, Bruno Santra, Sampa Smith, Amos B., III Hedestam, Gunilla B. Karlsson Haynes, Barton Sodroski, Joseph TI Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds SO JOURNAL OF VIROLOGY LA English DT Article ID SMALL-MOLECULE INHIBITORS; CORECEPTOR BINDING-SITE; STRUCTURE-BASED DESIGN; MONOCLONAL-ANTIBODIES; ENTRY INHIBITORS; V3-SPECIFIC ANTIBODIES; CONFORMATIONAL-CHANGES; GP120 GLYCOPROTEINS; RECEPTOR-BINDING; ATOMIC-STRUCTURE AB The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCE Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine. C1 [Madani, Navid; Princiotto, Amy M.; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Madani, Navid; Sodroski, Joseph] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Easterhoff, David; Bradley, Todd; Luo, Kan; Williams, Wilton B.; Liao, Hua-Xin; Moody, M. Anthony; Haynes, Barton] Duke Univ, Med Ctr, Dept Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Easterhoff, David; Bradley, Todd; Luo, Kan; Williams, Wilton B.; Liao, Hua-Xin; Moody, M. Anthony; Haynes, Barton] Duke Univ, Med Ctr, Dept Immunol, Durham, NC USA. [Phad, Ganesh E.; Bernat, Nestor Vazquez; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Melillo, Bruno; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Santra, Sampa] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Sodroski, J (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA.; Sodroski, J (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU Ragon Institute of MGH, MIT and Harvard; HHS \ National Institutes of Health (NIH) [GM56550, AI24755, AI100645, AI90682]; amfAR, The American Foundation for AIDS Research (amfAR) [107431-45-RFNT]; International AIDS Vaccine Initiative (IAVI) FX This work, including the efforts of Navid Madani, was funded by Ragon Institute of MGH, MIT and Harvard. This work, including the efforts of Joseph G. Sodroski, Navid Madani, Amy M. Princiotto, Bruno N. Melillo, and Amos B. Smith, was funded by HHS vertical bar National Institutes of Health (NIH) (GM56550). This work, including the efforts of Joseph G. Sodroski, was funded by HHS vertical bar National Institutes of Health (NIH) (AI24755). This work, including the efforts of Joseph G. Sodroski, David Easterhoff, Todd Bradley, Kan Luo, Wilton B. Williams, Hua-Xin Liao, M. Anthony Moody, and Barton Haynes, was funded by HHS vertical bar National Institutes of Health (NIH) (AI100645). This work, including the efforts of Navid Madani, was funded by HHS vertical bar National Institutes of Health (NIH) (AI90682). This work, including the efforts of Navid Madani, was funded by amfAR, The American Foundation for AIDS Research (amfAR) (107431-45-RFNT). This work, including the efforts of Joseph G. Sodroski, was funded by International AIDS Vaccine Initiative (IAVI). NR 112 TC 6 Z9 6 U1 1 U2 13 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 MAY PY 2016 VL 90 IS 10 BP 5031 EP 5046 DI 10.1128/JVI.03211-15 PG 16 WC Virology SC Virology GA DK7SN UT WOS:000375126100016 PM 26962221 ER PT J AU Richardson, PG AF Richardson, Paul G. TI Dual inhibition of oncogenic targets for B-cell malignancies SO LANCET ONCOLOGY LA English DT Editorial Material ID REFRACTORY MULTIPLE-MYELOMA; PANOBINOSTAT C1 [Richardson, Paul G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. RP Richardson, PG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2016 VL 17 IS 5 BP 547 EP 549 DI 10.1016/S1470-2045(16)00109-1 PG 4 WC Oncology SC Oncology GA DK3PO UT WOS:000374829800033 PM 27049458 ER PT J AU Shah, A Ricci, KI Efstathiou, JA AF Shah, Anand Ricci, Kelsey I. Efstathiou, Jason A. TI Beyond a moonshot: insurance coverage for proton therapy SO LANCET ONCOLOGY LA English DT Editorial Material ID INTENSITY-MODULATED RADIOTHERAPY; PROSTATE-CANCER C1 [Shah, Anand] Columbia Univ, Med Ctr, Dept Radiat Oncol, New York, NY USA. [Ricci, Kelsey I.; Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP Efstathiou, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. EM jefstathiou@partners.org NR 6 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2016 VL 17 IS 5 BP 559 EP 561 PG 3 WC Oncology SC Oncology GA DK3PO UT WOS:000374829800041 PM 27301029 ER PT J AU Chow, EJ Stratton, KL Leisenring, WM Oeffinger, KC Sklar, CA Donaldson, SS Ginsberg, JP Kenney, LB Levine, JM Robison, LL Shnorhavorian, M Stovall, M Armstrong, GT Green, DM AF Chow, Eric J. Stratton, Kayla L. Leisenring, Wendy M. Oeffinger, Kevin C. Sklar, Charles A. Donaldson, Sarah S. Ginsberg, Jill P. Kenney, Lisa B. Levine, Jennifer M. Robison, Leslie L. Shnorhavorian, Margarett Stovall, Marilyn Armstrong, Gregory T. Green, Daniel M. TI Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort SO LANCET ONCOLOGY LA English DT Article ID ALKYLATING AGENT EXPOSURE; YOUNG-ADULT CANCERS; LONG-TERM SURVIVORS; FERTILITY PRESERVATION; REPRODUCTIVE HEALTH; GONADAL-FUNCTION; ADOLESCENT; CYCLOPHOSPHAMIDE; INFERTILITY; RESERVE AB Background The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. Methods We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. Findings We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4-12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6-15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0.63, 95% CI 0.58-0.68; p<0.0001; female survivors: 0.87, 0.81-0.94; p<0.0001) or of having a livebirth (male survivors: 0.63, 0.58-0.69; p<0.0001; female survivors: 0.82, 0.76-0.89; p<0.0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0.60, 95% CI 0.51-0.71; p<0.0001), ifosfamide (0.42, 0.23-0.79; p=0.0069), procarbazine (0.30, 0.20-0.46; p<0.0001) and cisplatin (0.56, 0.39-0.82; p=0.0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m(2) increments: HR 0.82, 95% CI 0.79-0.86; p<0.0001). However, in female survivors, only busulfan (<450 mg/m(2) HR 0.22, 95% CI 0.06-0.79; p=0.020; >= 450 mg/m(2) 0.14, 0.03-0.55; p=0.0051) and doses of lomustine equal to or greater than 411 mg/m(2) (0.41, 0.17-0.98; p=0.046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0.85, 95% CI 0.74-0.98; p=0.023). Results for livebirth were similar to those for pregnancy. Interpretation Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. C1 [Chow, Eric J.; Stratton, Kayla L.; Leisenring, Wendy M.; Shnorhavorian, Margarett] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Chow, Eric J.; Shnorhavorian, Margarett] Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Oeffinger, Kevin C.; Sklar, Charles A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Donaldson, Sarah S.] Stanford Univ, Stanford, CA 94305 USA. [Ginsberg, Jill P.] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Kenney, Lisa B.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Levine, Jennifer M.] Columbia Univ, New York, NY USA. [Robison, Leslie L.; Armstrong, Gregory T.; Green, Daniel M.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Chow, EJ (reprint author), Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. EM ericchow@u.washington.edu FU American Lebanese-Syrian Associated Charities; National Cancer Institute, National Institutes of Health FX National Cancer Institute, National Institutes of Health, and the American Lebanese-Syrian Associated Charities. NR 35 TC 9 Z9 9 U1 0 U2 2 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 MAY PY 2016 VL 17 IS 5 BP 567 EP 576 DI 10.1016/S1470-2045(16)00086-3 PG 10 WC Oncology SC Oncology GA DK3PO UT WOS:000374829800048 PM 27020005 ER PT J AU Planchard, D Kim, TM Mazieres, J Quoix, E Riely, G Barlesi, F Souquet, PJ Smit, EF Groen, HJM Kelly, RJ Cho, BC Socinski, MA Pandite, L Nase, C Ma, B D'Amelio, A Mookerjee, B Curtis, CM Johnson, BE AF Planchard, David Kim, Tae Min Mazieres, Julien Quoix, Elisabeth Riely, Gregory Barlesi, Fabrice Souquet, Pierre-Jean Smit, Egbert F. Groen, Harry J. M. Kelly, Ronan J. Cho, B. C. Socinski, Mark A. Pandite, Lini Nase, Christine Ma, Bo D'Amelio, Anthony, Jr. Mookerjee, Bijoyesh Curtis, C. Martin, Jr. Johnson, Bruce E. TI Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID HARBORING BRAF MUTATIONS; MUTATED METASTATIC MELANOMA; MEK INHIBITION; V600 MUTATIONS; VEMURAFENIB; CHEMOTHERAPY; ADENOCARCINOMA; ERLOTINIB; FEATURES; CONFIDENCE AB Background Activating BRAF(V600E) (Val600Glu) mutations are found in about 1-2% of lung adenocarcinomas, which might provide an opportunity for targeted treatment in these patients. Dabrafenib is an oral selective inhibitor of BRAF kinase. We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer (NSCLC) positive for the BRAF(V600E) mutation. Methods In this phase 2, multicentre, non-randomised, open-label study, we enrolled previously treated and untreated patients with stage IV metastatic BRAF(V600E)-positive NSCLC. Patients received oral dabrafenib 150 mg twice daily. The primary endpoint was investigator-assessed overall response, which was assessed in patients who had received at least one dose of dabrafenib; safety was also assessed in this population. The study is ongoing but not enrolling patients in this cohort. This trial is registered with ClinicalTrials.gov, number NCT01336634. Findings Between Aug 3, 2011, and Feb 25, 2014, 84 patients were enrolled, six of whom had not previously received systemic treatment for NSCLC. 26 of the 78 previously treated patients achieved an investigator-assessed overall response (33% [95% CI 23-45]). Four of the six previously untreated patients had an objective response. One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten (12%), asthenia in four (5%), and basal-cell carcinoma in four (5%). Interpretation Dabrafenib showed clinical activity in BRAF(V600E)-positive NSCLC. Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options. C1 [Planchard, David] Gustave Roussy, Dept Med Oncol, Villejuif, France. [Kim, Tae Min] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Mazieres, Julien] Rangueil Larrey Hosp, Thorac Oncol Unit, Toulouse, France. [Mazieres, Julien] Univ Toulouse 3, F-31062 Toulouse, France. [Quoix, Elisabeth] Univ Hosp Strasbourg, Dept Pneumol, Strasbourg, France. [Riely, Gregory] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, Div Solid Tumor Oncol, 1275 York Ave, New York, NY 10021 USA. [Riely, Gregory] Weill Cornell Med Coll, Joan & Sanfor I Weill Dept Med, New York, NY USA. [Barlesi, Fabrice] Aix Marseille Univ, Assistance Publ Hop Marseille, Multidisciplinary Oncol & Therapeut Innovat Dept, Marseille, France. [Souquet, Pierre-Jean] Ctr Hosp Lyon Sud, Resp Med & Thorac Oncol Dept, F-69310 Pierre Benite, France. [Smit, Egbert F.] Vrije Univ VU Med Ctr, Dept Pulm Dis, Amsterdam, Netherlands. [Groen, Harry J. M.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis, NL-9713 AV Groningen, Netherlands. [Kelly, Ronan J.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Upper Aerodigest Malignancies Div, Baltimore, MD USA. [Cho, B. C.] Yonsei Univ, Coll Med, Seoul, South Korea. [Socinski, Mark A.] Univ Pittsburgh, Lung Canc Sect, Div Hematol Oncol, Pittsburgh, PA USA. [Pandite, Lini] Adaptimmune LLC, Philadelphia, PA USA. [Nase, Christine] GlaxoSmithKline, Collegeville, PA USA. [Ma, Bo] Biothera, Eagan, MN USA. [D'Amelio, Anthony, Jr.] Novartis Pharmaceut, King Of Prussia, PA USA. [Mookerjee, Bijoyesh] Novartis Pharmaceut, E Hanover, NJ USA. [Curtis, C. Martin, Jr.] Novartis Pharmaceut, Morrisville, NC USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Bruce_Johnson@dfci.harvard.edu FU GlaxoSmithKline FX GlaxoSmithKline. NR 36 TC 26 Z9 30 U1 1 U2 4 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 MAY PY 2016 VL 17 IS 5 BP 642 EP 650 DI 10.1016/S1470-2045(16)00077-2 PG 9 WC Oncology SC Oncology GA DK3PO UT WOS:000374829800055 PM 27080216 ER PT J AU Hasegawa, T Uno, H Wei, LJ AF Hasegawa, Takahiro Uno, Hajime Wei, Lee-Jen TI Neratinib after trastuzumab in patients with HER2-positive breast cancer SO LANCET ONCOLOGY LA English DT Letter C1 [Wei, Lee-Jen] Harvard Univ, Boston, MA 02115 USA. [Hasegawa, Takahiro] Shionogi & Co Ltd, Osaka, Japan. [Uno, Hajime] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wei, LJ (reprint author), Harvard Univ, Boston, MA 02115 USA. EM wei@hsph.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2016 VL 17 IS 5 BP E176 EP E176 PG 1 WC Oncology SC Oncology GA DK3PO UT WOS:000374829800005 PM 27301038 ER PT J AU Yock, TI Tarbell, NJ Yeap, BY Ebb, DH Weyman, E Eaton, BR Sherry, NA Jones, RM MacDonald, SM Pulsifer, MB Lavally, B Abrams, AN Huang, MS Marcus, KJ AF Yock, Torunn I. Tarbell, Nancy J. Yeap, Beow Y. Ebb, David H. Weyman, Elizabeth Eaton, Bree R. Sherry, Nicole A. Jones, Robin M. MacDonald, Shannon M. Pulsifer, Margaret B. Lavally, Beverly Abrams, Annah N. Huang, Mary S. Marcus, Karen J. TI Proton beam therapy for medulloblastoma Reply SO LANCET ONCOLOGY LA English DT Letter ID RADIATION-THERAPY; RISK MEDULLOBLASTOMA; BRAIN-STEM; CHEMOTHERAPY; TRIAL C1 [Yock, Torunn I.; Tarbell, Nancy J.; Weyman, Elizabeth; Eaton, Bree R.; MacDonald, Shannon M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ebb, David H.; Lavally, Beverly; Huang, Mary S.] Massachusetts Gen Hosp, Dept Pediat Oncol, Boston, MA 02114 USA. [Sherry, Nicole A.] Massachusetts Gen Hosp, Dept Pediat Endocrinol, Boston, MA 02114 USA. [Jones, Robin M.] Massachusetts Gen Hosp, Dept Pediat Neurol, Boston, MA 02114 USA. [Pulsifer, Margaret B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Abrams, Annah N.] Massachusetts Gen Hosp, Dept Child Psychiat, Boston, MA 02114 USA. [Eaton, Bree R.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Marcus, Karen J.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM TYOCK@mgh.harvard.edu NR 8 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2016 VL 17 IS 5 BP E174 EP E175 PG 4 WC Oncology SC Oncology GA DK3PO UT WOS:000374829800004 PM 27301036 ER PT J AU Butt, AA Yan, P Shaikh, OS Chung, RT Sherman, KE AF Butt, Adeel A. Yan, Peng Shaikh, Obaid S. Chung, Raymond T. Sherman, Kenneth E. CA ERCHIVES Study TI Sofosbuvir-based regimens in clinical practice achieve SVR rates closer to clinical trials: results from ERCHIVES SO LIVER INTERNATIONAL LA English DT Article DE DAA; ERCHIVES; ledipasvir; real life; simeprevir; Sofosbuvir; SVR ID HEPATITIS-C VIRUS; TREATMENT-NAIVE PATIENTS; PHASE-2 TRIAL; INFECTION; RIBAVIRIN; SURVIVAL; PEGINTERFERON; BOCEPREVIR; TELAPREVIR; ALPHA-2A AB Background & AimsSofosbuvir is widely prescribed for treatment of HCV infection. We compared the sustained virologic response rates (SVR12) and the haematologic toxicity of various sofosbuvir-based regimens in routine clinical practice. MethodsWe used ERCHIVES (Electronically Retrieved Cohort of HCV infected Veterans) to identify HCV-infected persons initiated on sofosbuvir-based regimens. Treatment duration and regimen were defined as per labelling guidelines. We excluded persons with HIV, positive hepatitis-B surface antigen, hepatocellular carcinoma and missing HCV RNA. ResultsAmong 4257 sofosbuvir-treated persons, sofosbuvir/simeprevir (30%), sofosbuvir/ledipasvir (29%) and sofosbuvir/ribavirin (23%) were the most common combinations prescribed. The mean age (SD) was 60.22 (6.3) years, 96% were male, 22.4% were black, 37.2% had cirrhosis, 29.7% were treatment-experienced; baseline mean HCV RNA was 6.73 log lIU/ml. Comorbidities included: 40.2% alcohol abuse or dependence, 39.7% drug abuse or dependence, 25.1% diabetes and 14.4% stage 3-5 chronic kidney disease. Overall, 86.7% completed a full course of treatment. Overall, SVR12 rates were 88-98% in the sofosbuvir/simeprevir group and 93-98% in the sofosbuvir/ledipasvir group and did not vary based on previous treatment history or cirrhosis at baseline. For genotype 2/3 patients treated with sofosbuvir/ribavirin, SVR12 rates ranged from 69 to 87% with lowest rates in treatment-experienced cirrhotics. For the sofosbuvir/simeprevir and sofosbuvir/ledipasvir groups, grade3/4 haematologic adverse events were uncommon; these trended back close to baseline values after completion of treatment. ConclusionsSofosbuvir-based regimens in clinical practice are associated with SVR rates comparable to those seen in clinical trials and low rates of grade 3/4 haematological adverse events. C1 [Butt, Adeel A.; Yan, Peng; Shaikh, Obaid S.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Butt, Adeel A.; Shaikh, Obaid S.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA USA. [Sherman, Kenneth E.] Univ Cincinnati, Coll Med, UC Hlth, Cincinnati, OH USA. RP Butt, AA (reprint author), Univ Dr C,Bldg 30,Mailstop 151, Pittsburgh, PA 15240 USA. EM aabutt@pitt.edu FU Gilead Sciences FX This work was supported in part by an investigator initiated grant from Gilead Sciences to Veterans Research Foundation of Pittsburgh (Principal Investigator Dr Butt). NR 20 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD MAY PY 2016 VL 36 IS 5 BP 651 EP 658 DI 10.1111/liv.13036 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK2UT UT WOS:000374770600006 PM 26616353 ER PT J AU Bradley, CJ Yabroff, KR Warren, JL Zeruto, C Chawla, N Lamont, EB AF Bradley, Cathy J. Yabroff, K. Robin Warren, Joan L. Zeruto, Christopher Chawla, Neetu Lamont, Elizabeth B. TI Trends in the Treatment of Metastatic Colon and Rectal Cancer in Elderly Patients SO MEDICAL CARE LA English DT Article DE colorectal cancer; treatment costs; chemotherapy use; antineoplastic agents; survival ID CETUXIMAB PLUS IRINOTECAN; COLORECTAL-CANCER; UNITED-STATES; CHEMOTHERAPY REGIMENS; 1ST-LINE TREATMENT; CLINICAL ONCOLOGY; AMERICAN SOCIETY; YOUNGER PATIENTS; PHASE-II; OXALIPLATIN AB Background: Little is known about the use and costs of antineoplastic regimens for elderly patients with metastatic colorectal cancer (mCRC). We report population-based trends over a 10-year period in the treatment, survival, and costs in mCRC patients, stratified by ages 65-74 and 75+. Methods: We used Surveillance, Epidemiology, and End Results-Medicare data for persons diagnosed with metastatic colon (N = 16117) or rectal cancer (N = 4008) between 2000 and 2009. We estimated the adjusted percent of patients who received antineoplastic agents, by type, number, and their costs 12 months following diagnosis. We report the percent of patients who received 3 or more of commonly prescribed agents and estimate survival for the 24-month period following diagnosis by age and treatment. Results: The percentage that received 3 or more agents increased from 3% to 73% in colon patients aged 65-74 and from 2% to 53% in patients 75+. Similar increases were observed in rectal patients. Average 1-year costs per patient in 2009 were $106,461 and $102,680 for colon and rectal cancers, respectively, reflecting an increase of 32% and 20%, for patients who received antineoplastic agents. Median survival increased by about 6 and 10 months, respectively, for colon and rectal patients aged 65-74 who received antineoplastic agents, but an improvement of only 1 month of median survival was observed for patients 75+. Conclusions: Expensive multiple agent regimens are increasingly used in older mCRC patients. For patients aged 64-75 years, these treatments may be associated with several months of additional life, but patients aged 75+ may incur considerable expense without any survival benefit. C1 [Bradley, Cathy J.] Univ Colorado, Colorado Comprehens Canc Ctr, Dept Hlth Syst Management & Policy, Aurora, CO 80045 USA. [Yabroff, K. Robin; Warren, Joan L.; Chawla, Neetu] NCI, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. [Zeruto, Christopher] Informat Management Serv Inc, Rockville, MD USA. [Lamont, Elizabeth B.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Lamont, Elizabeth B.] Massachusetts Gen Hosp, Ctr Canc, Dept Hlth Care Policy, Boston, MA 02114 USA. [Lamont, Elizabeth B.] Harvard Univ, Sch Med, Boston, MA USA. RP Bradley, CJ (reprint author), Univ Colorado, Colorado Comprehens Canc Ctr, Dept Hlth Syst Management & Policy, Aurora, CO 80045 USA. EM cathy.bradley@ucdenver.edu FU National Cancer Institute FX Financial support for this study was provided partially by a contract between C.J.B. and the National Cancer Institute. NR 49 TC 3 Z9 3 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAY PY 2016 VL 54 IS 5 BP 490 EP 497 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DK4OL UT WOS:000374897800012 PM 26900834 ER PT J AU Tracy, EE AF Tracy, Erin E. TI Intimate partner violence and the climacteric SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID PRIMARY-CARE; WOMEN; ABUSE C1 [Tracy, Erin E.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. RP Tracy, EE (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD MAY PY 2016 VL 23 IS 5 BP 479 EP 480 DI 10.1097/GME.0000000000000643 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DK8CE UT WOS:000375154000003 PM 27023863 ER PT J AU Altrock, PM Brendel, C Renella, R Orkin, SH Williams, DA Michor, F AF Altrock, Philipp M. Brendel, Christian Renella, Raffaele Orkin, Stuart H. Williams, David A. Michor, Franziska TI Mathematical Modeling of Erythrocyte Chimerism Informs Clinical Strategies for Sickle Cell Disease SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Altrock, Philipp M.; Michor, Franziska] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Altrock, Philipp M.; Michor, Franziska] Harvard Univ, Dept Biostat, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Altrock, Philipp M.] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA. [Brendel, Christian; Orkin, Stuart H.; Williams, David A.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Brendel, Christian; Renella, Raffaele; Orkin, Stuart H.; Williams, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Renella, Raffaele] Boston Childrens Hosp, Boston, MA USA. [Renella, Raffaele; Orkin, Stuart H.; Williams, David A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Renella, Raffaele] CHU Vaudois, Dept Med Chirurg Pediat, Lausanne, Switzerland. [Orkin, Stuart H.] Howard Hughes Med Inst, Cambridge, MA USA. [Orkin, Stuart H.] Harvard Stem Cell Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 314 BP S126 EP S127 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200311 ER PT J AU Brendel, C Guda, S Renella, R Bauer, DE Canver, MC Kim, YJ Heeney, MM Klatt, D Fogel, J Milsom, MD Orkin, SH Gregory, RI Williams, DA AF Brendel, Christian Guda, Swaroopa Renella, Raffaele Bauer, Daniel E. Canver, Matthew C. Kim, Young-Jo Heeney, Matthew M. Klatt, Denise Fogel, Jonathan Milsom, Michael D. Orkin, Stuart H. Gregory, Richard I. Williams, David A. TI Circumventing Hematopoietic Toxicities and Reversing Sickle Phenotype by Lineage-Specific BCL11A Knock Down and Gamma-Globin Induction SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Brendel, Christian; Guda, Swaroopa] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Renella, Raffaele; Bauer, Daniel E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, 44 Binney St, Boston, MA 02115 USA. [Canver, Matthew C.] Harvard Univ, Sch Med, Boston, MA USA. [Kim, Young-Jo; Fogel, Jonathan] Boston Childrens Hosp, Boston, MA USA. [Canver, Matthew C.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Klatt, Denise] Hannover Med Sch, Hannover, Germany. [Milsom, Michael D.] German Canc Res Ctr, Heidelberg, Germany. [Orkin, Stuart H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston Childrens Hosp,Dana Farber Canc Inst,Harva, Boston, MA 02115 USA. [Gregory, Richard I.] Boston Childrens Hosp, Harvard Stem Cell Inst, Boston, MA USA. [Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp,Harvard Stem Cell Inst, 44 Binney St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 282 BP S113 EP S113 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200279 ER PT J AU Clark-Matott, J Graebner, AK Bass, CE Simon, DK AF Clark-Matott, Joanne Graebner, Allison K. Bass, Caroline E. Simon, David K. TI Overexpression of Pitx3 in the SNpc and Protection from MPTP Toxicity SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Clark-Matott, Joanne; Graebner, Allison K.; Simon, David K.] BIDMC, Neurol, Boston, MA USA. [Bass, Caroline E.] Univ Buffalo, Dept Pharmacol & Toxicol, Buffalo, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 376 BP S150 EP S150 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200373 ER PT J AU Comander, J Carvalho, L Wassmer, S Xiao, R Plovie, E Langsdorf, A Lim, L Er, BH Wu, DM Eliott, D Kim, LA Vandenberghe, LH AF Comander, Jason Carvalho, Livia Wassmer, Sarah Xiao, Ru Plovie, Eva Langsdorf, Aliete Lim, Lawrence Er, Brian Hafl Wu, David M. Eliott, Dean Kim, Leo A. Vandenberghe, Luk H. TI Novel Surgical Method for Intravitreal AAV Administration Overcomes Transduction Barriers in Non-Human Primates SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Comander, Jason; Carvalho, Livia; Wassmer, Sarah; Xiao, Ru; Plovie, Eva; Langsdorf, Aliete; Er, Brian Hafl; Vandenberghe, Luk H.] Ocular Genom Inst, Boston, MA USA. [Comander, Jason; Carvalho, Livia; Wassmer, Sarah; Xiao, Ru; Plovie, Eva; Langsdorf, Aliete; Lim, Lawrence; Er, Brian Hafl; Wu, David M.; Eliott, Dean; Kim, Leo A.; Vandenberghe, Luk H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Carvalho, Livia; Wassmer, Sarah; Xiao, Ru; Plovie, Eva; Vandenberghe, Luk H.] Grousbeck Gene Therapy Ctr, Boston, MA USA. [Carvalho, Livia; Wassmer, Sarah; Xiao, Ru; Plovie, Eva; Langsdorf, Aliete; Lim, Lawrence; Kim, Leo A.; Vandenberghe, Luk H.] Schepens Eye Res Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 29 BP S13 EP S14 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200030 ER PT J AU Daley, H Nikiforow, S Murad, J Negre, H Reider, J Sentman, C Snykers, S Allen, R Galinsky, I Munshi, N Stone, R Soiffer, R Ritz, J Baumeister, S AF Daley, Heather Nikiforow, Sarah Murad, Joana Negre, Helene Reider, Jake Sentman, Charles Snykers, Sarah Allen, Rachel Galinsky, Ilene Munshi, Nikhil Stone, Richard Soiffer, Robert Ritz, Jerome Baumeister, Suzanne TI Validation of Manufacturing NKG2D Chimeric Antigen Receptor T Cells for a First-In-Human Clinical Trial in AML/MDS and Multiple Myeloma SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Daley, Heather; Nikiforow, Sarah; Negre, Helene; Galinsky, Ilene; Munshi, Nikhil; Stone, Richard; Soiffer, Robert; Ritz, Jerome; Baumeister, Suzanne] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nikiforow, Sarah; Munshi, Nikhil; Stone, Richard; Soiffer, Robert; Ritz, Jerome; Baumeister, Suzanne] Harvard Univ, Sch Med, Boston, MA USA. [Murad, Joana; Reider, Jake] Celdara Med LLC, Lebanon, NH USA. [Sentman, Charles] Geisel Sch Med Dartmouth, Hanover, NH USA. [Snykers, Sarah; Allen, Rachel] Celyad SA, Mont St Guibert, Belgium. [Baumeister, Suzanne] Boston Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 71 BP S31 EP S31 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200072 ER PT J AU Eichler, FS Duncan, C Amartino, H Aziz-Bose, R Baruchel, A Dansereau, C Dalle, JH Gaspar, HB Gissen, P Kohn, DB Larghero, J Lund, TC Miller, WP Musolino, PL O'Meara, T Orchard, PJ Paker, AM Shah, AJ Shamir, E Raymond, GV Sankar, R Smith, NJC Thrasher, AJ Aubourg, P Williams, DA AF Eichler, Florian S. Duncan, Christine Amartino, Hernan Aziz-Bose, Razina Baruchel, Andre Dansereau, Colleen Dalle, Jean-Hugues Gaspar, H. Bobby Gissen, Paul Kohn, Donald B. Larghero, Jerome Lund, Troy C. Miller, Weston P. Musolino, Patricia L. O'Meara, Tara Orchard, Paul J. Paker, Asif M. Shah, Ami J. Shamir, Esther Raymond, Gerald V. Sankar, Raman Smith, Nicholas J. C. Thrasher, Adrian J. Aubourg, Patrick Williams, David A. TI A Phase 2/3 Study of the Efficacy and Safety of Ex Vivo Gene Therapy with Lenti-DTM Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Eichler, Florian S.; Aziz-Bose, Razina; Musolino, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Duncan, Christine; Williams, David A.] Boston Childrens Hosp, Boston, MA USA. [Amartino, Hernan] Fundagen, Buenos Aires, DF, Argentina. [Baruchel, Andre; Dalle, Jean-Hugues] Hop Univ Robert Debre, Paris, France. [Dansereau, Colleen] Boston Childrens Hosp, Boston, MA USA. [Gaspar, H. Bobby; Gissen, Paul; Thrasher, Adrian J.] UCL, London, England. [Kohn, Donald B.; Shah, Ami J.; Sankar, Raman] Univ Calif Los Angeles, Los Angeles, CA USA. [Larghero, Jerome] Hop St Louis, Paris, France. [Lund, Troy C.; Miller, Weston P.; Orchard, Paul J.; Raymond, Gerald V.] Univ Minnesota, Minneapolis, MN USA. [O'Meara, Tara; Paker, Asif M.; Shamir, Esther] Bluebird Bio, Cambridge, MA USA. [Smith, Nicholas J. C.] Women & Childrens Hosp, South Adelaide, Australia. [Aubourg, Patrick] INSERM, Paris, France. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 250 BP S98 EP S99 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200247 ER PT J AU Gong, Y Kok, R Mu, DK Gao, GP Eichler, F AF Gong, Yi Kok, Rene Mu, Dakai Gao, Guangping Eichler, Florian TI Intrathecal Delivery of rAAV9-ABCD1 by Osmotic Pump in a Mouse Model of Adrenomyeloneuropathy SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Gong, Yi; Kok, Rene; Mu, Dakai; Eichler, Florian] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. [Gao, Guangping] Univ Massachusetts, Sch Med, Gene Therapy Ctr, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 295 BP S118 EP S119 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200292 ER PT J AU Grosskopf, A Rabkin, SD Martuza, RL Wakimoto, H AF Grosskopf, Anna Rabkin, Samuel D. Martuza, Robert L. Wakimoto, Hiroaki TI Tracking Target Cell Fate After Oncolytic Herpes Simplex Virus Infection SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Grosskopf, Anna; Rabkin, Samuel D.; Martuza, Robert L.; Wakimoto, Hiroaki] Massachusetts Gen Hosp, Neurosurg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 107 BP S46 EP S46 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200108 ER PT J AU Gyorgy, B Ingelsson, M Loov, C Takeda, S Lannfelt, L Hyman, BT Breakefield, XO AF Gyorgy, Bence Ingelsson, Martin Loov, Camilla Takeda, Shuko Lannfelt, Lars Hyman, Bradley T. Breakefield, Xandra O. TI CRISPR-Cas9 Mediated Gene Editing in a Monogenic Form of Alzheimer's Disease SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Gyorgy, Bence; Loov, Camilla; Takeda, Shuko; Hyman, Bradley T.; Breakefield, Xandra O.] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. [Ingelsson, Martin; Lannfelt, Lars] Uppsala Univ, Dept Geriatr, Uppsala, Sweden. NR 0 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 567 BP S226 EP S227 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200560 ER PT J AU Gyorgy, B Wassmer, S Carvalho, L Maguire, C Vandenberghe, LH AF Gyorgy, Bence Wassmer, Sarah Carvalho, Livia Maguire, Casey Vandenberghe, Luk H. TI Exosome-Associated AAV Enhances Retinal Transduction Following Intravitreal Injection SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Gyorgy, Bence; Maguire, Casey] Massachusetts Gen Hosp, Charlestown, MA USA. [Wassmer, Sarah; Carvalho, Livia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Ocular Genom Inst,Schepens Eye Re, Boston, MA USA. [Wassmer, Sarah; Carvalho, Livia; Vandenberghe, Luk H.] Grousbeck Gene Therapy Ctr, Boston, MA USA. [Vandenberghe, Luk H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Schepens Eye Res Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 594 BP S235 EP S235 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200585 ER PT J AU Hudry, E Dashkoff, J Lerner, P Takeda, S Truong, N Maguire, C Hyman, BT AF Hudry, Eloise Dashkoff, Jonathan Lerner, Paul Takeda, Shuko Truong, Nhi Maguire, Casey Hyman, Bradley T. TI Tailored Expression of a Transgene to Specific Cell Types in the Central Nervous System After Peripheral Injection of AAV9 SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Hudry, Eloise; Dashkoff, Jonathan; Lerner, Paul; Takeda, Shuko; Truong, Nhi; Maguire, Casey; Hyman, Bradley T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 616 BP S244 EP S244 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200607 ER PT J AU Kleinstiver, BP Pattanayak, V Prew, MS Tsai, SQ Nguyen, NT Joung, JK AF Kleinstiver, Benjamin P. Pattanayak, Vikram Prew, Michelle S. Tsai, Shengdar Q. Nguyen, Nhu T. Joung, J. Keith TI High-Fidelity CRISPR-Cas9 Nucleases with No Detectable Genome-Wide Off-Target Effects SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Kleinstiver, Benjamin P.; Pattanayak, Vikram; Prew, Michelle S.; Tsai, Shengdar Q.; Nguyen, Nhu T.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 10 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 731 BP S288 EP S288 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200719 ER PT J AU Landegger, L Pang, BF Wassmer, S Gluck, S Galvin, A Stankovic, KM Holt, JR Vandenberghe, LH AF Landegger, Lukas Pang, Bifeng Wassmer, Sarah Gluck, Sarah Galvin, Alice Stankovic, Konstantina M. Holt, Jeff R. Vandenberghe, Luk H. TI Novel Synthetic AAV Efficiently Transduces Neurosensory Hair Cells in the Cochlea SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Landegger, Lukas; Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Pang, Bifeng; Gluck, Sarah; Galvin, Alice; Holt, Jeff R.] Harvard Univ, Sch Med, Dept Otolaryngol, Boston Childrens Hosp, Boston, MA 02115 USA. [Wassmer, Sarah; Vandenberghe, Luk H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Grousbeck Gene Therapy Ctr,Schepens Eye Res Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 269 BP S107 EP S107 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200266 ER PT J AU Meliani, A Fitzpatrick, Z Boisgerault, F Ronzitti, G Collaud, F Charles, S Maguire, CA Mingozzi, F AF Meliani, Amine Fitzpatrick, Zachary Boisgerault, Florence Ronzitti, Giuseppe Collaud, Fanny Charles, Severine Maguire, Casey A. Mingozzi, Federico TI Enhanced Liver Transduction and Efficient Protection from Pre-Existing Neutralizing Antibodies with Exosome-Associated AAV8 Vectors SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Meliani, Amine; Fitzpatrick, Zachary; Boisgerault, Florence; Ronzitti, Giuseppe; Collaud, Fanny; Charles, Severine; Mingozzi, Federico] Genethon, Evry, France. [Maguire, Casey A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 595 BP S235 EP S236 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200586 ER PT J AU Pacouret, S Mevel, M Bouzelha, M Maurer, A Shelke, R Xiao, R Penaud-Budloo, M Turunen, H Broucque, F Blouin, V Moullier, P Ayuso, E Vandenberghe, LH AF Pacouret, Simon Mevel, Mathieu Bouzelha, Mohammed Maurer, Anna Shelke, Rajani Xiao, Ru Penaud-Budloo, Magalie Turunen, Heikki Broucque, Frederic Blouin, Veronique Moullier, Philippe Ayuso, Eduard Vandenberghe, Luk H. TI Development and Validation of Identity and Homogeneity Assays for AAV Preparations SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Pacouret, Simon; Maurer, Anna; Shelke, Rajani; Xiao, Ru; Turunen, Heikki; Vandenberghe, Luk H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Schepens Eye Res Inst,Dept Opht, Boston, MA USA. [Pacouret, Simon; Maurer, Anna; Shelke, Rajani; Xiao, Ru; Turunen, Heikki] Grousbeck Gene Therapy Ctr, Boston, MA USA. [Mevel, Mathieu; Bouzelha, Mohammed; Penaud-Budloo, Magalie; Broucque, Frederic; Blouin, Veronique; Moullier, Philippe; Ayuso, Eduard] Univ Nantes, Nantes Univ Hosp, INSERM UMR 1089, Atlantic Gene Therapies, Nantes, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 34 BP S15 EP S15 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200035 ER PT J AU Pellegatta, S Savoldo, B Su, C Ferrone, S Finocchiaro, G Dotti, G AF Pellegatta, Serena Savoldo, Barbara Su, Chuang Ferrone, Soldano Finocchiaro, Gaetano Dotti, Gianpietro TI Chondroitin Sulfate Proteoglycan 4 (CSPG4)-Redirected T Cells Eliminate Glioblastoma-Derived Neurospheres SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Pellegatta, Serena; Finocchiaro, Gaetano] Fdn IRCCS Ist Neurol C Besta, Unit Mol Neurooncol, Milan, Italy. [Pellegatta, Serena; Savoldo, Barbara; Su, Chuang; Dotti, Gianpietro] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Ferrone, Soldano] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 507 BP S202 EP S202 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200501 ER PT J AU Shapir, N Miari, R Sundback, CA Pomerantseva, I Aronson, JP Katnani, HA Mwizerwa, O Tse, H Goltsman, H Fuerst, Y Moraly, Y Blum, S Harnof, S Neil, GA AF Shapir, Nir Miari, Reem Sundback, Cathryn A. Pomerantseva, Irina Aronson, Joshua P. Katnani, Husam A. Mwizerwa, Olive Tse, Herman Goltsman, Haim Fuerst, Yaron Moraly H, Yonit Blum, Shany Harnof, Sagi Neil, Garry A. TI TARGT(CNS) for the Treatment of Central Nervous System Disorders SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Shapir, Nir; Miari, Reem; Goltsman, Haim; Fuerst, Yaron; Moraly H, Yonit; Blum, Shany] Medgen Med Israel Ltd, R&D, Misgav, Israel. [Sundback, Cathryn A.; Pomerantseva, Irina] Massachusetts Gen Hosp, Dept Surg, Ctr Regenerat Med, Boston, MA 02114 USA. [Aronson, Joshua P.; Katnani, Husam A.; Mwizerwa, Olive; Tse, Herman] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Harnof, Sagi] Sheba Hosp, Dept Neurosurg, Ramat Gan, Israel. [Neil, Garry A.] Medgenics Inc, Wayne, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 598 BP S237 EP S237 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200589 ER PT J AU Tabebordbar, M Zhu, KX Cheng, J Widrick, J Yan, W Xiao, R Vandenberghe, L Zhang, F Wagers, A AF Tabebordbar, Mohammadsharif Zhu, Kexian Cheng, Jason Widrick, Jeffrey Yan, Winston Xiao, Ru Vandenberghe, Luk Zhang, Feng Wagers, Amy TI In Vivo DMD Gene Editing in Muscles and Muscle Stem Cells of Dystrophic Mice SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Tabebordbar, Mohammadsharif; Zhu, Kexian; Cheng, Jason; Wagers, Amy] Harvard Univ, Cambridge, MA 02138 USA. [Widrick, Jeffrey] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Genet, Boston, MA USA. [Widrick, Jeffrey] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Genom, Boston, MA USA. [Yan, Winston; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA USA. [Xiao, Ru; Vandenberghe, Luk] Schepens Eye Res Inst, Grousbeck Gene Therapy Ctr, Boston, MA USA. [Xiao, Ru; Vandenberghe, Luk] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 483 BP S191 EP S192 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200478 ER PT J AU Tsuchiya, M Kumar, P Bhattacharyya, S Kalurupalle, S Vasudevan, S Martindale, J Gorospe, M Biswas, R AF Tsuchiya, Motohiro Kumar, Parameet Bhattacharyya, Sharmistha Kalurupalle, Swathi Vasudevan, Shobha Martindale, Jennifer Gorospe, Myriam Biswas, Roopa TI Regulation of Inflammation in Cystic Fibrosis Lung Epithelial Cells by miR-155 SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Tsuchiya, Motohiro; Kumar, Parameet; Bhattacharyya, Sharmistha; Kalurupalle, Swathi; Biswas, Roopa] Uniformed Serv Univ Hlth Sci, Anat Physiol & Genet, Bethesda, MD 20814 USA. [Vasudevan, Shobha] Massachusetts Gen Hosp, Genet, Boston, MA 02114 USA. [Martindale, Jennifer; Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 146 BP S59 EP S59 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200147 ER PT J AU Turunen, HT Zinn, E Vandenberghe, LH AF Turunen, Heikki T. Zinn, Eric Vandenberghe, Luk H. TI Assay Conditions Significantly Alter AAV Neutralizing Antibody Determination SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Turunen, Heikki T.; Zinn, Eric; Vandenberghe, Luk H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med,Schepens Eye Res Inst, Grousbeck Gene Therapy Ctr,Ocular Genom Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 467 BP S184 EP S185 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200462 ER PT J AU Wassmer, S Comander, J Carvalho, L Xiao, R Plovic, E Langsdorf, A Lim, L Hafler, B Wu, DM Eliott, D Kim, LA Vandenberghe, LH AF Wassmer, Sarah Comander, Jason Carvalho, Livia Xiao, Ru Plovic, Eva Langsdorf, Aliete Lim, Lawrence Hafler, Brian Wu, David M. Eliott, Dean Kim, Leo A. Vandenberghe, Luk H. TI Delayed Inflammatory Response to Intravitreal AAV Gene Transfer in Non-Human Primates SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Wassmer, Sarah; Carvalho, Livia; Xiao, Ru; Plovic, Eva; Vandenberghe, Luk H.] Grousbeck Gene Therapy Ctr, Boston, MA USA. [Wassmer, Sarah; Comander, Jason; Carvalho, Livia; Xiao, Ru; Plovic, Eva; Langsdorf, Aliete; Lim, Lawrence; Hafler, Brian; Wu, David M.; Eliott, Dean; Kim, Leo A.; Vandenberghe, Luk H.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Wassmer, Sarah; Comander, Jason; Carvalho, Livia; Xiao, Ru; Plovic, Eva; Langsdorf, Aliete; Hafler, Brian; Vandenberghe, Luk H.] Ocular Genom Inst, Boston, MA USA. [Wassmer, Sarah; Carvalho, Livia; Xiao, Ru; Plovic, Eva; Lim, Lawrence; Kim, Leo A.; Vandenberghe, Luk H.] Schepens Eye Res Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 80 BP S35 EP S35 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200081 ER PT J AU Xiao, R Wang, L Carvalho, L Wassmer, S Vandenberghe, LH AF Xiao, Ru Wang, Li Carvalho, Livia Wassmer, Sarah Vandenberghe, Luk H. TI In Silico Reconstructed Ancestral Adeno-Associated Viruses Transduce Mouse Anterior Segment SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Xiao, Ru; Wang, Li; Carvalho, Livia; Wassmer, Sarah; Vandenberghe, Luk H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Grousbeck Gene Therapy Ctr,Ocular Genom Inst,Sche, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 608 BP S241 EP S241 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200599 ER PT J AU Choteau, L Parny, M Francois, N Bertin, B Fumery, M Dubuquoy, L Takahashi, K Colombel, JF Jouault, T Poulain, D Sendid, B Jawhara, S AF Choteau, L. Parny, M. Francois, N. Bertin, B. Fumery, M. Dubuquoy, L. Takahashi, K. Colombel, J-F Jouault, T. Poulain, D. Sendid, B. Jawhara, S. TI Role of mannose-binding lectin in intestinal homeostasis and fungal elimination SO MUCOSAL IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CANDIDA-ALBICANS; NEISSERIA-MENINGITIDIS; EXPERIMENTAL COLITIS; CROHNS-DISEASE; RECEPTOR; MICE; INDUCTION; DECTIN-1; CELLS AB Mannose-binding lectin (MBL) is a soluble lectin of the innate immune system that is produced by the liver and secreted into the circulation where it activates the lectin complement pathway, enhances phagocytosis of microorganisms by leukocytes, and modulates inflammation. MBL can recognize patterns on the surface of different pathogens, including Candida albicans. Our aims were to investigate whether MBL is expressed in the gut epithelium and to examine its effect on the modulation of intestinal inflammation and C. albicans elimination. Using reverse transcriptase-PCR, MBL transcripts were highly expressed in different parts of the mouse gut. MBL expression was also detected by immunoblotting and immunolocalization in response to C. albicans colonization of the gut; the highest expression of MBL was detected in the stomach. Blocking MBL by administering mannans to mice increased C. albicans colonization. MBL-deficient mice had a higher level of colonization than wild-type mice. Dextran sodium sulfate-induced colitis promoted C. albicans dissemination to the kidneys and lungs of MBL-deficient mice. MBL-deficient mice exhibited elevated expression of interleukin (IL)-17, IL-23, dectin-1, and Toll-like receptor-4. This study shows that MBL expression is induced in the gut in response to C. albicans sensing and is required for intestinal homeostasis and host defense against C. albicans. C1 [Choteau, L.; Parny, M.; Bertin, B.; Fumery, M.; Dubuquoy, L.; Jouault, T.; Poulain, D.; Sendid, B.; Jawhara, S.] Univ Lille Nord France, Lille, France. [Choteau, L.; Parny, M.; Bertin, B.; Fumery, M.; Dubuquoy, L.; Jouault, T.; Poulain, D.; Sendid, B.; Jawhara, S.] UDSL, Lille, France. [Choteau, L.; Parny, M.; Bertin, B.; Fumery, M.; Dubuquoy, L.; Jouault, T.; Poulain, D.; Sendid, B.; Jawhara, S.] INSERM U995, Lille, France. [Choteau, L.; Poulain, D.; Sendid, B.] CHRU Lille, F-59037 Lille, France. [Francois, N.] Serv Parasitol Mycol, Pole Biol Pathol Genet, Lille, France. [Takahashi, K.] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Colombel, J-F] Icahn Sch Med Mt Sinai, Dept Gastroenterol, New York, NY 10029 USA. RP Jawhara, S (reprint author), Univ Lille Nord France, Lille, France.; Jawhara, S (reprint author), UDSL, Lille, France.; Jawhara, S (reprint author), INSERM U995, Lille, France. EM samir.jawhara-3@univ-lille2.fr RI Dubuquoy, laurent/J-4978-2015 OI Dubuquoy, laurent/0000-0003-3596-5497 FU FP7 Health "ALLFUN" project "Fungi in the setting of inflammation, allergy and auto-immune diseases: translating basic science into clinical practices" [260338]; BIOASTER by AVIESAN (France's National Alliance for Life Sciences and Health) [ARN-10-AIRT-03]; digestScience Foundation FX This work was funded by the FP7 Health 260338 "ALLFUN" project "Fungi in the setting of inflammation, allergy and auto-immune diseases: translating basic science into clinical practices". This work was also funded through BIOASTER by AVIESAN (France's National Alliance for Life Sciences and Health grant no. ARN-10-AIRT-03). The authors thank the digestScience Foundation for their support. NR 46 TC 1 Z9 1 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD MAY PY 2016 VL 9 IS 3 BP 767 EP 776 DI 10.1038/mi.2015.100 PG 10 WC Immunology SC Immunology GA DK9TV UT WOS:000375275300017 PM 26442658 ER PT J AU Guo, JS Jing, RR Lv, X Wang, XY Li, JQ Li, L Li, CL Wang, DG Bi, BB Chen, XJ Yang, JH AF Guo, Jisheng Jing, Ruirui Lv, Xin Wang, Xiaoyue Li, Junqiang Li, Lin Li, Cuiling Wang, Daoguang Bi, Baibing Chen, Xinjun Yang, Jing-Hua TI H2A/K pseudogene mutation may promote cell proliferation SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE H2A/K; LncRNA; Quantitative proteomics; Cell proliferation ID PROTEOMICS-BASED IDENTIFICATION; TUMOR-ASSOCIATED ANTIGEN; HUMAN DHX9 HELICASE; COLORECTAL-CANCER; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; DNA-REPLICATION; POOR-PROGNOSIS; UP-REGULATION; EXPRESSION AB Little attention has been paid to the histone H2A/K pseudogene. Results from our laboratory showed that 7 of 10 kidney cancer patients carried a mutant H2A/K pseudogene; therefore, we were interested in determining the relationship between mutant H2A/K and cell proliferation. We used shotgun and label-free proteomics methods to study whether mutant H2A/K IncRNAs affected cell proliferation. Quantitative proteomic analysis indicated that the expression of mutant H2A/K IncRNAs resulted in the upregulation of many oncogenes, which promoted cell proliferation. Further interaction analyses revealed that a proliferating cell nuclear antigen (PCNA)-protein interaction network, with PCNA in the center, contributes to cell proliferation in cells expressing the mutant H2A/K IncRNAs. Western blotting confirmed the critical upregulation of PCNA by mutant H2A/K IncRNA expression. Finally, the promotion of cell proliferation by mutant H2A/K IncRNAs (C290T, C228A and A45G) was confirmed using cell proliferation assays. Although we did not determine the exact mechanism by which the oncogenes were upregulated by the mutant H2A/K IncRNAs, we confirmed that the mutant H2A/K IncRNAs promoted cell proliferation by upregulating PCNA and other oncogenes. The hypothesis that cell proliferation is promoted by the mutant H2A/K IncRNAs was supported by the protein expression and cell proliferation assay results. Therefore, mutant H2A/K IncRNAs may be a new factor in renal carcinogenesis. (C) 2016 Elsevier B.V. All rights reserved. C1 [Guo, Jisheng; Jing, Ruirui; Lv, Xin; Wang, Xiaoyue; Li, Junqiang; Li, Lin; Li, Cuiling; Wang, Daoguang; Bi, Baibing; Chen, Xinjun; Yang, Jing-Hua] Shandong Univ, Canc Res Ctr, Sch Med, Jinan 250012, Peoples R China. [Yang, Jing-Hua] Boston Univ, Dept Surg, VA Boston Healthcare Syst, Sch Med, Boston, MA USA. RP Yang, JH (reprint author), Shandong Univ, Canc Res Ctr, Sch Med, Jinan 250012, Peoples R China.; Yang, JH (reprint author), Boston Univ, Dept Surg, VA Boston Healthcare Syst, Sch Med, Boston, MA USA. EM sdu_crc_group1@126.com FU National Natural Science Foundation of China [31471322, 30928031]; Shandong Province Major Science and Technology Project [2015ZDXX0802A02] FX This work was supported by grants from the National Natural Science Foundation of China (#31471322 and #30928031) and Shandong Province Major Science and Technology Project (2015ZDXX0802A02). This study was the result of work partially supported with the resources and facilities of the VA Boston Healthcare System, USA, and of the Cancer Research Center, Shandong University, China. NR 50 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAY PY 2016 VL 787 BP 32 EP 42 DI 10.1016/j.mrfmmm.2016.02.010 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA DK3FD UT WOS:000374801600004 PM 26953487 ER PT J AU Mansouri, M Bellon-Echeverria, I Rizk, A Ehsaei, Z Cosentino, CC Silva, CS Xie, Y Boyce, FM Davis, MW Neuhauss, SCF Taylor, V Ballmer-Hofer, K Berger, I Berger, P AF Mansouri, Maysam Bellon-Echeverria, Itxaso Rizk, Aurelien Ehsaei, Zahra Cosentino, Chiara Cianciolo Silva, Catarina S. Xie, Ye Boyce, Frederick M. Davis, M. Wayne Neuhauss, Stephan C. F. Taylor, Verdon Ballmer-Hofer, Kurt Berger, Imre Berger, Philipp TI Highly efficient baculovirus-mediated multigene delivery in primary cells SO NATURE COMMUNICATIONS LA English DT Article ID MULTIPROTEIN COMPLEX PRODUCTION; MAMMALIAN-CELLS; GENE-TRANSFER; EXPRESSION SYSTEM; PROTEIN EXPRESSION; EUKARYOTIC CELLS; INSECT CELLS; VECTORS; GENERATION; COMBINATORIAL AB Multigene delivery and subsequent cellular expression is emerging as a key technology required in diverse research fields including, synthetic and structural biology, cellular reprogramming and functional pharmaceutical screening. Current viral delivery systems such as retro-and adenoviruses suffer from limited DNA cargo capacity, thus impeding unrestricted multigene expression. We developed MultiPrime, a modular, non-cytotoxic, non-integrating, baculovirus-based vector system expediting highly efficient transient multigene expression from a variety of promoters. MultiPrime viruses efficiently transduce a wide range of cell types, including non-dividing primary neurons and induced-pluripotent stem cells (iPS). We show that MultiPrime can be used for reprogramming, and for genome editing and engineering by CRISPR/Cas9. Moreover, we implemented dual-host-specific cassettes enabling multiprotein expression in insect and mammalian cells using a single reagent. Our experiments establish MultiPrime as a powerful and highly efficient tool, to deliver multiple genes for a wide range of applications in primary and established mammalian cells. C1 [Mansouri, Maysam; Rizk, Aurelien; Xie, Ye; Ballmer-Hofer, Kurt; Berger, Philipp] Paul Scherrer Inst, Mol Cell Biol, Biomol Res, CH-5232 Villigen, Switzerland. [Bellon-Echeverria, Itxaso; Silva, Catarina S.; Berger, Imre] European Mol Biol Lab, Grenoble Outstn, BP 181, F-38042 Grenoble 9, France. [Ehsaei, Zahra; Taylor, Verdon] Univ Basel, Dept Biomed, CH-4058 Basel, Switzerland. [Cosentino, Chiara Cianciolo; Neuhauss, Stephan C. F.] Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland. [Boyce, Frederick M.] Massachusetts Gen Hosp, Dept Neurol, Cambridge, MA 02139 USA. [Davis, M. Wayne] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Davis, M. Wayne] Univ Utah, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA. [Berger, Imre] Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England. RP Berger, P (reprint author), Paul Scherrer Inst, Mol Cell Biol, Biomol Res, CH-5232 Villigen, Switzerland.; Berger, I (reprint author), European Mol Biol Lab, Grenoble Outstn, BP 181, F-38042 Grenoble 9, France.; Berger, I (reprint author), Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England. EM imre.berger@bristol.ac.uk; Philipp.Berger@psi.ch FU Swiss National Science Foundation [31003A-146975, 3100A0-118351]; European Commission (EC) [279039, 613879, 283570]; Iranian Ministry of Science FX This work was supported by the Swiss National Science Foundation (31003A-146975 and 3100A0-118351 to P.B.), the European Commission (EC) Framework programme (FP) seven projects ComplexINC, SynSignal and Biostruct-X (contracts nr. 279039, 613879 and 283570 to I.B.) and a fellowship of the Iranian Ministry of Science (to M.M.). We acknowledge the assistance and support of the Center for Microscopy and Image Analysis, University of Zurich for performing zebrafish in vivo imaging. We would like to thank Mayanka Asthana for help with VEGF labelling and Dr Stefan Jakobs for providing gRNA plasmids. NR 51 TC 2 Z9 2 U1 16 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2016 VL 7 AR 11529 DI 10.1038/ncomms11529 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2IR UT WOS:000375458200001 PM 27143231 ER PT J AU Mieczkowski, J Cook, A Bowman, SK Mueller, B Alver, BH Kundu, S Deaton, AM Urban, JA Larschan, E Park, PJ Kingston, RE Tolstorukov, MY AF Mieczkowski, Jakub Cook, April Bowman, Sarah K. Mueller, Britta Alver, Burak H. Kundu, Sharmistha Deaton, Aimee M. Urban, Jennifer A. Larschan, Erica Park, Peter J. Kingston, Robert E. Tolstorukov, Michael Y. TI MNase titration reveals differences between nucleosome occupancy and chromatin accessibility SO NATURE COMMUNICATIONS LA English DT Article ID DROSOPHILA GENOME; REGULATORY REGIONS; RNA-SEQ; DNA; TRANSCRIPTION; ORGANIZATION; RESOLUTION; ACETYLATION; ACTIVATION; REPRESSION AB Chromatin accessibility plays a fundamental role in gene regulation. Nucleosome placement, usually measured by quantifying protection of DNA from enzymatic digestion, can regulate accessibility. We introduce a metric that uses micrococcal nuclease (MNase) digestion in a novel manner to measure chromatin accessibility by combining information from several digests of increasing depths. This metric, MACC (MNase accessibility), quantifies the inherent heterogeneity of nucleosome accessibility in which some nucleosomes are seen preferentially at high MNase and some at low MNase. MACC interrogates each genomic locus, measuring both nucleosome location and accessibility in the same assay. MACC can be performed either with or without a histone immunoprecipitation step, and thereby compares histone and non-histone protection. We find that changes in accessibility at enhancers, promoters and other regulatory regions do not correlate with changes in nucleosome occupancy. Moreover, high nucleosome occupancy does not necessarily preclude high accessibility, which reveals novel principles of chromatin regulation. C1 [Mieczkowski, Jakub; Cook, April; Bowman, Sarah K.; Mueller, Britta; Kundu, Sharmistha; Deaton, Aimee M.; Kingston, Robert E.; Tolstorukov, Michael Y.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Mieczkowski, Jakub; Cook, April; Bowman, Sarah K.; Mueller, Britta; Kundu, Sharmistha; Deaton, Aimee M.; Kingston, Robert E.; Tolstorukov, Michael Y.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Alver, Burak H.; Park, Peter J.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Urban, Jennifer A.; Larschan, Erica] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. RP Kingston, RE; Tolstorukov, MY (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Kingston, RE; Tolstorukov, MY (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu; tolstorukov@molbio.mgh.harvard.edu OI Urban, Jennifer/0000-0002-6621-8358; Mieczkowski, Jakub/0000-0002-2091-012X FU National Institute of General Medical Sciences of the NIH [R01GM043901, R37GM048405, R01GM082798]; Leukemia and Lymphoma Society FX We thank the MGH Molecular Biology NextGen Sequencing Core. R.E.K. and P.J.P. were supported by the National Institute of General Medical Sciences of the NIH (R01GM043901 and R37GM048405 to R.E.K.; R01GM082798 to P.J.P.). B.M. was supported in part by a fellowship from the Leukemia and Lymphoma Society. NR 46 TC 9 Z9 9 U1 6 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2016 VL 7 AR 11485 DI 10.1038/ncomms11485 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL2WA UT WOS:000375494700001 PM 27151365 ER PT J AU Morganella, S Alexandrov, LB Glodzik, D Zou, XQ Davies, H Staaf, J Sieuwerts, AM Brinkman, AB Martin, S Ramakrishna, M Butler, A Kim, HY Borg, A Sotiriou, C Futreal, PA Campbell, PJ Span, PN Van Laere, S Lakhani, SR Eyfjord, JE Thompson, AM Stunnenberg, HG de Vijver, MJV Martens, JWM Borresen-Dale, AL Richardson, AL Kong, G Thomas, G Sale, J Rada, C Stratton, MR Birney, E Nik-Zainal, S AF Morganella, Sandro Alexandrov, Ludmil B. Glodzik, Dominik Zou, Xueqing Davies, Helen Staaf, Johan Sieuwerts, Anieta M. Brinkman, Arie B. Martin, Sancha Ramakrishna, Manasa Butler, Adam Kim, Hyung-Yong Borg, Ake Sotiriou, Christos Futreal, P. Andrew Campbell, Peter J. Span, Paul N. Van Laere, Steven Lakhani, Sunil R. Eyfjord, Jorunn E. Thompson, Alastair M. Stunnenberg, Hendrik G. de Vijver, Marc J. van Martens, John W. M. Borresen-Dale, Anne-Lise Richardson, Andrea L. Kong, Gu Thomas, Gilles Sale, Julian Rada, Cristina Stratton, Michael R. Birney, Ewan Nik-Zainal, Serena TI The topography of mutational processes in breast cancer genomes SO NATURE COMMUNICATIONS LA English DT Article ID MISMATCH REPAIR; HOMOLOGOUS-RECOMBINATION; CHROMATIN ORGANIZATION; FISSION YEAST; ABASIC SITE; MATING-TYPE; DNA-REPAIR; REPLICATION; SIGNATURES; SPECIFICITY AB Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis. C1 [Morganella, Sandro; Futreal, P. Andrew; Birney, Ewan] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England. [Alexandrov, Ludmil B.; Glodzik, Dominik; Zou, Xueqing; Davies, Helen; Martin, Sancha; Ramakrishna, Manasa; Butler, Adam; Campbell, Peter J.; Stratton, Michael R.; Nik-Zainal, Serena] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Alexandrov, Ludmil B.] Los Alamos Natl Lab, Theoret Biol & Biophys T 6, Los Alamos, NM 87545 USA. [Alexandrov, Ludmil B.] Los Alamos Natl Lab, Ctr Nonlinear Studies, Los Alamos, NM 87545 USA. [Staaf, Johan; Borg, Ake] Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, SE-22381 Lund, Sweden. [Sieuwerts, Anieta M.; Martens, John W. M.] Erasmus Univ, Dept Med Oncol, Erasmus MC Canc Inst, Med Ctr, NL-3015 CN Rotterdam, Netherlands. [Sieuwerts, Anieta M.; Martens, John W. M.] Erasmus Univ, Canc Genom Netherlands, NL-3015 CN Rotterdam, Netherlands. [Brinkman, Arie B.] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 GA Nijmegen, Netherlands. [Kim, Hyung-Yong; Kong, Gu] Hanyang Univ, Dept Pathol, Coll Med, Seoul 133791, South Korea. [Sotiriou, Christos] Univ Libre Bruxelles, Breast Canc Translat Res Lab, Inst Jules Bordet, Bd Waterloo 121, B-1000 Brussels, Belgium. [Futreal, P. Andrew] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77230 USA. [Span, Paul N.] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, NL-6525 GA Nijmegen, Netherlands. [Span, Paul N.] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands. [Van Laere, Steven] GZA Hosp Sint Augustinus, Translat Canc Res Unit, Antwerp, Belgium. [Van Laere, Steven] Univ Antwerp, Oncol Res Ctr, B-2610 Antwerp, Belgium. [Lakhani, Sunil R.] Univ Queensland, Ctr Clin Res, Brisbane, Qld 4059, Australia. [Lakhani, Sunil R.] Univ Queensland, Sch Med, Brisbane, Qld 4059, Australia. [Lakhani, Sunil R.] Royal Brisbane & Womens Hosp, Pathol Queensland, Brisbane, Qld, Australia. [Eyfjord, Jorunn E.] Univ Iceland, Fac Med, Canc Res Lab, IS-101 Reykjavik, Iceland. [Thompson, Alastair M.] MD Anderson Canc Res Ctr, Dept Breast Surg Oncol, 1400 Pressler St, Houston, TX 77030 USA. [Thompson, Alastair M.] Univ Dundee, Dept Surg Oncol, Dundee DD1 9SY, Scotland. [de Vijver, Marc J. van] Univ Amsterdam, Acad Med Ctr, Dept Pathol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Borresen-Dale, Anne-Lise] Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, Inst Canc Res, N-0310 Oslo, Norway. [Borresen-Dale, Anne-Lise] Univ Oslo, KG Jebsen Ctr Breast Canc Res, Inst Clin Med, N-0310 Oslo, Norway. [Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Richardson, Andrea L.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Thomas, Gilles] Synergie Lyon Canc, Ctr Leon Berard, 28 Rue Laennec, Lyon 08, France. [Sale, Julian; Rada, Cristina] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England. [Nik-Zainal, Serena] Cambridge Univ Hosp NHS Fdn Trust, East Anglian Med Genet Serv, Cambridge CB2 9NB, England. RP Nik-Zainal, S (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.; Nik-Zainal, S (reprint author), Cambridge Univ Hosp NHS Fdn Trust, East Anglian Med Genet Serv, Cambridge CB2 9NB, England. EM snz@sanger.ac.uk RI Span, Paul/G-4710-2012; OI Span, Paul/0000-0002-1930-6638; Birney, Ewan/0000-0001-8314-8497; Alexandrov, Ludmil/0000-0003-3596-4515; Martin, Sancha/0000-0001-6213-5259 FU ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (a European research project - European Community's Seventh Framework Programme (FP7)) [242006]; Triple Negative project - Wellcome Trust [077012/Z/05/Z]; HER2+ project - Institut National du Cancer (INCa) in France [226-2009, 02-2011, 41-2012, 144-2008, 06-2012]; Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A111218-SC01]; US Department of Energy National Nuclear Security Administration [DE-AC52-06NA25396]; National Nuclear Security Administration of the United States Department of Energy; Breast Cancer Somatic Genetic Study (BASIS); J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory; EU; Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer [NIH/NCI 5 P50 CA168504-02]; EU-FP7-DDR response project; FNRS (Fonds National de la Recherche Scientifique); National Research Foundation of Korea (NRF) [NRF 2015R1A2A1A10052578]; EMBL; Wellcome Trust Intermediate Fellowship [WT100183MA]; COMSIG Consortium - Wellcome Trust Strategic Award [101126/B/13/Z] FX This analysis has been performed on data from a project funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (a European research project funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006); the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (Grants No. 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01). We would like to acknowledge the Wellcome Trust Sanger Institute Sequencing Core Facility, Core IT Facility and Cancer Genome Project Core IT team and Cancer Genome Project Core Laboratory team for general support. This research also used resources provided by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the US Department of Energy National Nuclear Security Administration under Contract No. DE-AC52-06NA25396. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the United States Department of Energy. S.M. is funded through the Breast Cancer Somatic Genetic Study (BASIS). L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. D.G. is supported by the EU-FP7-SUPPRESSTEM project. A.L.R. is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA168504-02). M.S. was supported by the EU-FP7-DDR response project. C.S. is funded by FNRS (Fonds National de la Recherche Scientifique). G.K. is supported by National Research Foundation of Korea (NRF) grants NRF 2015R1A2A1A10052578. E.B. is funded by EMBL. SN-Z is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). S.N.-Z. and X.Z. also work under the auspices of the COMSIG Consortium, supported by a Wellcome Trust Strategic Award (101126/B/13/Z). We would like to acknowledge all members of the ICGC Breast Cancer Working Group, ICGC Asian Breast Cancer Project, and Oslo Breast Cancer Consortium (OSBREAC). NR 53 TC 14 Z9 14 U1 7 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2016 VL 7 AR 11383 DI 10.1038/ncomms11383 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK9AX UT WOS:000375223100001 PM 27136393 ER PT J AU Robinson, EB St Pourcain, B Anttila, V Kosmicki, JA Bulik-Sullivan, B Grove, J Maller, J Samocha, KE Sanders, SJ Ripke, S Martin, J Hollegaard, MV Werge, T Hougaard, DM Neale, BM Evans, DM Skuse, D Mortensen, PB Borglum, AD Ronald, A Smith, GD Daly, MJ AF Robinson, Elise B. St Pourcain, Beate Anttila, Verneri Kosmicki, Jack A. Bulik-Sullivan, Brendan Grove, Jakob Maller, Julian Samocha, Kaitlin E. Sanders, Stephan J. Ripke, Stephan Martin, Joanna Hollegaard, Mads V. Werge, Thomas Hougaard, David M. Neale, Benjamin M. Evans, David M. Skuse, David Mortensen, Preben Bo Borglum, Anders D. Ronald, Angelica Smith, George Davey Daly, Mark J. CA iPSYCH-SSI Broad Autism Grp TI Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population SO NATURE GENETICS LA English DT Article ID DE-NOVO; TRAITS; MUTATIONS; VARIABILITY; PHENOTYPES; COMPONENTS; ETIOLOGY; DISEASES AB Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology. C1 [Robinson, Elise B.; Anttila, Verneri; Kosmicki, Jack A.; Bulik-Sullivan, Brendan; Maller, Julian; Samocha, Kaitlin E.; Ripke, Stephan; Martin, Joanna; Neale, Benjamin M.; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Robinson, Elise B.; Anttila, Verneri; Kosmicki, Jack A.; Bulik-Sullivan, Brendan; Maller, Julian; Samocha, Kaitlin E.; Ripke, Stephan; Martin, Joanna; Neale, Benjamin M.; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA USA. [Robinson, Elise B.; Anttila, Verneri; Kosmicki, Jack A.; Bulik-Sullivan, Brendan; Maller, Julian; Samocha, Kaitlin E.; Ripke, Stephan; Martin, Joanna; Neale, Benjamin M.; Daly, Mark J.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Robinson, Elise B.; Anttila, Verneri; Kosmicki, Jack A.; Bulik-Sullivan, Brendan; Maller, Julian; Samocha, Kaitlin E.; Ripke, Stephan; Martin, Joanna; Neale, Benjamin M.; Daly, Mark J.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Evans, David M.; Smith, George Davey] Univ Bristol, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England. [St Pourcain, Beate] Max Planck Inst Psycholinguist, Nijmegen, Netherlands. [Kosmicki, Jack A.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Grove, Jakob; Mortensen, Preben Bo; Borglum, Anders D.] Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark. [Grove, Jakob; Werge, Thomas; Mortensen, Preben Bo; Borglum, Anders D.] IPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Copenhagen, Denmark. [Grove, Jakob; Borglum, Anders D.] Aarhus Univ, iSEQ, Ctr Integrat Sequencing, Aarhus, Denmark. [Grove, Jakob] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark. [Samocha, Kaitlin E.] Harvard Univ, Sch Med, Program Genet & Genom, Biol & Biomed Sci, Boston, MA USA. [Sanders, Stephan J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Ripke, Stephan] Charite, Dept Psychiat & Psychotherapy, Campus Mitte, Berlin, Germany. [Hollegaard, Mads V.; Hougaard, David M.] Statens Serum Inst, Dept Congenital Disorders, Ctr Neonatal Screening, DK-2300 Copenhagen, Denmark. [Werge, Thomas] Mental Hlth Serv Copenhagen, Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, Copenhagen, Denmark. [Werge, Thomas] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark. [Neale, Benjamin M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Evans, David M.] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Skuse, David] UCL, Inst Child Hlth, Behav Sci Unit, London, England. [Mortensen, Preben Bo] Univ Aarhus, Natl Ctr Register Based Res, Aarhus, Denmark. [Ronald, Angelica] Birkbeck Univ London, Ctr Brain & Cognit Dev, Dept Psychol Sci, London, England. RP Robinson, EB; Daly, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM erobinson@atgu.mgh.harvard.edu; mjdaly@atgu.mgh.harvard.edu RI Davey Smith, George/A-7407-2013; Hansen, Thomas Folkmann/O-5965-2014; OI Bybjerg-Grauholm, Jonas/0000-0003-1705-4008; Evans, David/0000-0003-0663-4621; Davey Smith, George/0000-0002-1407-8314; Moran, Jennifer/0000-0002-5664-4716; Bakvad-Hansen, Marie/0000-0002-5881-1776; Hansen, Thomas Folkmann/0000-0001-6703-7762; Sanders, Stephan/0000-0001-9112-5148; Martin, Joanna/0000-0002-8911-3479; Grove, Jakob/0000-0003-2284-5744 FU Wellcome Trust [102215/2/13/2]; Medical Research Council Integrative Epidemiology Unit [MC_UU_12013/1-9]; National Institute of Mental Health [1K01MH099286-01A1, 5U01MH094432-02]; Brain Behavior Research Foundation (NARSAD) [22379]; Lundbeck Foundation; universities and university hospital of Aarhus; universities and university hospital of Copenhagen; Stanley Foundation; Simons Foundation [SFARI 311789] FX We thank S. Hyman, T. Lehner and N. Kanwisher for comments on the manuscript. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council, the Wellcome Trust (grant 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Autism Speaks (7132) provided support for the analysis of autistic trait-related data in ALSPAC (to B.S.P.). This work was also supported by the Medical Research Council Integrative Epidemiology Unit (MC_UU_12013/1-9). This publication is the work of the authors, and E.B.R. and M.J.D. will serve as guarantors for the contents of this paper. The ALSPAC GWAS data were generated by the Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. E.B.R. was funded by National Institute of Mental Health grant 1K01MH099286-01A1 and Brain Behavior Research Foundation (NARSAD) Young Investigator grant 22379. 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. The iPSYCH project is funded by the Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.) and the National Institute of Mental Health (5U01MH094432-02 to M.J.D.). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found on the ExAC website (see URLs). This work was also supported by a grant from the Simons Foundation (SFARI 307705; to S.J.S.). NR 34 TC 28 Z9 28 U1 5 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAY PY 2016 VL 48 IS 5 BP 552 EP + DI 10.1038/ng.3529 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DK3RC UT WOS:000374834100015 PM 26998691 ER PT J AU Zaidi, M Iqbal, J AF Zaidi, Mone Iqbal, Jameel TI Closing the loop on the bone-resorbing osteoclast SO NATURE MEDICINE LA English DT Editorial Material AB A new study shows in mice that tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL), which stimulates osteoclasts to remove bone, binds to the G-protein-coupled receptor LGR4 to prevent excessive bone removal. In mouse models of osteoporosis, a recombinant LGR4 ectodomain reduces bone loss. C1 [Zaidi, Mone] Icahn Sch Med Mt Sinai, Mt Sinai Bone Program, New York, NY 10029 USA. [Iqbal, Jameel] Los Angeles VA Med Ctr, Dept Pathol, Los Angeles, CA USA. RP Zaidi, M (reprint author), Icahn Sch Med Mt Sinai, Mt Sinai Bone Program, New York, NY 10029 USA. EM Mone.zaidi@mssm.edu NR 12 TC 1 Z9 1 U1 5 U2 6 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 MAY PY 2016 VL 22 IS 5 BP 460 EP 461 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DL3DI UT WOS:000375514000006 PM 27149217 ER PT J AU Holmes, JA Chung, RT AF Holmes, Jacinta A. Chung, Raymond T. TI HCV compartmentalization in HCC: driver, passenger or both? SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY LA English DT Editorial Material ID HEPATITIS-C VIRUS; PROTEIN-KINASE-R; HEPATOCELLULAR-CARCINOMA; REPLICATION; RNA AB Hepatocellular carcinoma is associated with HCV infection but the underlying interplay between virus and tumour remains to be elucidated. Now, Harouaka et al. report that in patients with HCV-related cirrhosis, HCV replication is restricted within liver tissue originating from hepatocellular carcinoma, with an associated increase in the diversity and complexity of the HCV quasispecies. C1 [Holmes, Jacinta A.; Chung, Raymond T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. RP Chung, RT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM chung.raymond@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5045 EI 1759-5053 J9 NAT REV GASTRO HEPAT JI Nat. Rev. Gastroenterol. Hepatol. PD MAY PY 2016 VL 13 IS 5 BP 254 EP U17 DI 10.1038/nrgastro.2016.46 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK7ST UT WOS:000375126700002 PM 27006254 ER PT J AU Hydbring, P Malumbres, M Sicinski, P AF Hydbring, Per Malumbres, Marcos Sicinski, Piotr TI Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID DNA-END RESECTION; DAMAGE CHECKPOINT ACTIVATION; HISTONE GENE-TRANSCRIPTION; BREAST-CANCER CELLS; NEURAL STEM-CELLS; CDK2-DEPENDENT PHOSPHORYLATION; ANDROGEN RECEPTOR; ESTROGEN-RECEPTOR; HOMOLOGOUS RECOMBINATION; MITOCHONDRIAL-FUNCTION AB The roles of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression are well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important functions in other cellular processes, such as transcription, DNA damage repair, control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or CDKs, independently of their respective cell cycle partners, suggesting that there was a substantial divergence in the functions of these proteins during evolution. C1 [Hydbring, Per; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Hydbring, Per; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Malumbres, Marcos] Spanish Natl Canc Res Ctr CNIO, E-28029 Madrid, Spain. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Sicinski, P (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM peter_sicinski@dfci.harvard.edu FU US National Institutes of Health (NIH) [R01 CA083688, R01 CA132740, P01 CA080111]; Spanish Ministry of Economy and Competitiveness [SAF2012-38215, SAF2014-57791-REDC, BFU2014-52125-REDT]; Comunidad de Madrid [S2010/BMD-2470] FX This work was supported by US National Institutes of Health (NIH) grants R01 CA083688, R01 CA132740 and P01 CA080111 to P.S., and grants from the Spanish Ministry of Economy and Competitiveness (SAF2012-38215, SAF2014-57791-REDC and BFU2014-52125-REDT) and Comunidad de Madrid (S2010/BMD-2470) to M.M.. NR 173 TC 10 Z9 11 U1 9 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD MAY PY 2016 VL 17 IS 5 BP 280 EP 292 DI 10.1038/nrm.2016.27 PG 13 WC Cell Biology SC Cell Biology GA DJ9MG UT WOS:000374537000007 PM 27033256 ER PT J AU Borisy, G Heald, R Howard, J Janke, C Musacchio, A Nogales, E AF Borisy, Gary Heald, Rebecca Howard, Jonathon Janke, Carsten Musacchio, Andrea Nogales, Eva TI Microtubules: 50 years on from the discovery of tubulin SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Article ID COLCHICINE; MECHANISM; BINDING AB Next year will be the 50th anniversary of the discovery of tubulin. To celebrate this discovery, six leaders in the field of microtubule research reflect on key findings and technological breakthroughs over the past five decades, discuss implications for therapeutic applications and provide their thoughts on what questions need to be addressed in the near future. C1 [Borisy, Gary] Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. [Heald, Rebecca] Univ Calif Berkeley, Div Cell & Dev Biol, Berkeley, CA 94720 USA. [Heald, Rebecca] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Howard, Jonathon] Yale Univ, Dept Mol Biophys & Biochem, POB 6666, New Haven, CT 06510 USA. [Janke, Carsten] PSL Res Univ, Inst Curie, Ctr Univ, CNRS,UMR3348, Batiment 110, F-91405 Orsay, France. [Musacchio, Andrea] Max Planck Inst Mol Physiol, Dept Mechanist Cell Biol, Otto Hahn Str 11, D-44227 Dortmund, Germany. [Musacchio, Andrea] Univ Duisburg Essen, Ctr Med Biotechnol, Fac Biol, Univ Str, D-45141 Essen, Germany. [Nogales, Eva] Univ Calif Berkeley, Biochem Biophys & Struct Biol Div, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Nogales, Eva] Howard Hughes Med Inst, Chevy Chase, MD USA. [Nogales, Eva] Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. RP Borisy, G (reprint author), Forsyth Inst, 245 First St, Cambridge, MA 02142 USA.; Heald, R (reprint author), Univ Calif Berkeley, Div Cell & Dev Biol, Berkeley, CA 94720 USA.; Heald, R (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.; Howard, J (reprint author), Yale Univ, Dept Mol Biophys & Biochem, POB 6666, New Haven, CT 06510 USA.; Janke, C (reprint author), PSL Res Univ, Inst Curie, Ctr Univ, CNRS,UMR3348, Batiment 110, F-91405 Orsay, France.; Musacchio, A (reprint author), Max Planck Inst Mol Physiol, Dept Mechanist Cell Biol, Otto Hahn Str 11, D-44227 Dortmund, Germany.; Musacchio, A (reprint author), Univ Duisburg Essen, Ctr Med Biotechnol, Fac Biol, Univ Str, D-45141 Essen, Germany.; Nogales, E (reprint author), Univ Calif Berkeley, Biochem Biophys & Struct Biol Div, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.; Nogales, E (reprint author), Howard Hughes Med Inst, Chevy Chase, MD USA.; Nogales, E (reprint author), Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. EM gborisy@forsyth.org; bheald@berkeley.edu; jonathon.howard@yale.edu; carsten.janke@curie.fr; andrea.musacchio@mpi-dortmund.mpg.de; enogales@lbl.gov RI Howard, Jonathon/J-7492-2016; Janke, Carsten/A-7279-2011; OI Howard, Jonathon/0000-0003-0086-1196; Janke, Carsten/0000-0001-7053-2000; Musacchio, Andrea/0000-0003-2362-8784 FU HHMI; NIGMS NIH HHS [P01 GM051487, R01 GM110386] NR 6 TC 3 Z9 3 U1 6 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD MAY PY 2016 VL 17 IS 5 BP 322 EP 328 DI 10.1038/nrm.2016.45 PG 7 WC Cell Biology SC Cell Biology GA DJ9MG UT WOS:000374537000011 PM 27103327 ER PT J AU Sundermann, EE Wang, CL Katz, M Zimmerman, ME Derby, CA Hall, CB Ozelius, LJ Lipton, RB AF Sundermann, Erin Elizabeth Wang, Cuiling Katz, Mindy Zimmerman, Molly E. Derby, Carol A. Hall, Charles B. Ozelius, Laurie J. Lipton, Richard B. TI Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein epsilon 4 on memory decline in older adults SO NEUROBIOLOGY OF AGING LA English DT Article DE ApoE epsilon 4; CETP; I405V; Gene-gene interaction; Memory decline ID ALZHEIMERS-DISEASE RISK; CETP GENE; CARDIOVASCULAR-DISEASE; DEMENTIA; ASSOCIATION; POLYMORPHISMS; ALLELE; AGE; IMPAIRMENT AB Apolipoprotein epsilon 4 (ApoE4) is a strong genetic risk factor for sporadic Alzheimer's disease and memory decline in older adults. A single-nucleotide polymorphism in the cholesteryl ester transfer protein (CETP) gene (isoleucine to valine; V405) is associated with slower memory decline and a lower risk of Alzheimer's disease. As both genes regulate cholesterol, we hypothesized that the favorable CETPV405 allele may buffer the effect of ApoE4 on memory decline in older adults. Using linear regression, we examined the interactive effect of ApoE4 by CETPV405 on memory decline among 909 community-dwelling, nondemented, older adults (>= 70 years) from the Einstein Aging Study. Episodic memory was measured using the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR). There was a significant ApoE x CETP interaction on decline in pFCSRT+IR scores (p = 0.01). ApoE4 carriers experienced faster decline than noncarriers among CETPI405I homozygotes (p = 0.007) and in CETPI405V heterozygotes (p = 0.015) but not in CETPV405V homozygotes (p = 0.614). Results suggest that the CETPV405 allele buffers ApoE4-associated memory decline in a gene dose-dependent manner. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sundermann, Erin Elizabeth; Wang, Cuiling; Katz, Mindy; Zimmerman, Molly E.; Derby, Carol A.; Hall, Charles B.; Lipton, Richard B.] Albert Einstein Coll Med, Einstein Aging Study, Bronx, NY 10467 USA. [Sundermann, Erin Elizabeth; Wang, Cuiling; Katz, Mindy; Zimmerman, Molly E.; Derby, Carol A.; Hall, Charles B.; Lipton, Richard B.] Albert Einstein Coll Med, Dept Neurol, 1225 Morris Pk Ave,Van Etten 3C5B, Bronx, NY 10461 USA. [Wang, Cuiling; Derby, Carol A.; Hall, Charles B.; Lipton, Richard B.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Zimmerman, Molly E.] Fordham Univ, Dept Psychol, Bronx, NY 10458 USA. [Ozelius, Laurie J.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. RP Sundermann, EE (reprint author), Albert Einstein Coll Med, Dept Neurol, 1225 Morris Pk Ave,Van Etten 3C5B, Bronx, NY 10461 USA. EM erin.sundermann@einstein.yu.edu FU National Institutes on Aging program [PO1 AG03949]; National Institutes of Health CTSA from the National Center for Advancing Translational Sciences [1UL1TR001073]; Sylvia and Lenard Marx Foundation; Czap Foundation FX This research was supported by the Einstein Aging Study (PO1 AG03949) from the National Institutes on Aging program; the National Institutes of Health CTSA (1UL1TR001073) from the National Center for Advancing Translational Sciences, the Sylvia and Lenard Marx Foundation, and the Czap Foundation. The contents of this article are solely the responsibility of the authors and do not necessary represent the official view of the NCRR or NIH. Role of the sponsor: the National Institutes on Aging 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 article. NR 32 TC 0 Z9 0 U1 2 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 MAY PY 2016 VL 41 AR 200.e7 DI 10.1016/j.neurobiolaging.2016.02.006 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DK7TU UT WOS:000375129400022 PM 27033407 ER PT J AU Schuster, RM Hoeppner, SS Evins, AE Gilman, JM AF Schuster, Randi Melissa Hoeppner, Susanne S. Evins, A. Eden Gilman, Jodi M. TI Early Onset Marijuana Use Is Associated With Learning Inefficiencies SO NEUROPSYCHOLOGY LA English DT Article DE marijuana; memory; learning; neurocognition; adolescence ID ADULT CANNABIS USERS; WHITE-MATTER; EPISODIC MEMORY; SEX-DIFFERENCES; ALCOHOL-USE; ENDOCANNABINOID SYSTEM; MAGNETIC-RESONANCE; PREFRONTAL CORTEX; DECISION-MAKING; WORKING-MEMORY AB Objective: Verbal memory difficulties are the most widely reported and persistent cognitive deficit associated with early onset marijuana use. Yet, it is not known what memory stages are most impaired in those with early marijuana use. Method: Forty-eight young adults, aged 18-25, who used marijuana at least once per week and 48 matched nonusing controls (CON) completed the California Verbal Learning Test, Second Edition (CVLT-II). Marijuana users were stratified by age of initial use: early onset users (EMJ), who started using marijuana at or before age 16 (n = 27), and late onset marijuana user group (LMJ), who started using marijuana after age 16 (n = 21). Outcome variables included trial immediate recall, total learning, clustering strategies (semantic clustering, serial clustering, ratio of semantic to serial clustering, and total number of strategies used), delayed recall, and percent retention. Results: Learning improved with repetition, with no group effect on the learning slope. EMJ learned fewer words overall than LMJ or CON. There was no difference between LMJ and CON in total number of words learned. Reduced overall learning mediated the effect on reduced delayed recall among EMJ, but not CON or LMJ. Learning improved with greater use of semantic versus serial encoding, but this did not vary between groups. EMJ was not related to delayed recall after adjusting for encoding. Conclusions: Young adults reporting early onset marijuana use had learning weaknesses, which accounted for the association between early onset marijuana use and delayed recall. No amnestic effect of marijuana use was observed. C1 [Schuster, Randi Melissa; Hoeppner, Susanne S.; Evins, A. Eden; Gilman, Jodi M.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Schuster, Randi Melissa; Hoeppner, Susanne S.; Evins, A. Eden; Gilman, Jodi M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Schuster, RM (reprint author), 60 Staniford St, Boston, MA 02114 USA. EM rschuster@mgh.harvard.edu FU Norman E. Zinberg Fellowship in Addiction Psychiatry; Livingston Fellowship from Harvard Medical School; Louis V. Gerstner III Research Scholar Award through Massachusetts General Hospital; Pfizer Inc; Forum Pharmaceuticals; GSK; [1K01DA034093]; [K24 DA030443] FX This publication was made possible by support from 1K01DA034093 (Jodi M. Gilman); K24 DA030443 (A. Eden Evins); and by the Norman E. Zinberg Fellowship in Addiction Psychiatry and Livingston Fellowship from Harvard Medical School and the Louis V. Gerstner III Research Scholar Award through Massachusetts General Hospital (Randi Melissa Schuster).; A. Eden Evins has received research grant support to her institution from Pfizer Inc, Forum Pharmaceuticals and GSK and honoraria for advisory board work from Pfizer and Reckitt Benckiser. NR 78 TC 1 Z9 1 U1 3 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 EI 1931-1559 J9 NEUROPSYCHOLOGY JI Neuropsychology PD MAY PY 2016 VL 30 IS 4 BP 405 EP 415 DI 10.1037/neu0000281 PG 11 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA DK2XM UT WOS:000374777700003 PM 26986749 ER PT J AU Bick, SKB Eskandar, EN AF Bick, Sarah K. B. Eskandar, Emad N. TI Neuromodulation for restoring memory SO NEUROSURGICAL FOCUS LA English DT Article DE deep brain stimulation; memory; Alzheimer disease; traumatic brain injury ID DEEP-BRAIN-STIMULATION; INTRACRANIAL SELF-STIMULATION; NUCLEUS BASALIS MAGNOCELLULARIS; TRANSCRANIAL MAGNETIC STIMULATION; ACTIVE-AVOIDANCE RETENTION; HIGH-FREQUENCY STIMULATION; VAGUS NERVE-STIMULATION; TEMPORAL-LOBE EPILEPSY; ALZHEIMERS-DISEASE; ELECTRICAL-STIMULATION AB Disorders of learning and memory have a large social and economic impact in today's society. Unfortunately, existing medical treatments have shown limited clinical efficacy or potential for modification of the disease course. Deep brain stimulation is a successful treatment for movement disorders and has shown promise in a variety of other diseases including psychiatric disorders. The authors review the potential of neuromodulation for the treatment of disorders of learning and memory. They briefly discuss learning circuitry and its involvement in Alzheimer disease and traumatic brain injury. They then review the literature supporting various targets for neuromodulation to improve memory in animals and humans. Multiple targets including entorhinal cortex, fornix, nucleus basalis of Meynert, basal ganglia, and pedunculopontine nucleus have shown a promising potential for improving dysfunctional memory by mechanisms such as altering firing patterns in neuronal networks underlying memory and increasing synaptic plasticity and neurogenesis. Significant work remains to be done to translate these findings into durable clinical therapies. C1 [Bick, Sarah K. B.; Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. RP Bick, SKB (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. EM sbick@partners.org NR 113 TC 2 Z9 2 U1 3 U2 9 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD MAY PY 2016 VL 40 IS 5 AR E5 DI 10.3171/2016.3.FOCUS162 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DK7PX UT WOS:000375119300007 PM 27132526 ER PT J AU Magnain, C Wang, H Sakadzic, S Fischl, B Boas, DA AF Magnain, Caroline Wang, Hui Sakadzic, Sava Fischl, Bruce Boas, David A. TI En face speckle reduction in optical coherence microscopy by frequency compounding SO OPTICS LETTERS LA English DT Article ID TOMOGRAPHY IMAGES; CONTRAST AB We report the use of frequency compounding to significantly reduce speckle noise in optical coherence microscopy, more specifically on the en face images. This method relies on the fact that the speckle patterns recorded from different wavelengths simultaneously are independent; hence their summation yields significant reduction in noise, with only a single acquisition. The results of our experiments with microbeads show that the narrow confocal parameter, due to a high numerical aperture objective, restricts the axial resolution loss that would otherwise theoretically broaden linearly with the number of optical frequency bands used. This speckle reduction scheme preserves the lateral resolution since it is performed on individual A-scans. Finally, we apply this technique to images of fixed human brain tissue, showing significant improvements in contrast-to-noise ratio with only moderate loss of axial resolution, in an effort to improve automatic three-dimensional detection of cells and fibers in the cortex. (C) 2016 Optical Society of America C1 [Magnain, Caroline; Wang, Hui; Sakadzic, Sava; Fischl, Bruce; Boas, David A.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Fischl, Bruce] MIT, Comp Sci & AI Lab, Cambridge, MA 02139 USA. RP Magnain, C (reprint author), Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM cmagnain@nmr.mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) [P41EB015896, R01EB006758, R01EB019956, R21EB018907]; National Institute on Aging (NIA) [5R01AG008122, R01AG016495]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1R21DK10827701]; National Institute of Neurological Disorders and Stroke (NINDS) [R01NS0525851, R01NS070963, R01NS083534, R21NS072652, 5U01NS086625]; National Institute of Mental Health (NIMH) [1R21MH106796]; National Cancer Institute (NCI) [5U01CA154601]; NIH Shared Instrument Grant [1S10RR019307, 1S10RR023043, 1S10RR023401]; NIH Blueprint for Neuroscience Research [5U01MH093765] FX National Institute of Biomedical Imaging and Bioengineering (NIBIB) (P41EB015896, R01EB006758, R01EB019956, R21EB018907); National Institute on Aging (NIA) (5R01AG008122, R01AG016495); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (1R21DK10827701); National Institute of Neurological Disorders and Stroke (NINDS) (R01NS0525851, R01NS070963, R01NS083534, R21NS072652, 5U01NS086625); National Institute of Mental Health (NIMH) (1R21MH106796); National Cancer Institute (NCI) (5U01CA154601); NIH Shared Instrument Grant (1S10RR019307, 1S10RR023043, 1S10RR023401); NIH Blueprint for Neuroscience Research (5U01MH093765). NR 23 TC 0 Z9 0 U1 2 U2 8 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 EI 1539-4794 J9 OPT LETT JI Opt. Lett. PD MAY 1 PY 2016 VL 41 IS 9 BP 1925 EP 1928 DI 10.1364/OL.41.001925 PG 4 WC Optics SC Optics GA DK6ZH UT WOS:000375073900008 PM 27128040 ER PT J AU Amini, A Jasem, J Jones, BL Robin, TP McDermott, JD Bhatia, S Raben, D Jimeno, A Bowles, DW Karam, SD AF Amini, Arya Jasem, Jagar Jones, Bernard L. Robin, Tyler P. McDermott, Jessica D. Bhatia, Shilpa Raben, David Jimeno, Antonio Bowles, Daniel W. Karam, Sana D. TI Predictors of overall survival in human papillomavirus-associated oropharyngeal cancer using the National Cancer Data Base SO ORAL ONCOLOGY LA English DT Article DE Human papillomavirus (HPV); National Cancer Data Base (NCDB); Oropharynx cancer; Survival outcomes; Chemoradiation; Head and neck squamous cell carcinoma ID SQUAMOUS-CELL CARCINOMA; LOCALLY ADVANCED HEAD; DISTANT METASTASIS; REGIONAL CONTROL; DE-ESCALATION; LYMPH-NODES; NECK-CANCER; HIGH-RISK; RADIOTHERAPY; CHEMOTHERAPY AB Objectives: This study identifies clinical characteristics associated with HPV-positive oropharynx squamous cell carcinoma (OPSCC) and evaluates predictors of overall survival (OS) in HPV-positive patients undergoing definitive treatment within the National Cancer Data Base (NCDB). Material and methods: The NCDB was queried for patients P18 years old with OPSCC and known HPV status who underwent definitive treatment: surgery, radiation (RT), chemotherapy-RT (CRT), surgery + RT, surgery + CRT (S-CRT). Cox proportional hazards model was used for multivariate analysis (MVA) to evaluate predictors of OS by HPV status. Results: 3952 patients were included: 2454 (62%) were HPV-positive. Median follow up was 23.7 months (range, 1.0-54.5). Unadjusted 2-year OS rates for HPV-positive vs. negative were 93.1% vs. 77.8% (p < 0.001) with an adjusted hazard ratio of 0.44 (95% CI, 0.36-0.53; p < 0.001). MVA identified multimodality treatment including CRT (HR, 0.42; p = 0.024) and S-RT (HR, 0.30; p = 0.024), but not S-CRT (HR, 0.51; p = 0.086), as predictors for improved OS in HPV-positive stage III-IVB disease. Multimodality treatment including S-CRT was associated with longer OS in HPV-negative OPSCC. Nodal stage was poorly associated with OS in HPV-positive cancers. The presence of positive margins and/or extracapsular extension was associated with worse OS in HPV-negative (HR, 2.11; p = 0.008) but not HPV positive OPSCC (HR, 1.61; p = 0.154). Conclusion: The established demographic and clinical features of HPV-positive OPSCC were corroborated in the NCDB. Population analysis suggests that AJCC staging is poorly associated with OS in HPV-positive cancer, and traditional high-risk features may be less impactful. Bimodality therapy appears beneficial in HPV-positive HNSCC. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Amini, Arya; Jones, Bernard L.; Robin, Tyler P.; Bhatia, Shilpa; Raben, David; Karam, Sana D.] Univ Colorado, Sch Med, Dept Radiat Oncol, 1665 Aurora Court,Room 1032, Aurora, CO 80045 USA. [Jasem, Jagar] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [McDermott, Jessica D.; Bowles, Daniel W.] Eastern Colorado Hlth Care Syst, Denver Vet Affairs Med Ctr, Denver, CO USA. [McDermott, Jessica D.; Jimeno, Antonio; Bowles, Daniel W.] Univ Colorado, Sch Med, Dept Med, Div Med Oncol, Aurora, CO 80045 USA. RP Karam, SD (reprint author), Univ Colorado, Sch Med, Dept Radiat Oncol, 1665 Aurora Court,Room 1032, Aurora, CO 80045 USA. EM arya.amini@ucdenver.edu; sana.karam@ucdenver.edu OI Jones, Bernard/0000-0001-7169-559X NR 31 TC 5 Z9 5 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD MAY PY 2016 VL 56 BP 1 EP 7 DI 10.1016/j.oraloncology.2016.02.011 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DK3VF UT WOS:000374844800008 PM 27086480 ER PT J AU Diercks, GR Keamy, D Kinane, TB Skotko, B Schwartz, A Grealish, E Dobrowski, J Soose, R Hartnick, CJ AF Diercks, Gillian R. Keamy, Donald Kinane, Thomas Bernard Skotko, Brian Schwartz, Allison Grealish, Ellen Dobrowski, John Soose, Ryan Hartnick, Christopher J. TI Hypoglossal Nerve Stimulator Implantation in an Adolescent With Down Syndrome and Sleep Apnea SO PEDIATRICS LA English DT Article ID UPPER-AIRWAY STIMULATION; CHILDREN; MANAGEMENT; DIAGNOSIS AB Obstructive sleep apnea (OSA) is more common in children with Down syndrome, affecting up to 60% of patients, and may persist in up to 50% of patients after adenotonsillectomy. These children with persistent moderate to severe OSA require continuous positive airway pressure, which is often poorly tolerated, or even tracheotomy for severe cases. The hypoglossal nerve stimulator is an implantable device that produces an electrical impulse to the anterior branches of the hypoglossal nerve, resulting in tongue protrusion in response to respiratory variation. It is an effective treatment of sleep apnea in select adult patients because it allows for alleviation of tongue base collapse, improving airway obstruction. Herein we describe the first pediatric hypoglossal nerve stimulator implantation, which was performed in an adolescent with Down syndrome and refractory severe OSA (apnea hypopnea index [AHI]: 48.5 events/hour). The patient would not tolerate continuous positive airway pressure and required a long-standing tracheotomy. Hypoglossal nerve stimulator therapy was well tolerated and effective, resulting in significant improvement in the patient's OSA (overall AHI: 3.4 events/hour; AHI: 2.5-9.7 events/hour at optimal voltage settings depending on sleep stage and body position). Five months after implantation, the patient's tracheotomy was successfully removed and he continues to do well with nightly therapy. C1 [Diercks, Gillian R.; Keamy, Donald; Dobrowski, John; Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Diercks, Gillian R.; Keamy, Donald; Dobrowski, John; Hartnick, Christopher J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kinane, Thomas Bernard; Skotko, Brian; Schwartz, Allison] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Keamy, Donald; Kinane, Thomas Bernard; Grealish, Ellen] Massachusetts Gen Hosp, Dept Pediat Sleep Associates, Boston, MA 02114 USA. [Skotko, Brian; Schwartz, Allison] Massachusetts Gen Hosp, Dept Pediat, Div Med Genet, Down Syndrome Program, Boston, MA 02114 USA. [Soose, Ryan] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM christopher_hartnick@meei.harvard.edu FU Massachusetts Eye and Ear Infirmary FX Inspire Medical Systems provided the devices used in this study free of charge. Massachusetts Eye and Ear Infirmary staff and facilities waved professional, facility, and operating room fees for this study. NR 12 TC 1 Z9 1 U1 5 U2 5 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 MAY PY 2016 VL 137 IS 5 AR e20153663 DI 10.1542/peds.2015-3663 PG 5 WC Pediatrics SC Pediatrics GA DK8XZ UT WOS:000375214300031 ER PT J AU Melton, DW Lei, XF Gelfond, JAL Shireman, PK AF Melton, David W. Lei, XiuFen Gelfond, Jonathan A. L. Shireman, Paula K. TI Dynamic macrophage polarization-specific miRNA patterns reveal increased soluble VEGF receptor 1 by miR-125a-5p inhibition SO PHYSIOLOGICAL GENOMICS LA English DT Article DE microRNAs; temporal; M1; M2a; M2c; VEGF ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-ASSOCIATED MACROPHAGES; IN-VIVO; INFLAMMATORY RESPONSE; ACTIVATED MACROPHAGES; HUMAN MONOCYTES; EXPRESSION; MICRORNAS; ANGIOGENESIS; FLT-1 AB Dynamic, epigenetic mechanisms can regulate macrophage phenotypes following exposure to different stimulating conditions and environments. However, temporal patterns of microRNAs (miRNAs or miRs) across multiple macrophage polarization phenotypes have not been defined. We determined miRNA expression in bone marrow-derived murine macrophages over multiple time points (0.5, 1, 3, 24 h) following exposure to cytokines and/or LPS. We hypothesized that dynamic changes in miRNAs regulate macrophage phenotypes. Changes in macrophage polarization markers were detected as early as 0.5 and as late as 24 h; however, robust responses for most markers occurred within 3 h. In parallel, many polarization-specific miRNAs were also changed by 3 h and expressed divergent patterns between M1 and M2a conditions, with increased expression in M1 (miR-155, 199a-3p, 214-3p, 455-3p, and 125a) or M2a (miR-511 and 449a). Specifically, miR-125a-5p exhibited divergent patterns: increased at 12-24 h in M1 macrophages and decreasing trend in M2a. VEGF in the culture media of macrophages was dependent upon the polarization state, with greatly diminished VEGF in M2a compared with M1 macrophage culture media despite similar VEGF in cell lysates. Inhibition of miR-125a-5p in media-only controls (MO) and M1 macrophages greatly increased expression and secretion of soluble VEGF receptor-1 (sVEGFR1) leading to diminished VEGF in the culture media, partially converting MO and M1 into an M2a phenotype. Thus, the divergent expression patterns of polarization-specific miRNAs led to the identification and demonstrated the regulation of a specific macrophage polarization phenotype, sVEGFR1 by inhibition of miR-125a-5p. C1 [Melton, David W.; Lei, XiuFen; Shireman, Paula K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, 7703 Floyd Curl Dr,MC 7741, San Antonio, TX 78229 USA. [Gelfond, Jonathan A. L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Melton, David W.; Gelfond, Jonathan A. L.; Shireman, Paula K.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Melton, David W.; Lei, XiuFen; Shireman, Paula K.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Shireman, PK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, 7703 Floyd Curl Dr,MC 7741, San Antonio, TX 78229 USA. EM shireman@uthscsa.edu FU National Heart, Lung, and Blood Institute Grants [HL-074236, HL-110743]; Veterans Administration Merit Review [1I01BX001186]; Institute for the Integration of Medicine and Science [UL1 TR001120] FX This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-074236 and HL-110743, the Veterans Administration Merit Review (1I01BX001186), and the Institute for the Integration of Medicine and Science, UL1 TR001120. NR 88 TC 2 Z9 2 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAY 1 PY 2016 VL 48 IS 5 BP 345 EP 360 DI 10.1152/physiolgenomics.00098.2015 PG 16 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA DK7SS UT WOS:000375126600003 PM 26884460 ER PT J AU Thorndike, AN Riis, J Levy, DE AF Thorndike, Anne N. Riis, Jason Levy, Douglas E. TI Social norms and financial incentives to promote employees' healthy food choices: A randomized controlled trial SO PREVENTIVE MEDICINE LA English DT Article DE Food choice; Worksite; Obesity prevention; Social norms; Financial incentives ID POINT-OF-PURCHASE; EATING BEHAVIOR; PUBLIC-HEALTH; OBESITY; INTERVENTION; ARCHITECTURE; METAANALYSIS; CAFETERIA; ENVIRONMENTS; RESTAURANTS AB Objective. Population-level strategies to improve healthy food choices are needed for obesity prevention. We conducted a randomized controlled trial of 2672 employees at the Massachusetts General Hospital who were regular customers of the hospital cafeteria with all items labeled green (healthy), yellow (less healthy), or red (unhealthy) to determine if social norm (peer-comparison) feedback with or without financial incentives increased employees' healthy food choices. Methods. Participants were randomized in 2012 to three arms: 1) monthly letter with social norm feedback about healthy food purchases, comparing employee to "all" and to "healthiest" customers (feedback-only); 2) monthly letter with social norm feedback plus small financial incentive for increasing green purchases (feedback-incentive); or 3) no contact (control). The main outcome was change in proportion of green-labeled purchases at the end of 3-month intervention. Post-hoc analyses examined linear trends. Results. At baseline, the proportion of green-labeled purchases (50%) did not differ between arms. At the end of the 3-month intervention, the percentage increase in green-labeled purchases was larger in the feedback-incentive arm compared to control (2.2% vs. 0.1%, P = 0.03), but the two intervention arms were not different. The rate of increase in green-labeled purchases was higher in both feedback-only (P = 0.04) and feedback-incentive arms (P=0.004) compared to control. At the end of a 3-month wash-out, there were no differences between control and intervention arms. Conclusions. Social norms plus small financial incentives increased employees' healthy food choices over the short-term. Future research will be needed to assess the impact of this relatively low-cost intervention on employees' food choices and weight over the long-term. (C) 2016 Elsevier Inc. All rights reserved. C1 [Thorndike, Anne N.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Thorndike, Anne N.; Levy, Douglas E.] Harvard Univ, Sch Med, Boston, MA USA. [Riis, Jason] Harvard Univ, Sch Business, Boston, MA 02163 USA. [Levy, Douglas E.] Massachusetts Gen Hosp, Dept Med, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Riis, Jason] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. RP Thorndike, AN (reprint author), 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM athorndike@partners.org FU Robert Wood Johnson Foundation's Pioneer Portfolio; Donaghue Foundation; NIH/NHLBI grant [K23 HL93221] FX This research is supported by the Robert Wood Johnson Foundation's Pioneer Portfolio and the Donaghue Foundation. Dr. Thorndike was supported by NIH/NHLBI grant K23 HL93221. The other authors have no financial disclosures to report. NR 51 TC 1 Z9 1 U1 8 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD MAY PY 2016 VL 86 BP 12 EP 18 DI 10.1016/j.ypmed.2016.01.017 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DK6QQ UT WOS:000375050200003 PM 26827617 ER PT J AU Brusasco, C Corradi, F De Ferrari, A Ball, L Kacmarek, RM Pelosi, P AF Brusasco, Claudia Corradi, Francesco De Ferrari, Alessandra Ball, Lorenzo Kacmarek, Robert M. Pelosi, Paolo TI CPAP Devices for Emergency Prehospital Use: Looking Inside of It-Reply SO RESPIRATORY CARE LA English DT Letter C1 [Brusasco, Claudia; Corradi, Francesco; Pelosi, Paolo] EO Osped Galliera, Dept Anesthesia & Intens Care, Genoa, Italy. [De Ferrari, Alessandra; Ball, Lorenzo] Univ Genoa, Dept Surg Sci & Integrated Diagnost, Genoa, Italy. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Resp Care, Boston, MA 02114 USA. RP Brusasco, C (reprint author), EO Osped Galliera, Dept Anesthesia & Intens Care, Genoa, Italy. RI Ball, Lorenzo/K-7612-2016; Corradi, Francesco/C-5207-2009 OI Ball, Lorenzo/0000-0002-3876-4730; NR 1 TC 0 Z9 0 U1 0 U2 1 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD MAY PY 2016 VL 61 IS 5 BP 719 EP 720 DI 10.4187/respcare.04782 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DL0VC UT WOS:000375349700022 PM 27121628 ER PT J AU Halpin, DMG Vogelmeier, C Pieper, MP Metzdorf, N Richard, F Anzueto, A AF Halpin, David M. G. Vogelmeier, Claus Pieper, Michael P. Metzdorf, Norbert Richard, Frank Anzueto, Antonio TI Effect of tiotropium on COPD exacerbations: A systematic review SO RESPIRATORY MEDICINE LA English DT Review DE Anticholinergic; Antimuscarinic; COPD; Long-acting muscarinic antagonist ID OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED-TRIAL; HEALTH OUTCOMES; PARALLEL-GROUP; LUNG-FUNCTION; UPLIFT TRIAL; EFFICACY; SAFETY; SALMETEROL; BRONCHODILATOR AB Background: Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation. Methods: As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies. Results: Exacerbations were a primary endpoint in 12 publications (five studies: four comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) compared with placebo and long-acting beta(2)-agonists. Tiotropium also showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting beta(2)-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler (R) 18 mu g/Respimat (R) 5 mu g). Conclusions: The results of this comprehensive systematic review demonstrate tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Halpin, David M. G.] Univ Exeter, Sch Med, Royal Devon & Exeter Hosp, Exeter, Devon, England. [Vogelmeier, Claus] Univ Marburg, Univ Med Ctr Giessen & Marburg, German Ctr Lung Res, Dept Med Pulm & Crit Care Med, Marburg, Germany. [Pieper, Michael P.] Boehringer Ingelheim Pharma GmbH & Co KG, Resp Dis Res, Biberach, Germany. [Metzdorf, Norbert; Richard, Frank] Boehringer Ingelheim Pharma GmbH Co KG, Ingelheim, Germany. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Pulm Dis, Crit Care Med, San Antonio, TX 78229 USA. [Anzueto, Antonio] Audie L Murphy Mem Vet Hosp Div, South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Halpin, DMG (reprint author), Royal Devon & Exeter Hosp, Dept Resp Med, Barrack Rd, Exeter EX2 5DW, Devon, England. EM d.halpin@nhs.net OI Richard, Frank/0000-0003-1027-3814 FU Boehringer Ingelheim FX Writing assistance was provided by Leigh Prevost and Natalie Dennis from PAREXEL, which was funded by Boehringer Ingelheim. NR 53 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD MAY PY 2016 VL 114 BP 1 EP 8 DI 10.1016/j.rmed.2016.02.012 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DK8WJ UT WOS:000375209000001 PM 27109805 ER PT J AU Schure, MB Borson, S Nguyen, HQ Trittschuh, EH Thielke, SM Pike, KC Adams, SG Fan, VS AF Schure, Mark B. Borson, Soo Nguyen, Huong Q. Trittschuh, Emily H. Thielke, Stephen M. Pike, Kenneth C. Adams, Sandra G. Fan, Vincent S. TI Associations of cognition with physical functioning and health-related quality of life among COPD patients SO RESPIRATORY MEDICINE LA English DT Article DE Cognition; COPD; Physical functioning; Quality of life; Physical activity; Affective symptoms; Motor strength ID OBSTRUCTIVE PULMONARY-DISEASE; OLDER MEXICAN-AMERICANS; CONSTRUCT-VALIDITY; SURVEY SF-36; PART-B; IMPAIRMENT; TRAIL; FRAILTY; PHENOTYPE; OUTCOMES AB Background: Neurocognitive impairment has been described in COPD patients, but little is known about its relationship with physical functioning and health-related quality of life (HRQL) in this chronically ill patient group. Methods: 301 stable COPD patients completed the Trail Making Test (TMT-A: psychomotor speed and TMT-B: executive control); 198 patients completed the Memory Impairment Screen (MIS). Standardization of TMT-A and TMT-B scores to a normative population yielded classifications of normal, borderline, or impaired cognitive status. Using multivariable regression, we examined the relationship between the TMT-A, TMT-B, and MIS with physical functioning (physical activity, 6-min walk test, and grip strength) and health-related quality of life (HRQL) measured with the Chronic Respiratory Questionnaire and the SF-36. Results: Nearly 30% of patients had either borderline or impaired cognition on the TMT-A or TMT-B. Adjusted models indicated that those with either borderline or impaired cognitive functioning had weaker grip strength (TMT-A borderline: beta = -2.9, P < 0.05; TMT-B borderline: beta = -3.0, P < 0.05; TMT-B impaired: beta = -2.5, P < 0.05) and lower scores on the mental health component summary score (MCS-SF-36 HRQOL) measure (TMT-A impaired: beta = -4.7, P < 0.01). No adjusted significant associations were found for other physical functioning measures or the other HRQL measures. Impaired memory showed a significant association only with the MCS scale. Conclusions: Cognitive function was not associated with most standard indicators of physical function or most measures of HRQL in COPD patients. Both TMT-A and TMT-B were associated with weaker grip strength, and the TMT-A and MIS with poorer mental health. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Schure, Mark B.] Montana State Univ, Dept Hlth & Human Dev, POB 173540, Bozeman, MT 59717 USA. [Borson, Soo; Trittschuh, Emily H.; Thielke, Stephen M.] Univ Washington, Dept Psychiat & Behav Sci, Sch Med, Box 356560, Seattle, WA 98195 USA. [Nguyen, Huong Q.] Kaiser Permanente So Calif, 100 S Los Robies, Pasadena, CA 91101 USA. [Nguyen, Huong Q.; Thielke, Stephen M.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, 1660 S Columbian Way, Seattle, WA 98108 USA. [Pike, Kenneth C.] Univ Washington, Off Nursing Res, 1959 NE Pacific St, Seattle, WA 98195 USA. [Adams, Sandra G.] Univ Texas Hlth Sci Ctr San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Adams, Sandra G.] South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Fan, Vincent S.] Ctr Innovat VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, 1660 S Columbian Way, Seattle, WA 98108 USA. [Fan, Vincent S.] Univ Washington, Dept Med, 1959 NE Pacific St, Seattle, WA 98195 USA. RP Schure, MB (reprint author), 305 Herrick Hall,POB 173540, Bozeman, MT 59717 USA. EM mark.schure@montana.edu FU National Heart, Lung, and Blood Institute (NHLBI) [R01HL093146] FX This grant was funded by grant R01HL093146 from the National Heart, Lung, and Blood Institute (NHLBI). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the VA. NR 47 TC 0 Z9 0 U1 4 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD MAY PY 2016 VL 114 BP 46 EP 52 DI 10.1016/j.rmed.2016.03.005 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DK8WJ UT WOS:000375209000006 PM 27109810 ER PT J AU Lu, JJ Li, H Baccei, A Sasaki, T Gilbert, DM Lerou, PH AF Lu, Junjie Li, Hu Baccei, Anna Sasaki, Takayo Gilbert, David M. Lerou, Paul H. TI Influence of ATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID COPY NUMBER; ATAXIA-TELANGIECTASIA; IPSCS; INSTABILITY; REPAIR; ORGANIZATION; INTEGRATION; MUTATION; STRESS; CANCER AB Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM-deficient iPSCs relative to wild-type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral (RV) reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DDR reveals unique vulnerability of early replicating open chromatin to RV vectors. C1 [Lu, Junjie; Baccei, Anna; Lerou, Paul H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pediat Newborn Med,Harvard Stem Cell Inst, Boston, MA USA. [Lu, Junjie; Baccei, Anna; Lerou, Paul H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet,Dept Med,Harvard Stem Cell Inst, Boston, MA USA. [Li, Hu] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Ctr Individualized Med, Rochester, MN USA. [Sasaki, Takayo; Gilbert, David M.] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. [Lerou, Paul H.] Massachusetts Gen Hosp, Dept Pediat, Div Neonatol, Founders Bldg,526C,55 Fruit St, Boston, MA 02114 USA. RP Lerou, PH (reprint author), Massachusetts Gen Hosp, Dept Pediat, Div Neonatol, Founders Bldg,526C,55 Fruit St, Boston, MA 02114 USA. EM plerou@partners.org FU NICHD [R00HD061981]; Mayo Clinic Center for Individualized Medicine; Mayo Clinic Center for Regenerative Medicine; [R21CA161666]; [P01GM085354] FX The authors thank Jeanne Carroll and Ruggero Spadafora for critical reading of the article. Norman Gerry at the Coriell Institute for technical assistance. This work was supported by the NICHD grant R00HD061981 to P.H.L. H.L. is supported by Mayo Clinic Center for Individualized Medicine and Mayo Clinic Center for Regenerative Medicine. D.M.G. is supported by R21CA161666 and P01GM085354. NR 39 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD MAY 1 PY 2016 VL 25 IS 9 BP 740 EP 747 DI 10.1089/scd.2015.0393 PG 8 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA DK3YT UT WOS:000374854000007 PM 26935587 ER PT J AU Romano, JG Smith, EE Liang, L Gardener, H Campo-Bustillo, I Khatri, P Bhatt, DL Fonarow, GC Sacco, RL Schwamm, LH AF Romano, Jose G. Smith, Eric E. Liang, Li Gardener, Hannah Campo-Bustillo, Iszet Khatri, Pooja Bhatt, Deepak L. Fonarow, Gregg C. Sacco, Ralph L. Schwamm, Lee H. TI Distinct Short-Term Outcomes in Patients With Mild Versus Rapidly Improving Stroke Not Treated With Thrombolytics SO STROKE LA English DT Article DE dyslipidemias; National Institutes of Health; outcome assessment (health care); risk factors; stroke ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; INTRAVENOUS THROMBOLYSIS; GUIDELINES-STROKE; SCALE SCORES; SYMPTOMS; ELIGIBILITY; RECOVERY; DEFICITS; REGISTRY AB Background and Purpose-Mild stroke (MS) and rapidly improving stroke (RIS) symptoms are common stroke presentations. Our objective is to describe the short-term outcomes in this population. Methods-A retrospective analysis of patients with ischemic stroke in the Get With The Guidelines-Stroke registry who arrived 4.5 hours from symptom onset not treated with thrombolytics because of MS and RIS. Outcomes included in-hospital death, home discharge, independent ambulation at discharge, and length of stay; these were analyzed for the categories of MS, RIS, and MS+RIS. Multivariable models evaluated the associations of individual and hospital covariates with outcomes. Results-Among 42 394 patients with MS and RIS not treated with thrombolytics, 27% were not discharged directly home, 27.2% did not ambulate independently, and 61.1% had length of stay 3 days, despite a low in-hospital mortality of 0.8%. Adjusted outcomes were better for MS+RIS compared with MS; RIS also had better independent ambulation and home discharge compared with MS. Among those with a documented National Institutes of Health Stroke Scale, 25% of those with National Institutes of Health Stroke Scale 0 to 5 and half of those with National Institutes of Health Stroke Scale >5 could not be discharged directly to home or ambulate independently. Older individuals, women, blacks, transport by ambulance, delayed arrival, greater severity and greater burden of vascular risk factors, except for dyslipidemia, had worse adjusted outcomes for home discharge and independent ambulation. Conclusions-A significant proportion of patients with MS and RIS not treated with thrombolytics have suboptimal discharge outcomes. We found significant differences between MS, RIS, and MS+RIS and identified factors associated with worse outcomes. C1 [Romano, Jose G.; Gardener, Hannah; Campo-Bustillo, Iszet; Sacco, Ralph L.] Univ Miami, Miller Sch Med, Dept Neurol, Coral Gables, FL 33124 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Liang, Li] Duke Clin Res Inst, Durham, NC USA. [Khatri, Pooja] Univ Cincinnati, Inst Neurosci, Cincinnati, OH USA. [Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiol,Dept Internal Med,Heart & Vasc Ctr, Boston, MA 02115 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Dept Internal Med, Div Cardiol, Los Angeles, CA 90024 USA. [Schwamm, Lee H.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Romano, JG (reprint author), 1120 NW 14th St,Suite 1357, Miami, FL 33136 USA. EM jromano@med.miami.edu FU Genentech, Inc FX This study was supported by a grant from Genentech, Inc, to the University of Miami. Genentech had no role in study design, data analysis, or article preparation. NR 34 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAY PY 2016 VL 47 IS 5 BP 1278 EP 1285 DI 10.1161/STROKEAHA.115.011528 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DK6QM UT WOS:000375049700027 PM 26987870 ER PT J AU Song, S Fonarow, GC Olson, DM Liang, L Schulte, PJ Hernandez, AF Peterson, ED Reeves, MJ Smith, EE Schwamm, LH Saver, JL AF Song, Sarah Fonarow, Gregg C. Olson, DaiWai M. Liang, Li Schulte, Phillip J. Hernandez, Adrian F. Peterson, Eric D. Reeves, Mathew J. Smith, Eric E. Schwamm, Lee H. Saver, Jeffrey L. TI Association of Get With The Guidelines-Stroke Program Participation and Clinical Outcomes for Medicare Beneficiaries With Ischemic Stroke SO STROKE LA English DT Article DE Medicare; patient discharge; quality improvement; quality of health care; stroke ID AMERICAN-HEART-ASSOCIATION; PERFORMANCE-MEASURES; HEALTH-CARE; QUALITY; ATTACK; INTERVENTION; IMPROVEMENT; COSTS AB Background and Purpose-Get With The Guidelines (GWTG)-Stroke is a national, hospital-based quality improvement program developed by the American Heart Association. Although studies have suggested improved processes of care in GWTG-Stroke-participating hospitals, it is not known whether this improved care translates into improved clinical outcomes compared with nonparticipating hospitals. Methods-From all acute care US hospitals caring for Medicare beneficiaries with acute stroke between April 2003 and December 2008, we matched hospitals that joined the GWTG-Stroke program with similar hospitals that did not. Using a difference-in-differences design, we analyzed whether hospital participation in GWTG-Stroke was associated with a greater improvement in clinical outcomes compared with the underlying secular change. Results-The matching algorithm identified 366 GWTG-Stroke-adopting hospitals that cared for 88 584 acute ischemic stroke admissions and 366 non-GWTG-Stroke hospitals that cared for 85 401 acute ischemic stroke admissions. Compared with the Pre period (18-6 months before program implementation), in the Early period (0-6 months after program implementation), GWTG-Stroke hospitals had accelerated increases in discharge to home and reduced mortality at 30 days and 1 year. In the Sustained period (6-18 months after program implementation), the accelerated reduction in mortality at 1 year was sustained, with a trend toward sustained accelerated increase in discharge home. Conclusions-Hospital adoption of the GWTG-Stroke program was associated with improved functional outcomes at discharge and reduced postdischarge mortality. C1 [Song, Sarah] Rush Univ, Med Ctr, Dept Neurol, 1725 W Harrison St,Suite 1121, Chicago, IL 60612 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Dept Cardiol, Los Angeles, CA USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Olson, DaiWai M.] SW Texas State Univ, Dept Neurol, Dallas, TX USA. [Liang, Li; Schulte, Phillip J.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Hernandez, Adrian F.; Peterson, Eric D.] Duke Univ, Dept Cardiol, Durham, NC USA. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Song, S (reprint author), Rush Univ, Med Ctr, Dept Neurol, 1725 W Harrison St,Suite 1121, Chicago, IL 60612 USA. EM sarah_song@rush.edu OI Olson, DaiWai/0000-0002-9280-078X FU Janssen Pharmaceutical Companies of Johnson Johnson; Boeringher-Ingelheim; Merck; Bristol-Myers Squib/Sanofi Pharmaceutical Partnership; AHA Pharmaceutical Roundtable (PRT); University of California, Los Angeles (UCLA); Charles Drew University, Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly under National Institutes of Health (NIH)/National Institute on Aging [P30-AG021684]; UCLA Clinical and Translational Science Institute under NIH/National Center for Advancing Translational Sciences [UL1TR000124]; National Institute of Neurological Disorders and Stroke of the National Institutes of Health [U54NS081764]; AHA PRT; David and Stevie Spina FX Get With The Guidelines-Stroke (GWTG-Stroke) program was provided by the American Heart Association (AHA)/American Stroke Association. The GWTG-Stroke program is currently supported, in part, by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. GWTG-Stroke has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, and the AHA Pharmaceutical Roundtable (PRT). Research reported in this publication was supported by the University of California, Los Angeles (UCLA) and Charles Drew University, Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly under National Institutes of Health (NIH)/National Institute on Aging grant P30-AG021684, by the UCLA Clinical and Translational Science Institute under NIH/National Center for Advancing Translational Sciences grant number UL1TR000124, by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number U54NS081764, and by an award to UCLA from the AHA PRT and David and Stevie Spina. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 19 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAY PY 2016 VL 47 IS 5 BP 1294 EP 1302 DI 10.1161/STROKEAHA.115.011874 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DK6QM UT WOS:000375049700029 PM 27079809 ER PT J AU Orset, C Haelewyn, B Allan, SM Ansar, S Campos, F Cho, TH Durand, A El Amki, M Fatar, M Garcia-Yebenes, I Gauberti, M Grudzenski, S Lizasoain, I Lo, E Macrez, R Margaill, I Maysami, S Meairs, S Nighoghossian, N Orbe, J Paramo, JA Parienti, JJ Rothwell, NJ Rubio, M Waeber, C Young, AR Touze, E Vivien, D AF Orset, Cyrille Haelewyn, Benoit Allan, Stuart M. Ansar, Saema Campos, Francesco Cho, Tae Hee Durand, Anne El Amki, Mohamad Fatar, Marc Garcia-Yebenes, Isaac Gauberti, Maxime Grudzenski, Saskia Lizasoain, Ignacio Lo, Eng Macrez, Richard Margaill, Isabelle Maysami, Samaneh Meairs, Stephen Nighoghossian, Norbert Orbe, Josune Antonio Paramo, Jose Parienti, Jean-Jacques Rothwell, Nancy J. Rubio, Marina Waeber, Christian Young, Alan R. Touze, Emmanuel Vivien, Denis TI Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis SO STROKE LA English DT Article DE magnetic resonance imaging; middle cerebral artery; stroke; thrombolytic therapy; tissue-type plasminogen activator ID PLASMINOGEN-ACTIVATOR; THROMBOEMBOLIC STROKE; L-ARGININE; THROMBOLYSIS; METAANALYSIS; IMPROVES; IMPACT; RAT AB Background and Purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. Methods We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I-2=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I-2=42%; P-int<0.00001). Results remained unchanged after subgroup analyses. Conclusions Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial. C1 [Orset, Cyrille; Cho, Tae Hee; Gauberti, Maxime; Macrez, Richard; Orbe, Josune; Rubio, Marina; Young, Alan R.; Touze, Emmanuel; Vivien, Denis] GIP Cyceron, INSERM, UMR S U919, F-14074 Caen, France. [Orset, Cyrille; Haelewyn, Benoit] Univ Caen Normandie, Expt Stroke Res Platform, CURB, Caen, France. [Allan, Stuart M.; Ansar, Saema; Rothwell, Nancy J.] Univ Manchester, Fac Med & Hlth Sci, Manchester, Lancs, England. [Ansar, Saema] Neurol Univ Klin, Mannheim, Germany. [Campos, Francesco; Lo, Eng; Waeber, Christian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Lo, Eng] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Cho, Tae Hee; Durand, Anne; Nighoghossian, Norbert] Univ Lyon 1, CREATIS, CNRS UMR INSERM U1044 5520, Hosp Civils Lyon,Dept Stroke Med, F-69365 Lyon, France. [Cho, Tae Hee; Durand, Anne; Nighoghossian, Norbert] Univ Lyon 1, CREATIS, CNRS UMR INSERM U1044 5520, Hosp Civils Lyon,Dept Neuroradiol, F-69365 Lyon, France. [El Amki, Mohamad; Margaill, Isabelle] Fac Sci Pharmaceut & Biol Paris, Pharmacol Circulat Cerebrale EA4475, Paris, France. [Fatar, Marc; Grudzenski, Saskia] Heidelberg Univ, Univ Med Mannheim, Dept Neurol, Heidelberg, Germany. [Garcia-Yebenes, Isaac; Lizasoain, Ignacio] Univ Complutense Madrid, Fac Med, Dept Farmacol, Unidad Invest Neurovasc, Madrid, Spain. [Garcia-Yebenes, Isaac; Lizasoain, Ignacio] Hosp 12 Octubre I 12, Inst Invest, Madrid, Spain. [Orbe, Josune; Antonio Paramo, Jose] Univ Navarra, CIMA, Program Cardiovasc Dis, Lab Atherothrombosis, E-31080 Pamplona, Spain. [Ansar, Saema] Lund Univ, Dept Clin Sci, Div Expt Vasc Res, Lund, Sweden. [Campos, Francesco] Hosp Clin Univ, Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Dept Neurol,Neurovasc Area, Santiago De Compostela, Spain. [Parienti, Jean-Jacques] CHU Caen, Dept Biostat & Clin Res, F-14000 Caen, France. [Touze, Emmanuel] CHU Caen, Dept Neurol, F-14000 Caen, France. [Parienti, Jean-Jacques] Univ Caen Normandie, Risques Microbiens EA4655, Caen, France. [Waeber, Christian] Natl Univ Ireland Univ Coll Cork, Sch Pharm, Cork, Ireland. [Waeber, Christian] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol Therapeut, Cork, Ireland. RP Vivien, D (reprint author), GIP Cyceron, Blvd Henri Becquerel, F-14074 Caen, France. EM vivien@cyceron.fr RI Orbe, Josune/D-3082-2017; OI Orbe, Josune/0000-0001-6300-7670; Touze, Emmanuel/0000-0002-7254-2162; Allan, Stuart/0000-0001-9646-4456; Paramo, Jose A/0000-0003-1497-6242; VIVIEN, DENIS/0000-0002-7636-2185 FU RETICS [RD12/0014/0003]; Marie Curie Career Integration Grant [631246]; European program ARISE (FP7); National Institutes of Health grant [NS049263, NS055104]; INSERM (French National Institute for Health and Medical Research); Foundation for Medical Research [FRM/NoDEQ20140329555]; Regional Council of Lower Normandy; [PI12/00710]; [RD12/0042/009]; [SAF2011-23354] FX This work was supported by Spanish grants PI12/00710 and RD12/0042/009; SAF2011-23354; RETICS RD12/0014/0003; Marie Curie Career Integration Grant (631246); European program ARISE (FP7); National Institutes of Health grants (NS049263 and NS055104); grants from the INSERM (French National Institute for Health and Medical Research), the Foundation for Medical Research (FRM/NoDEQ20140329555), and the Regional Council of Lower Normandy. NR 34 TC 1 Z9 1 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAY PY 2016 VL 47 IS 5 BP 1312 EP 1318 DI 10.1161/STROKEAHA.116.012238 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DK6QM UT WOS:000375049700031 PM 27032444 ER PT J AU Molina, G Bordeianou, L Shellito, P Sylla, P AF Molina, George Bordeianou, Liliana Shellito, Paul Sylla, Patricia TI Transanal endoscopic resection with peritoneal entry: a word of caution SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-American-Gastrointestinal-and-Endoscopic-Surgeons (SAGES) CY APR 15-18, 2015 CL Nashville, TN SP Soc Amer Gastrointestinal & Endoscop Surg DE Transanal endoscopic resection; Transanal endoscopic microsurgery (TEM); Transanal minimally invasive surgery (TAMIS); Rectal cancer; Adenomas; Peritoneal entry ID MINIMALLY INVASIVE SURGERY; RECTAL NEOPLASMS; LOCAL EXCISION; MICROSURGERY; OUTCOMES; PORT; COMPLICATIONS; EXPERIENCE; ADENOMAS; TUMORS AB Peritoneal entry during transanal endoscopic microsurgery (TEM) can usually be managed transanally with full-thickness suture closure by experienced operators. The preliminary safety of transanal minimally invasive surgery (TAMIS) has been demonstrated, but the reported experience with upper rectal tumors is limited. The incidence and management of peritoneal entry during transanal endoscopic surgery across various platforms have not been previously evaluated. Retrospective analysis of a prospectively maintained database of all transanal endoscopic resections performed at a single institution between January 2008 and December 2014 was conducted. Cases with and without peritoneal entry were evaluated with respect to transanal platform used, surgical indication, size, location and distance from the anal verge, and incidence of postoperative complications. A total of 78 transanal endoscopic procedures were performed on 76 patients using the rigid transanal endoscopic operation (TEO, 65.4 %), TEM (26.9 %), and TAMIS platform (7.7 %). The most common surgical indication included endoscopically unresectable adenomas (50 %). The average distance of lesions from the anal verge (AV) was 9.6 cm (range 4-20 cm). Peritoneal entry occurred in 22 cases (28.2 %). Platform used (TAMIS vs. rigid, p < 0.05), mean distance from the AV (p < 0.0001), location along the rectum (p = 0.01), and mean specimen size (p = 0.01) were associated with a higher likelihood of peritoneal entry. All rectal defects associated with peritoneal entry were successfully closed transanally except for two (TEM and TEO) cases that required conversion to laparoscopic low anterior resection and laparoscopic Hartmann's, respectively. There were four TAMIS cases that required conversion to TEO platforms. In this high-risk TEM, TEO, and TAMIS series (one-third of rectal lesions located in the upper rectum), 91 % of all peritoneal entries were managed transanally without increased morbidity. TAMIS for upper rectal lesions was associated with a high risk of complicated peritoneal entry requiring conversion to a rigid platform. C1 [Molina, George; Bordeianou, Liliana; Shellito, Paul] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Sylla, Patricia] Mt Sinai Hosp, Dept Surg, 5 East 98th St Box 1249, New York, NY 10029 USA. RP Sylla, P (reprint author), Mt Sinai Hosp, Dept Surg, 5 East 98th St Box 1249, New York, NY 10029 USA. EM patricia.sylla@mountsinai.org NR 38 TC 5 Z9 5 U1 0 U2 1 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 MAY PY 2016 VL 30 IS 5 BP 1816 EP 1825 DI 10.1007/s00464-015-4452-y PG 10 WC Surgery SC Surgery GA DK7EG UT WOS:000375087100016 PM 26264697 ER PT J AU Zak, Y Petrusa, E Gee, DW AF Zak, Yulia Petrusa, Emil Gee, Denise W. TI Laparoscopic Roux-en-Y gastric bypass patients have an increased lifetime risk of repeat operations when compared to laparoscopic sleeve gastrectomy patients SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-American-Gastrointestinal-and-Endoscopic-Surgeons (SAGES) CY APR 15-18, 2015 CL Nashville, TN SP Soc Amer Gastrointestinal & Endoscop Surg DE Roux-en-Y gastric bypass; Sleeve gastrectomy; Re-operations; Complications; Outcomes ID BARIATRIC SURGERY CENTER; LONG-TERM OUTCOMES; AMERICAN-COLLEGE; STAPLE-LINE; FOLLOW-UP; METAANALYSIS; MULTICENTER; EXCELLENCE; EXPERIENCE; MORBIDITY AB Although long-term data have been published on the complications after laparoscopic Roux-en-Y gastric bypass (LRYGB), laparoscopic sleeve gastrectomy (LSG) is a relatively new procedure without a well-established long-term procedure-related morbidity profile. Our aim was to compare the 6-year data on re-operations occurring after and related to LRYGB versus LSG at a large academic bariatric center. Retrospective review of all the bariatric procedures at the Massachusetts General Hospital between 2009 and 2014. A total of 934 LRYGB and 553 LSG were performed. There were no significant differences in the gender, age, or BMI of the patients at the time of their index operations (p > 0.05 for all). A higher percentage of LRYGB patients required cholecystectomy as compared to LSG patients (5 vs. 2 %, X (2) = 8.63, p < 0.01). There was also a significant difference in the proportion of patients requiring re-operations for other reasons following LRYGB as compared to LSG (6.9 vs. 0.9 %, X (2) = 27.8, p < 0.01). A total of 32.8 % of these bypass patients underwent more than one re-operation, with a relative risk of 11.5 (95 % CI 4.69-28.5) as compared to those undergoing SG. A total of 9.3 % of secondary operations occurred at a mean of 1 month after the LRYGB for functional obstruction, with most of these cases related to a technical error. Other re-operations occurred in a delayed fashion, without a clearly identifiable intra-abdominal source in 22.2 %, due to adhesive bowel obstruction in 17.6 %, and internal hernia in 15.7 %. Non-healing ulcers and intussusception were responsible for a small percentage of re-operations (3.7 and 2.8 %). SG is associated with a relatively low rate of re-operations, while patients after LRYGB are at a significant long-term risk for multiple operative procedures. C1 [Zak, Yulia; Gee, Denise W.] Massachusetts Gen Hosp, 15 Parkman St,WAC 460, Boston, MA 02114 USA. [Petrusa, Emil] Massachusetts Gen Hosp, MGH Learning Lab, 3 Hawthorne Pl,Suite 105, Boston, MA 02114 USA. RP Zak, Y; Gee, DW (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WAC 460, Boston, MA 02114 USA. EM yulia.zak@gmail.com; epetrusa@partners.org; dgee@partners.org NR 23 TC 4 Z9 4 U1 0 U2 4 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 MAY PY 2016 VL 30 IS 5 BP 1833 EP 1838 DI 10.1007/s00464-015-4466-5 PG 6 WC Surgery SC Surgery GA DK7EG UT WOS:000375087100018 PM 26318429 ER PT J AU Ponce, AN Aosved, AC Cornish, JAE AF Ponce, Allison N. Aosved, Allison C. Cornish, Jennifer A. Erickson TI Parental Leave During Internship and Postdoctoral Psychology Training: APPIC Guidelines Revisited SO TRAINING AND EDUCATION IN PROFESSIONAL PSYCHOLOGY LA English DT Article DE parental leave; maternity leave; paternity leave; psychology; training ID MATERNITY LEAVE; HEALTH; CHILD AB This article introduces the updated Association of Psychology Postdoctoral and Internship Centers' (APPIC) APPIC Guidelines for Parental Leave During Internship and Postdoctoral Training and provides recommendations for addressing the complex issue of supporting parental leave during the course of a doctoral internship or postdoctoral training year. C1 [Ponce, Allison N.] Yale Univ, Sch Med, Dept Psychiat, 34 Pk St, New Haven, CT 06519 USA. [Aosved, Allison C.] VA Puget Sound, Amer Lake Div, Tacoma, WA USA. [Cornish, Jennifer A. Erickson] Univ Denver, Clin Training & Internship Consortium, Grad Sch Profess Psychol, Denver, CO 80208 USA. RP Ponce, AN (reprint author), Yale Univ, Sch Med, Dept Psychiat, 34 Pk St, New Haven, CT 06519 USA. EM allison.ponce@yale.edu NR 18 TC 1 Z9 1 U1 0 U2 1 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1931-3918 EI 1931-3926 J9 TRAIN EDUC PROF PSYC JI Train. Educ. Prof. Psychol. PD MAY PY 2016 VL 10 IS 2 BP 71 EP 77 DI 10.1037/tep0000109 PG 7 WC Psychology, Educational SC Psychology GA DK3DL UT WOS:000374796200002 ER PT J AU Chao, GF Krishna, N Aizer, AA Dalela, D Hanske, J Li, HH Meyer, CP Kim, SP Mahal, BA Reznor, G Schmid, M Choueiri, TK Nguyen, PL O'Leary, M Trinh, QD AF Chao, Grace F. Krishna, Nandita Aizer, Ayal A. Dalela, Deepansh Hanske, Julian Li, Hanhan Meyer, Christian P. Kim, Simon P. Mahal, Brandon A. Reznor, Gally Schmid, Marianne Choueiri, Toni K. Nguyen, Paul L. O'Leary, Michael Quoc-Dien Trinh TI Asian Americans and prostate cancer: A nationwide population-based analysis SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Prostate cancer; SEER; Racial disparities; Outcomes ID UNITED-STATES; RADICAL PROSTATECTOMY; CHROMOSOME 8Q24; RISK; SURVIVAL; MEN; US; SATISFACTION; CALIFORNIA; JAPANESE AB Introduction: It remains largely unknown if there are racial disparities in outcomes of prostate cancer (PCa) for Asian American and Pacific Islanders (PIs) (AAPIs). We examined differences in diagnosis, management, and survival of AAPI ethnic groups, relative to their non-Hispanic White (NHW) counterparts. Methods: Patients (n = 891,100) with PCa diagnosed between 1988 and 2010 within the surveillance, epidemiology, and end results database were extracted and stratified by ethnic group: Chinese, Japanese, Filipino, Hawaiian, Korean, Vietnamese, Asian Indian/Pakistani, PI, and Other Asian. The effect of ethnic group on stage at presentation, rates of definitive treatment, and PCa-specific mortality was assessed. The severity at diagnosis was defined as: localized (TxN0M0), regional (TxN1M0), or metastatic (TxNxM1). Results: Relative to NHWs, Asian Indian/Pakistani, Filipino, Hawaiian, and PI men had significantly worse outcomes. Filipino (odds ratio [OR] = 1.38, 95% CI: 1.27-1.51), Hawaiian, (OR = 1.70, 95% CI: 1.41-2.04), Asian Indian/Pakistani (OR = 1.37, 95% CI: 1.15-1.64), and PI men (OR = 1.90, 95% CI: 1.46-2.49) were more likely to present with metastatic PCa (P < 0.001). In patients with localized PCa, Filipino men were less likely to receive definitive treatment (OR = 0.91; 95% CI: 0.84-0.97; P = 0.005). Most AAPI groups had lower rates of PCa death except for Hawaiian (hazard ratio = 1.52; 95% CI: 1.30-1.77; P < 0.0001) and PI men (hazard ratio = 1.43; 95% CI: 1.12-1.82; P < 0.0001). Conclusions: Compared with NHWs, AAPI groups were more likely to present with advanced PCa but had better cancer-specific survival. Conversely, Hawaiian and PI men were at greater risk for PCa-specific mortality. Given the different cancer profiles, our results show that there is a need for disaggregation of AAPI data. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chao, Grace F.; Mahal, Brandon A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Krishna, Nandita; Hanske, Julian; Meyer, Christian P.; Reznor, Gally; Schmid, Marianne; O'Leary, Michael; Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol Surg, Boston, MA 02115 USA. [Krishna, Nandita; Hanske, Julian; Meyer, Christian P.; Reznor, Gally; Schmid, Marianne; O'Leary, Michael; Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Aizer, Ayal A.; Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. [Aizer, Ayal A.; Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Dalela, Deepansh; Li, Hanhan] Henry Ford Hlth Syst, Vattikuti Urol Inst, Ctr Outcomes Res Analyt & Evaluat, Detroit, MI USA. [Kim, Simon P.] Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Inst Urol, Cleveland, OH USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. RP Trinh, QD (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol Surg, Boston, MA 02115 USA.; Trinh, QD (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. EM trinh.qd@gmail.com FU Harvard Medical School, United States; Brigham and Women's Department of Urology Summer Internship; Vattikuti Urology Institute; Scholars in Medicine Office FX This work was supported by the Harvard Medical School, United States, Scholars in Medicine Office and the Brigham and Women's Department of Urology Summer Internship. Quoc-Dien Trinh is supported by an unrestricted educational grant from the Vattikuti Urology Institute and the Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital. NR 32 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD MAY PY 2016 VL 34 IS 5 DI 10.1016/j.urolonc.2015.11.013 PG 9 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DK6IO UT WOS:000375026400006 ER PT J AU Hayakawa, K Lo, EH AF Hayakawa, Kazuhide Lo, Eng H. TI Brain-peripheral cell crosstalk in white matter damage and repair SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE White matter injury; Monocyte/macrophage; Endothelial progenitor cell; Cell-based therapy ID ENDOTHELIAL PROGENITOR CELLS; MESENCHYMAL STEM-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; OLIGODENDROCYTE PRECURSOR CELLS; GROUP BOX 1; CENTRAL-NERVOUS-SYSTEM; MARROW STROMAL CELLS; TOLL-LIKE RECEPTORS; MULTIPLE-SCLEROSIS; CONTROLLED TRIAL AB White matter damage is an important part of cerebrovascular disease and may be a significant contributing factor in vascular mechanisms of cognitive dysfunction and dementia. It is well accepted that white matter homeostasis involves multifactorial interactions between all cells in the axon-glia-vascular unit. But more recently, it has been proposed that beyond cell-cell signaling within the brain per se, dynamic crosstalk between brain and systemic respohses such as circulating immune cells and stem/progenitor cells may also be important. In this review, we explore the hypothesis that peripheral cells contribute to damage and repair after white matter damage. Depending on timing, phenotype and context, monocyte/macrophage can possess both detrimental and beneficial effects on oligodendrogenesis and white matter remodeling. Endothelial progenitor cells (EPCs) can be activated after CNS injury and the response may also influence white matter repair process. These emerging findings support the hypothesis that peripheral-derived cells can be both detrimental or beneficial in white matter pathology in cerebrovascular disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. (c) 2015 Elsevier B.V. All rights reserved. C1 Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Hayakawa, K; Lo, EH (reprint author), Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. EM khayakawa1@partners.org; Lo@helix.mgh.harvard.edu FU NINDS NIH HHS [K99 NS080991] NR 99 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD MAY PY 2016 VL 1862 IS 5 SI SI BP 901 EP 908 DI 10.1016/j.bbadis.2015.08.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DK0NJ UT WOS:000374609200006 PM 26277436 ER PT J AU Xiong, L Reijmer, YD Charidimou, A Cordonnier, C Viswanathan, A AF Xiong, Li Reijmer, Yael D. Charidimou, Andreas Cordonnier, Charlotte Viswanathan, Anand TI Intracerebral hemorrhage and cognitive impairment SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Intracerebral hemorrhage; Cognitive impairment; Dementia; Small vessel disease; Neurodegenerative pathology ID CEREBRAL AMYLOID ANGIOPATHY; ENDOTHELIAL GROWTH-FACTOR; LONDON STROKE REGISTER; SMALL VESSEL DISEASE; POSTSTROKE DEMENTIA; CLINICAL-DIAGNOSIS; ISCHEMIC-STROKE; RISK-FACTORS; MICROBLEEDS; RATS AB Vascular cognitive impairment and vascular dementia are composed of cognitive deficits resulted from a range of vascular lesions and pathologies, including both ischemic and hemorrhagic. However the contribution of spontaneous intracerebral hemorrhage presumed due to small vessel diseases on cognitive impairment is underestimated, in contrast to the numerous studies about the role of ischemic vascular disorders on cognition. In this review we summarize recent findings from clinical studies and appropriate basic science research to better elucidate the role and possible mechanisms of intracerebral hemorrhage in cognitive impairment and dementia. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. (c) 2015 Elsevier B.V. All rights reserved. C1 [Xiong, Li; Reijmer, Yael D.; Charidimou, Andreas; Viswanathan, Anand] Harvard Univ, Sch Med, Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Xiong, Li] Wuhan Univ, Zhongnan Hosp, Dept Neurol, Wuhan 430071, Peoples R China. [Cordonnier, Charlotte] Lille Univ Hosp, Hop Roger Salengro, Dept Neurol & Stroke Unit, F-59037 Lille, France. RP Viswanathan, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. EM lxiong2@partners.org; yreijmer@mgh.harvard.edu; acharidimou@mgh.harvard.edu; charlotte.cordonnier@chru-lille.fr; aviswanathan1@partners.org NR 81 TC 1 Z9 1 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD MAY PY 2016 VL 1862 IS 5 SI SI BP 939 EP 944 DI 10.1016/j.bbadis.2015.12.011 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DK0NJ UT WOS:000374609200010 PM 26692171 ER PT J AU Rydingsward, JE Horkan, CM Mogensen, KM Quraishi, SA Amrein, K Christopher, KB AF Rydingsward, Jessica E. Horkan, Clare M. Mogensen, Kris M. Quraishi, Sadeq A. Amrein, Karin Christopher, Kenneth B. TI Functional Status in ICU Survivors and Out of Hospital Outcomes: A Cohort Study SO CRITICAL CARE MEDICINE LA English DT Article DE Functional Independence Measure; functional status; intensive care unit survivor; mortality ID INTENSIVE-CARE-UNIT; CRITICALLY-ILL PATIENTS; ACUTE RESPIRATORY-FAILURE; LONG-TERM OUTCOMES; CRITICAL ILLNESS; ACQUIRED WEAKNESS; OLDER-ADULTS; SEVERE SEPSIS; PROSPECTIVE MULTICENTER; EMERGENCY-DEPARTMENTS AB Objectives: Functional status at hospital discharge may be a risk factor for adverse events among survivors of critical illness. We sought to examine the association between functional status at hospital discharge in survivors of critical care and risk of 90-day all-cause mortality after hospital discharge. Design: Single-center retrospective cohort study. Setting: Academic Medical Center. Patients: Ten thousand three hundred forty-three adults who received critical care from 1997 to 2011 and survived hospitalization. Interventions: None. Measurements and Main Results: The exposure of interest was functional status determined at hospital discharge by a licensed physical therapist and rated based on qualitative categories adapted from the Functional Independence Measure. The main outcome was 90-day post hospital discharge all-cause mortality. A categorical risk-prediction score was derived and validated based on a logistic regression model of the function grades for each assessment. In an adjusted logistic regression model, the lowest quartile of functional status at hospital discharge was associated with an increased odds of 90-day postdischarge mortality compared with patients with independent functional status (odds ratio, 7.63 [95% CI, 3.83-15.22; p < 0.001]). In patients who had at least 7 days of physical therapy treatment prior to hospital discharge (n = 2,293), the adjusted odds of 90-day postdischarge mortality in patients with marked improvement in functional status at discharge was 64% less than patients with no change in functional status (odds ratio, 0.36 [95% CI, 0.24-0.53]; p < 0.001). Conclusions: Lower functional status at hospital discharge in survivors of critical illness is associated with increased postdischarge mortality. Furthermore, patients whose functional status improves before discharge have decreased odds of postdischarge mortality. C1 [Rydingsward, Jessica E.] Brigham & Womens Hosp, Dept Rehabil, 75 Francis St, Boston, MA 02115 USA. [Horkan, Clare M.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Mogensen, Kris M.] Brigham & Womens Hosp, Dept Nutr, 75 Francis St, Boston, MA 02115 USA. [Quraishi, Sadeq A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Amrein, Karin] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, Graz, Austria. [Christopher, Kenneth B.] Brigham & Womens Hosp, Dept Med, Nathan E Hellman Mem Lab, Div Renal, 75 Francis St, Boston, MA 02115 USA. RP Christopher, KB (reprint author), Brigham & Womens Hosp, Dept Med, Nathan E Hellman Mem Lab, Div Renal, 75 Francis St, Boston, MA 02115 USA. EM kbchristopher@partners.org FU ThriveRx; Wolf Rinke Associates; National Institutes of Health (NIH) [L30 TR001257]; Lungpacer; NIH; Doctella FX Ms. Mogensen received honoraria for speaking for various subunits of the Massachusetts Dietetic Association and the Academy of Nutrition and Dietetics. She received funding from ThriveRx (receives consulting fees for participating in the ThriveRx Nutrition Advisory Board. The function of the board is to review policies, procedures, and other clinical concerns of the company), Wolf Rinke Associates (provides continuing professional education primarily for registered dietitians and Ms. Mogensen receives royalties and one-time payments for educational modules that she has written), and the American Society for Parenteral and Enteral Nutrition (she has received honoraria for speaking at Clinical Nutrition Week and for speaking or moderating various Webinars). Dr. Quraishi received funding from the National Institutes of Health (NIH) (L30 TR001257) and from Lungpacer. He has disclosed that his wife, Ayesha N. Khalid, MD, MBA, receives salary from Doctella. His institution received grant support from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 70 TC 3 Z9 3 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2016 VL 44 IS 5 BP 869 EP 879 DI 10.1097/CCM.0000000000001627 PG 11 WC Critical Care Medicine SC General & Internal Medicine GA DJ7BF UT WOS:000374366200003 PM 26929191 ER PT J AU Abdul-Ghani, M Del Prato, S Chilton, R DeFronzo, RA AF Abdul-Ghani, Muhammad Del Prato, Stefano Chilton, Robert DeFronzo, Ralph A. TI SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study SO DIABETES CARE LA English DT Article ID TYPE-2 DIABETES-MELLITUS; RANDOMIZED CONTROLLED-TRIAL; PIOGLITAZONE CLINICAL-TRIAL; INSULIN SENSITIVITY; GLYCEMIC CONTROL; GLUCOSE CONTROL; BLOOD-PRESSURE; MICROVASCULAR OUTCOMES; MYOCARDIAL-INFARCTION; MACROVASCULAR EVENTS AB Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium-glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA(1c), body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin's metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients. C1 [Abdul-Ghani, Muhammad; DeFronzo, Ralph A.] Univ Texas San Antonio, Hlth Sci Ctr, Div Diabet, San Antonio, TX USA. [Abdul-Ghani, Muhammad] Hamad Gen Hosp, Diabet & Obes Clin Res Ctr, Dept Med, Doha, Qatar. [Del Prato, Stefano] Univ Pisa, Sch Med, Dept Clin & Expt Med, I-56100 Pisa, Italy. [Chilton, Robert] Univ Texas San Antonio, Div Cardiol, Hlth Sci Ctr, San Antonio, TX USA. [Chilton, Robert] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Abdul-Ghani, M; DeFronzo, RA (reprint author), Univ Texas San Antonio, Hlth Sci Ctr, Div Diabet, San Antonio, TX USA.; Abdul-Ghani, M (reprint author), Hamad Gen Hosp, Diabet & Obes Clin Res Ctr, Dept Med, Doha, Qatar. EM abdulghani@uthscsa.edu; albarado@uthscsa.edu RI Del Prato, Stefano/K-3405-2016 OI Del Prato, Stefano/0000-0002-5388-0270 FU Qatar Foundation [NPRP 4-248-3-076]; National Institutes of Health [R01 DK097554-01, 5R01DK24093]; South Texas Veterans Health Care System FX M.A.-G. receives grant support from the Qatar Foundation (NPRP 4-248-3-076). M.A.-G. (R01 DK097554-01) and R.A.D. (5R01DK24093) have received grant support from the National Institutes of Health. The salary of R.A.D. is partially supported by the South Texas Veterans Health Care System. NR 56 TC 19 Z9 19 U1 2 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2016 VL 39 IS 5 BP 717 EP 725 DI 10.2337/dc16-0041 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6MU UT WOS:000375039000012 PM 27208375 ER PT J AU Smith, RJ Goldfine, AB Hiatt, WR AF Smith, Robert J. Goldfine, Allison B. Hiatt, William R. TI Evaluating the Cardiovascular Safety of New Medications for Type 2 Diabetes: Time to Reassess? SO DIABETES CARE LA English DT Article ID ACUTE CORONARY SYNDROME; MELLITUS; OUTCOMES; EVENTS AB The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstration of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardiovascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientific community and the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development. C1 [Smith, Robert J.] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Smith, Robert J.] Brown Univ, Dept Hlth Serv Policy & Practice, Sch Publ Hlth, Providence, RI 02912 USA. [Smith, Robert J.] Providence VA Med Ctr, Ocean State Res Inst, Providence, RI USA. [Goldfine, Allison B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Res Div, Boston, MA 02115 USA. [Hiatt, William R.] Univ Colorado, Sch Med, Div Cardiol, Aurora, CO USA. [Hiatt, William R.] CPC Clin Res, Aurora, CO USA. RP Smith, RJ (reprint author), Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA.; Smith, RJ (reprint author), Brown Univ, Dept Hlth Serv Policy & Practice, Sch Publ Hlth, Providence, RI 02912 USA.; Smith, RJ (reprint author), Providence VA Med Ctr, Ocean State Res Inst, Providence, RI USA. EM robert_j_smith@brown.edu NR 14 TC 6 Z9 6 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2016 VL 39 IS 5 BP 738 EP 742 DI 10.2337/dc15-2237 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6MU UT WOS:000375039000015 PM 27208377 ER PT J AU Azad, N Bahn, GD Emanuele, NV Agrawal, L Ge, L Reda, D Klein, R Reaven, PD Hayward, R AF Azad, Nasrin Bahn, Gideon D. Emanuele, Nicholas V. Agrawal, Lily Ge, Ling Reda, Dominic Klein, Ronald Reaven, Peter D. Hayward, Rodney CA VADT Study Grp TI Association of Blood Glucose Control and Lipids With Diabetic Retinopathy in the Veterans Affairs Diabetes Trial (VADT) SO DIABETES CARE LA English DT Article ID RISK-FACTORS; SERUM-LIPIDS; HARD EXUDATE; COMPLICATIONS; PROGRESSION; MELLITUS; PREVALENCE; DIAGNOSIS; THERAPY AB OBJECTIVE This study examined whether lipids modify the relationship between intensive glucose control (INT) and diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS The incidence and progression of DR were assessed in 858 of 1,791 participants with 7-field stereoscopic fundus photographs at baseline and 5 years later. RESULTS Odds of DR progression were lower by similar to 40% in those with baseline total cholesterol (TC) >= 200 mg/dL (P = 0.007), LDL-C >= 120 mg/dL (P < 0.02), or HDL-C >= 40 mg/dL (P < 0.007) in the INT arm versus standard glycemic treatment. Odds of DR progression were reduced by similar to 40% in those who had TC <= 140 mg/dL (P <= 0.024), triglycerides (TG) <= 120 mg/dL (P = 0.004), or HDL-C >= 45 mg/dL (P = 0.01) at the fifth year. Odds of DR progression were lower by similar to 40-50% with reductions of TC by >= 40 mg/dL (P < 0.0001), of LDL-C of >= 40 mg/dL (P < 0.004), and of TG by >= 60 mg/dL (P = 0.004) at the fifth year. Odds of DR progression increased by 80% with increases in TC of >= 20 mg/dL (P < 0.0001) and by 180% with increases in LDL-C by >= 60 mg/dL (P < 0.004). After adjusting for covariants, those with higher TC at baseline and lower TC during and at the fifth year and higher HDL-C throughout study had significantly decreased odds of DR progression in INT. CONCLUSIONS INT was associated with decreased odds of progression but not with onset of retinopathy in those with worse lipid levels at baseline and more improved lipid levels during the study. Higher HDL-C was consistently associated with better response to INT throughout the study. C1 [Azad, Nasrin; Emanuele, Nicholas V.; Agrawal, Lily] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Endocrinol Sect, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. [Bahn, Gideon D.; Ge, Ling; Reda, Dominic] Coordinating Ctr, Cooperat Studies Program, Hines, IL USA. [Klein, Ronald] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Reaven, Peter D.] Carl T Hayden VA Med Ctr, Endocrinol Sect, Phoenix, AZ USA. [Hayward, Rodney] Ann Arbor VA Healthcare Syst, Ann Arbor, MI USA. RP Azad, N (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Endocrinol Sect, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. EM nasrin.azad@va.gov FU Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; National Eye Institute; Sanofi; GlaxoSmithKline; Novo Nordisk; Roche; Kos Pharmaceuticals; Merck; Amylin FX The study was sponsored by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. There was also generous support from the National Eye Institute.; Medications and financial support were provided by Sanofi, GlaxoSmithKline, Novo Nordisk, Roche, Kos Pharmaceuticals, Merck, and Amylin. These companies had no role in the design of the study, in the accrual or analysis of the data, or in the preparation or approval of the manuscript. NR 37 TC 0 Z9 0 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2016 VL 39 IS 5 BP 816 EP 822 DI 10.2337/dc15-1897 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6MU UT WOS:000375039000026 PM 27006510 ER PT J AU Weisman, A Rovinski, R Farooqi, MA Lovblom, LE Halpern, EM Boulet, G Eldelekli, D Keenan, HA Brent, MH Paul, N Bril, V Cherney, DZ Perkins, BA AF Weisman, Alanna Rovinski, Randy Farooqi, Mohammed A. Lovblom, Leif E. Halpern, Elise M. Boulet, Genevieve Eldelekli, Devrim Keenan, Hillary A. Brent, Michael H. Paul, Narinder Bril, Vera Cherney, David Z. Perkins, Bruce A. TI Commonly Measured Clinical Variables Are Not Associated With Burden of Complications in Long-standing Type 1 Diabetes: Results From the Canadian Study of Longevity in Diabetes SO DIABETES CARE LA English DT Letter ID DISEASE; RESISTANCE; DURATION; MEDALIST; COHORT C1 [Weisman, Alanna; Rovinski, Randy; Farooqi, Mohammed A.; Lovblom, Leif E.; Halpern, Elise M.; Boulet, Genevieve; Eldelekli, Devrim; Perkins, Bruce A.] Univ Toronto, Mt Sinai Hosp, Dept Med, Div Endocrinol & Metab, Toronto, ON M5G 1X5, Canada. [Keenan, Hillary A.] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Brent, Michael H.] Univ Toronto, Dept Med, Dept Ophthalmol & Vis Sci, Toronto, ON, Canada. [Paul, Narinder] Univ Hlth Network, Div Cardiothorac Radiol, Joint Dept Med Imaging, Toronto, ON, Canada. [Bril, Vera] Univ Toronto, Dept Med, Div Neurol,Univ Hlth Network,Krembil Neurosci Ctr, Ellen & Martin Prosserman Ctr Neuromuscular Dis, Toronto, ON, Canada. [Cherney, David Z.] Univ Toronto, Dept Med, Div Nephrol, Toronto, ON, Canada. RP Perkins, BA (reprint author), Univ Toronto, Mt Sinai Hosp, Dept Med, Div Endocrinol & Metab, Toronto, ON M5G 1X5, Canada. EM bperkins@mtsinai.on.ca NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2016 VL 39 IS 5 BP E67 EP E68 DI 10.2337/dc16-0102 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK6MU UT WOS:000375039000001 PM 27006509 ER PT J AU Economopoulos, KP Ward, NL Phillips, CD Teshager, A Patel, P Mohamed, MM Hakimian, S Cox, SB Ahmed, R Moaven, O Kaliannan, K Alam, SN Haller, JF Goldstein, AM Bhan, AK Malo, MS Hodin, RA AF Economopoulos, K. P. Ward, N. L. Phillips, C. D. Teshager, A. Patel, P. Mohamed, M. M. Hakimian, S. Cox, S. B. Ahmed, R. Moaven, O. Kaliannan, K. Alam, S. N. Haller, J. F. Goldstein, A. M. Bhan, A. K. Malo, M. S. Hodin, R. A. TI Prevention of antibiotic-associated metabolic syndrome in mice by intestinal alkaline phosphatase SO DIABETES OBESITY & METABOLISM LA English DT Article DE azithromycin; intestinal alkaline phosphatase; metabolic syndrome; mice ID RANDOMIZED CONTROLLED-TRIAL; GUT MICROBIOTA; PSEUDOMONAS-AERUGINOSA; UNITED-STATES; EARLY-LIFE; OBESITY; DIET; CONSEQUENCES; AZITHROMYCIN; RESPONSES AB Aims: To examine whether co-administration of intestinal alkaline phosphatase (IAP) with antibiotics early in life may have a preventive role against metabolic syndrome (MetS) in mice. Methods: A total of 50 mice were allocated to four treatment groups after weaning. Mice were treated with azithromycin (AZT) +/- IAP, or with no AZT +/- IAP, for three intermittent 7-day cycles. After the last treatment course, the mice were administered a regular chow diet for 5 weeks and subsequently a high-fat diet for 5 weeks. Body weight, food intake, water intake, serum lipids, glucose levels and liver lipids were compared. 16S rRNA gene pyrosequencing was used to determine the differences in microbiome composition. Results: Exposure to AZT early in life rendered mice susceptible to MetS in adulthood. Co-administration of IAP with AZT completely prevented this susceptibility by decreasing total body weight, serum lipids, glucose levels and liver lipids to the levels of control mice. These effects of IAP probably occur as a result of changes in the composition of specific bacterial taxa at the genus and species levels (e.g. members of Anaeroplasma and Parabacteroides). Conclusions: Co-administration of IAP with AZT early in life prevents mice from susceptibility to the later development of MetS. This effect is associated with alterations in the composition of the gut microbiota. IAP may represent a novel treatment against MetS in humans. C1 [Economopoulos, K. P.; Teshager, A.; Patel, P.; Mohamed, M. M.; Hakimian, S.; Ahmed, R.; Moaven, O.; Kaliannan, K.; Alam, S. N.; Malo, M. S.; Hodin, R. A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. [Ward, N. L.] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Ward, N. L.] Univ Wyoming, Dept Bot, Laramie, WY 82071 USA. [Phillips, C. D.; Cox, S. B.] Res & Testing Lab, Lubbock, TX USA. [Phillips, C. D.] Texas Tech Univ, Dept Biol Sci, Lubbock, TX 79409 USA. [Haller, J. F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit, Boston, MA 02115 USA. [Goldstein, A. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA 02115 USA. [Bhan, A. K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hodin, RA (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM rhodin@mgh.harvard.edu FU Ellison Medical Foundation FX This study was supported by a grant from The Ellison Medical Foundation. NR 47 TC 2 Z9 2 U1 4 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 EI 1463-1326 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD MAY PY 2016 VL 18 IS 5 BP 519 EP 527 DI 10.1111/dom.12645 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DJ5WG UT WOS:000374280900010 PM 26876427 ER PT J AU Softic, S Cohen, DE Kahn, CR AF Softic, Samir Cohen, David E. Kahn, C. Ronald TI Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review DE NAFLD; NASH; Fructose; HFD; Metabolism; De novo lipogenesis; Liver ID STEAROYL-COA DESATURASE-1; ATP-CITRATE-LYASE; SUGAR-SWEETENED BEVERAGES; ANTISENSE OLIGONUCLEOTIDE INHIBITORS; INSULIN-RESISTANCE; METABOLIC SYNDROME; NONALCOHOLIC STEATOHEPATITIS; URIC-ACID; HIGH-CARBOHYDRATE; UNITED-STATES AB Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD. C1 [Softic, Samir; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, 1 Joslin Pl, Boston, MA 02215 USA. [Softic, Samir] Boston Childrens Hosp, Dept Gastroenterol Hepatol & Nutr, Boston, MA USA. [Cohen, David E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02115 USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu OI Softic, Samir/0000-0003-1419-9789 FU NIH [R01 DK031036, R01 DK033201, R37 DK048873, R01 DK056626, R01 DK103046, K12 HD000850] FX This work was supported in part by NIH Grants R01 DK031036 and R01 DK033201 to C.R.K, R37 DK048873, R01 DK056626, and R01 DK103046 to D.E.C, and K12 HD000850 to S.S. NR 131 TC 12 Z9 12 U1 10 U2 25 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD MAY PY 2016 VL 61 IS 5 SI SI BP 1282 EP 1293 DI 10.1007/s10620-016-4054-0 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK1JH UT WOS:000374667800007 PM 26856717 ER PT J AU Corey, KE Rinella, ME AF Corey, Kathleen E. Rinella, Mary E. TI Medical and Surgical Treatment Options for Nonalcoholic Steatohepatitis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review DE Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Vitamin E; Pioglitazone; Weight loss surgery ID FATTY LIVER-DISEASE; PLACEBO-CONTROLLED-TRIAL; RANDOMIZED CONTROLLED-TRIAL; Y GASTRIC BYPASS; WEIGHT-LOSS; VITAMIN-E; INSULIN-RESISTANCE; HEPATIC STEATOSIS; BARIATRIC SURGERY; CARDIOVASCULAR EVENTS AB Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the USA with a growing prevalence worldwide. Nonalcoholic steatohepatitis (NASH), progressive form of NAFLD, can lead to the development of cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. Treatment of NASH may decrease the risk of progressive disease. Treatment for NAFLD should center around weight loss and exercise. Pharmacotherapy with vitamin E and pioglitazone should be considered for those with NASH, especially those with fibrosis. Weight loss surgery is also an effective treatment for NASH in individuals with other indications for surgery. In this review, we will discuss the currently available therapies for NASH including lifestyle, pharmacologic, and surgical options. C1 [Corey, Kathleen E.; Rinella, Mary E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Liver Ctr, Boston, MA USA. [Corey, Kathleen E.; Rinella, Mary E.] Northwestern Univ, Feinberg Sch Med, Dept Gastroenterol & Hepatol, Chicago, IL 60611 USA. RP Corey, KE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Liver Ctr, Boston, MA USA.; Corey, KE (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Gastroenterol & Hepatol, Chicago, IL 60611 USA. EM kcorey@partners.org; mrinella@nm.org FU NIDDK NIH HHS [K23 DK099422, P30 DK040561] NR 83 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD MAY PY 2016 VL 61 IS 5 SI SI BP 1387 EP 1397 DI 10.1007/s10620-016-4083-8 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK1JH UT WOS:000374667800017 PM 26942734 ER PT J AU Baksh, SN Gellad, WF Alexander, GC AF Baksh, Sheriza N. Gellad, Walid F. Alexander, G. Caleb TI Maximizing the Post-Approval Safety of Flibanserin: A Role for Regulators, Clinicians, and Patients SO DRUG SAFETY LA English DT Article ID SEXUAL DESIRE DISORDER; PREMENOPAUSAL WOMEN EFFICACY AB In August 2015, the US Food and Drug Administration (FDA) made the controversial decision to approve flibanserin (Addyi((R))) for women experiencing hypoactive sexual desire disorder. A number of factors contributed to disagreements regarding the FDA's decision, including the product's two prior failed FDA reviews, the unmet need of women with this disorder, extensive advocacy and politicization surrounding the product's relevance to women and sexual health, the potential for widespread off-label use, and the product's tenuous risk/benefit profile. Despite that, attention now shifts to maximizing the safe use of the product, including the optimal means to avoid numerous drug-drug interactions as well as the concomitant use of alcohol, both of which potentiate the risks of dizziness, hypotension, and syncope. Although the FDA has implemented a comprehensive Risk Evaluation and Mitigation Strategies program to maximize the product's safe use, patients, clinicians, and regulators must exhibit heightened vigilance early in the product's post-market life. C1 [Baksh, Sheriza N.; Alexander, G. Caleb] Johns Hopkins Univ, Ctr Drug Safety & Effectiveness, Baltimore, MD 21205 USA. [Baksh, Sheriza N.; Alexander, G. Caleb] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St W6035, Baltimore, MD 21205 USA. [Gellad, Walid F.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA 15261 USA. [Alexander, G. Caleb] Johns Hopkins Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. RP Alexander, GC (reprint author), Johns Hopkins Univ, Ctr Drug Safety & Effectiveness, Baltimore, MD 21205 USA.; Alexander, GC (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St W6035, Baltimore, MD 21205 USA.; Alexander, GC (reprint author), Johns Hopkins Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. EM galexan9@jhmi.edu NR 21 TC 1 Z9 2 U1 0 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD MAY PY 2016 VL 39 IS 5 BP 375 EP 380 DI 10.1007/s40264-015-0389-2 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DJ6NM UT WOS:000374330200002 PM 26798050 ER PT J AU Cohen, AH Wang, RP Wilkinson, M MacDonald, P Lim, AR Takahashi, E AF Cohen, Andrew H. Wang, Rongpin Wilkinson, Molly MacDonald, Patrick Lim, Ashley R. Takahashi, Emi TI Development of human white matter fiber pathways: From newborn to adult ages SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE Development; White matter; Newborn; Diffusion imaging; Tractography ID RESOLUTION DIFFUSION TRACTOGRAPHY; HUMAN BRAIN; PRESCHOOL-CHILDREN; HUMAN FETAL; SPHERICAL DECONVOLUTION; HEMISPHERIC ASYMMETRIES; IMAGING TRACTOGRAPHY; TENSOR TRACTOGRAPHY; COMPUTED-TOMOGRAPHY; CORPUS-CALLOSUM AB Major long-range white matter pathways (cingulum, fornix, uncinate fasciculus [UF], inferior frontooccipital fasciculus [IFOF], inferior longitudinal fasciculus [ILF], thalamocortical [TC], and corpus callosal [CC] pathways) were identified in eighty-three healthy humans ranging from newborn to adult ages. We tracked developmental changes using high-angular resolution diffusion MR tractography. Fractional anisotropy (FA), apparent diffusion coefficient, number, length, and volume were measured in pathways in each subject. Newborns had fewer, and more sparse, pathways than those of the older subjects. FA, number, length, and volume of pathways gradually increased with age and reached a plateau between 3 and 5 years of age. Data were further analyzed by normalizing with mean adult values as well as with each subject's whole brain values. Comparing subjects of 3 years old and under to those over 3 years old, the studied pathways showed differential growth patterns. The CC, bilateral cingulum, bilateral TC, and the left IFOF pathways showed significant growth both in volume and length, while the bilateral fornix, bilateral ILF and bilateral UF showed significant growth only in volume. The TC and CC took similar growth patterns with the whole brain. FA values of the cingulum and IFOF, and the length of ILF showed leftward asymmetry. The fornix, ILF and UF occupied decreased space compared to the whole brain during development with higher FA values, likely corresponding to extensive maturation of the pathways compared to the mean whole brain maturation. We believe that the outcome of this study will provide an important database for future reference. (C) 2016 ISDN. Published by Elsevier Ltd. All rights reserved. C1 [Cohen, Andrew H.; Wilkinson, Molly; MacDonald, Patrick; Lim, Ashley R.; Takahashi, Emi] Northeastern Univ, Dept Behav Neurosci, Boston, MA 02115 USA. [Cohen, Andrew H.; Wang, Rongpin; Wilkinson, Molly; MacDonald, Patrick; Lim, Ashley R.; Takahashi, Emi] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Newborn Med,Dept Med, 300 Longwood Ave, Boston, MA 02115 USA. [Wang, Rongpin] Guizhou Prov Peoples Hosp, Dept Radiol, 83 Zhong Shan Dong Lu, Guiyang 550002, Guizhou Provinc, Peoples R China. [Wang, Rongpin; Takahashi, Emi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. [Wang, Rongpin; Takahashi, Emi] Harvard Univ, Sch Med, Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, 300 Longwood Ave, Boston, MA 02115 USA. RP Takahashi, E (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA. EM emi@nmr.mgh.harvard.edu FU Boston Children's Hospital (BCH); NICHD [R01HD078561, R21HD069001]; NINDS [R03NS091587] FX This work was supported by Boston Children's Hospital (BCH), NICHD (R01HD078561, R21HD069001) (ET), and NINDS (R03NS091587) (ET). Hui Xue and Thomas J. Re provided technical, and Priya Kabaria provided editorial assistance. NR 93 TC 4 Z9 5 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 EI 1873-474X J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD MAY PY 2016 VL 50 BP 26 EP 38 DI 10.1016/j.ijdevneu.2016.02.002 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA DK2AH UT WOS:000374716500004 PM 26948153 ER PT J AU Fried, R Petty, C Faraone, SV Hyder, LL Day, H Biederman, J AF Fried, Ronna Petty, Carter Faraone, Stephen V. Hyder, Laran L. Day, Helen Biederman, Joseph TI Is ADHD a Risk Factor for High School Dropout? A Controlled Study SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE ADHD; adolescence; dropout ID ATTENTION-DEFICIT HYPERACTIVITY; DEFICIT/HYPERACTIVITY DISORDER; GRADE RETENTION; PSYCHIATRIC COMORBIDITY; SUBTHRESHOLD DIAGNOSES; LATE-ONSET; CHILDREN; OUTCOMES; ADULTS; ASSOCIATION AB Objective: This study examined whether ADHD was an independent contributor to grade retention when adjusting for IQ, learning disorders, and social class. Method: Outcome data was from participants in studies at Massachusetts General Hospital (n = 404 ADHD, n = 349 controls) who underwent psychiatric interviews, socioeconomic status measures, and IQ testing. Results: 28% of individuals with ADHD repeated a grade compared with 7% of controls (p < .001). Among participants with ADHD, social class, and IQ were significant predictors of high school dropout or repeated grade. An interaction effect of ADHD and gender was also found with females with ADHD having a higher risk ratio for repeated grade/dropout compared with males with ADHD. Conclusion: Participants with ADHD were significantly more likely to repeat a grade, adjusting for all other variables indicating the critical importance of early identification of ADHD to help mitigate adverse educational outcomes. (J. of Att. Dis. 2016; 20(5) 383-389) C1 [Fried, Ronna; Petty, Carter; Hyder, Laran L.; Day, Helen] Massachusetts Gen Hosp, Pediat Psychopharmacol Program, Warren 705,55 Fruit St, Boston, MA 02114 USA. [Fried, Ronna; Biederman, Joseph] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Child & Adolescent Psychiat Res, Syracuse, NY 13210 USA. [Fried, Ronna; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. RP Fried, R (reprint author), Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. EM rfried@partners.org FU MGH Pediatric Psychopharmacology Philanthropy Fund 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 MGH Pediatric Psychopharmacology Philanthropy Fund. NR 35 TC 2 Z9 2 U1 14 U2 22 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 EI 1557-1246 J9 J ATTEN DISORD JI J. Atten. Disord. PD MAY PY 2016 VL 20 IS 5 SI SI BP 383 EP 389 DI 10.1177/1087054712473180 PG 7 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA DJ6MP UT WOS:000374327900001 PM 23382575 ER PT J AU Yanamadala, V Koffie, RM Shankar, GM Kumar, JI Buchlak, QD Puthenpura, V Frosch, MP Gudewicz, TM Borges, LF Shin, JH AF Yanamadala, Vijay Koffie, Robert M. Shankar, Ganesh M. Kumar, Jay I. Buchlak, Quinlan D. Puthenpura, Vidya Frosch, Matthew P. Gudewicz, Thomas M. Borges, Lawrence F. Shin, John H. TI Spinal cord glioblastoma: 25 years of experience from a single institution SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Glioblastoma; Spinal cord; Spinal cord glioblastoma ID OF-THE-LITERATURE; RADIATION-THERAPY; CONUS MEDULLARIS; MULTIFORME; SURVIVAL; TEMOZOLOMIDE; STRATEGIES; PATIENT AB Accounting for less than 0.2% of all glioblastomas, high grade gliomas of the spinal cord are very rare. Here, we discuss our approach to managing patients with high grade spinal cord glioma and review the literature on the subject. Six patients with high grade spinal cord gliomas who presented to our institution between 1990 and 2015 were reviewed. Each patient underwent subtotal surgical resection, with a subset receiving adjuvant chemotherapy and radiation. Our primary outcomes of interest were preoperative and post-operative functional status. One year survival rate was 100%. All patients had stable or improved American Spine Injury Association score immediately after surgery, which was maintained at 3 months in 83.3% of patients. Karnofsky Performance Status (KPS) was stable at 3 month follow up in 50% of patients, but all had decreased KPS 1 year after surgery. A subset of patients received postoperative radiation and chemotherapy with 0% tumor recurrence rate at 3 months. We assessed the molecular profiles of tumors from two patients in our series and found that each had mutations in TP53, but had wildtype BRAF, IDH-1, and MGMT. Taken together, our data show that patients with high grade spinal cord gliomas have an excellent survival at 1 year, but with some decline in functional status within this period. Further studies are needed to elucidate the natural history of the disease and to explore the role of adjuvant targeted molecular therapies. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Yanamadala, Vijay; Koffie, Robert M.; Shankar, Ganesh M.; Kumar, Jay I.; Buchlak, Quinlan D.; Puthenpura, Vidya; Borges, Lawrence F.; Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,WACC 021, Boston, MA 02115 USA. [Frosch, Matthew P.; Gudewicz, Thomas M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Yanamadala, Vijay; Koffie, Robert M.; Shankar, Ganesh M.; Kumar, Jay I.; Buchlak, Quinlan D.; Frosch, Matthew P.; Gudewicz, Thomas M.; Borges, Lawrence F.; Shin, John H.] Harvard Univ, Sch Med, Boston, MA USA. RP Yanamadala, V (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,WACC 021, Boston, MA 02115 USA.; Yanamadala, V (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM vyanamadala@mgh.harvard.edu OI Shin, John/0000-0001-7490-8108 NR 30 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD MAY PY 2016 VL 27 BP 138 EP 141 DI 10.1016/j.jocn.2015.11.011 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DK0LZ UT WOS:000374605600026 PM 26755453 ER PT J AU Lee, D Yanamadala, V Shankar, GM Shin, JH AF Lee, Daniel Yanamadala, Vijay Shankar, Ganesh M. Shin, John H. TI Metastatic adrenal cortical carcinoma to T12 vertebrae SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Adrenal cortical carcinoma; Metastasis; Spinal metastasis ID SPINAL-CORD COMPRESSION; OF-THE-LITERATURE; ADRENOCORTICAL CARCINOMA; SURGICAL RESECTION; RANDOMIZED-TRIAL; MANAGEMENT; RADIOTHERAPY; DISEASE; CANCER; TUMORS AB We report spinal metastasis of adrenal cortical carcinoma (ACC) to the T12 vertebrae with epidural extension. ACC is a rare malignancy with poor prognosis and high rates of metastasis. However, spinal lesions of ACC are rare, and few have been reported in the literature. We discuss our management of this lesion and review the current understanding and treatment of ACC and spinal metastasis. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Lee, Daniel] Harvard Univ, Sch Med, Harvard MIT Sci & Technol, Boston, MA USA. [Yanamadala, Vijay; Shankar, Ganesh M.; Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,WACC 021, Boston, MA 02115 USA. [Lee, Daniel; Yanamadala, Vijay; Shankar, Ganesh M.; Shin, John H.] Harvard Univ, Sch Med, Boston, MA USA. RP Yanamadala, V (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,WACC 021, Boston, MA 02115 USA.; Yanamadala, V (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM vyanamadala@mgh.harvard.edu OI Shin, John/0000-0001-7490-8108 NR 42 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD MAY PY 2016 VL 27 BP 166 EP 169 DI 10.1016/j.jocn.2015.11.009 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DK0LZ UT WOS:000374605600032 PM 26765762 ER PT J AU Goyal, A Solus, JF Chan, MP Doyle, LA Schaffer, A Thakuria, M Horn, TD Duncan, LM Nazarian, RM AF Goyal, Amrita Solus, Jason F. Chan, May P. Doyle, Leona A. Schaffer, Andras Thakuria, Manisha Horn, Thomas D. Duncan, Lyn M. Nazarian, Rosalynn M. TI Cytokeratin 17 is highly sensitive in discriminating cutaneous lymphadenoma (a distinct trichoblastoma variant) from basal cell carcinoma SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article DE CK20; CK17; trichoblastoma; Merkel cell; basal cell carcinoma ID NODULAR TRICHOBLASTOMA; MICROGRAPHIC SURGERY; TRICHOEPITHELIOMA; DIFFERENTIATION; MARKER; EXPRESSION; DIAGNOSIS; PANEL AB BackgroundCutaneous lymphadenoma (CL) is rare neoplasm that clinically and histologically resembles basal cell carcinoma (BCC). CL, composed of dermal basaloid epithelial islands with prominent admixed lymphocytes, characteristically contains cytokeratin 20 (CK20)-positive Merkel cells (MCs). However, CK20 may be of limited use because of low MC density in small samples. CK17 is expressed diffusely throughout BCC. We investigated the discriminatory utility of CK17 and CK20 in CL and BCC. MethodsA retrospective clinicopathological review of 11 cases of CL and 14 BCC was performed. CK20-positive MCs within basaloid tumor lobules and CK17 immunohistochemical staining and pattern of expression were recorded. ResultsIntratumoral CK20-positive MCs were identified in 4/11 CL cases (36.4%) and 0/14 BCC cases (p=0.012, sensitivity=0.36). CK17 showed diffuse positive staining in all 14 BCC cases. CK17 showed a distinct patchy and peripheral rim staining in basaloid islands of 10/11 CL cases (p<0.001, sensitivity=0.91); one case showed patchy staining throughout tumor lobules. ConclusionsIn cases with a differential diagnosis of CL and BCC, CK20 staining of intratumoral MCs has a high positive predictive value for CL but is of low sensitivity. The pattern of CK17 expression is a highly sensitive marker for distinguishing CL from BCC in small samples. C1 [Goyal, Amrita; Horn, Thomas D.; Duncan, Lyn M.; Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dermatopathol Unit, 55 Fruit St,Warren 829A, Boston, MA 02114 USA. [Goyal, Amrita; Doyle, Leona A.; Thakuria, Manisha; Horn, Thomas D.; Duncan, Lyn M.; Nazarian, Rosalynn M.] Harvard Univ, Sch Med, Boston, MA USA. [Solus, Jason F.; Schaffer, Andras] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Chan, May P.] Univ Michigan Hlth Syst, Dept Pathol, Ann Arbor, MI USA. [Doyle, Leona A.; Thakuria, Manisha] Brigham & Womens Hosp, Boston, MA USA. RP Nazarian, RM (reprint author), Massachusetts Gen Hosp, Pathol Serv, Dermatopathol Unit, 55 Fruit St,Warren 829A, Boston, MA 02114 USA. EM rmnazarian@partners.org NR 34 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6987 EI 1600-0560 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD MAY PY 2016 VL 43 IS 5 BP 422 EP 429 DI 10.1111/cup.12700 PG 8 WC Dermatology; Pathology SC Dermatology; Pathology GA DK1KO UT WOS:000374671200003 PM 26968559 ER PT J AU D'Souza, N Hashimoto, DA Gurusamy, K Aggarwal, R AF D'Souza, Nigel Hashimoto, Daniel A. Gurusamy, Kurinchi Aggarwal, Rajesh TI Comparative Outcomes of Resident vs Attending Performed Surgery: A Systematic Review and Meta-Analysis SO JOURNAL OF SURGICAL EDUCATION LA English DT Review DE surgical education; surgical procedures; treatment outcomes; professional competence; patient safety ID Y GASTRIC BYPASS; SURGICAL OUTCOMES; LAPAROSCOPIC APPENDECTOMY; RECTAL-CANCER; PARTICIPATION; INVOLVEMENT; COMPLICATIONS; MORTALITY; STATEMENT; PROGRAM AB OBJECTIVE: To determine whether outcomes are different when surgery is performed by resident or attending surgeons, and which variables may affect outcomes. DESIGN: MEDLINE, EMBASE, and the Cochrane Library were searched from inception to May 2014 alongside the bibliographies of all included or relevant studies. Any study comparing outcomes from surgery performed by resident vs attending surgeons was eligible for inclusion. The main outcome measures were surgical complications (classified by Clavien-Dindo grade), death, operative time, and length of stay. Data were extracted independently by 2 authors and analyzed using the random-effects model. RESULTS: The final analysis included 182 eligible studies that enrolled 141 555 patients. Resident performed surgery took longer by 10.2 minutes (95% confidence interval (CI): 8.38-11.95), and had more Clavien-Dindo grade 1 (rate ratio = 1.14, 95% CI: 1.02-1.29) and grade 3a complications (rate ratio = 1.22, 95% CI: 1.04-1.44). Resident performed surgery resulted in fewer deaths (risk ratio = 0.83, 95% CI: 0.70-0.999) with a shorter length of stay of -0.49 days (95% CI: -0.77 to -0.21). Significant heterogeneity was present in 7 of 10 outcomes, which persisted during multiple subgroup analyses. CONCLUSIONS: Resident performed surgery appears to be safe in carefully selected patients. The significant amount of heterogeneity present in the study outcomes prevents generalizability of these results to specific clinical contexts. (C) 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved. C1 [D'Souza, Nigel] Salisbury Dist Hosp, Dept Gen Surg, Odstock Rd, Salisbury SP2 8BJ, Wilts, England. [Hashimoto, Daniel A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gurusamy, Kurinchi] UCL Med Sch, London, England. [Aggarwal, Rajesh] McGill Univ, Fac Med, Steinberg Ctr Simulat & Interact Learning, Montreal, PQ, Canada. [Aggarwal, Rajesh] McGill Univ, Dept Surg, Montreal, PQ H3A 2T5, Canada. RP D'Souza, N (reprint author), Salisbury Dist Hosp, Dept Gen Surg, Odstock Rd, Salisbury SP2 8BJ, Wilts, England. EM mrnigeldsouza@gmail.com FU Montreal General Hospital Foundation; Fonds de Recherche Sante Quebec FX Montreal General Hospital Foundation and the Fonds de Recherche Sante Quebec. NR 49 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 1931-7204 EI 1878-7452 J9 J SURG EDUC JI J. Surg. Educ. PD MAY-JUN PY 2016 VL 73 IS 3 BP 391 EP 399 DI 10.1016/j.jsurg.2016.01.002 PG 9 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA DK0PN UT WOS:000374614800007 PM 26966079 ER PT J AU Lopez, J Ameri, A Susarla, SM Reddy, S Soni, A Tong, JW Amini, N Ahmed, R May, JW Lee, WPA Dorafshar, A AF Lopez, Joseph Ameri, Afshin Susarla, Srinivas M. Reddy, Sashank Soni, Ashwin Tong, J. W. Amini, Neda Ahmed, Rizwan May, James W., Jr. Lee, W. P. Andrew Dorafshar, Amir TI Does Formal Research Training Lead to Academic Success in Plastic Surgery? A Comprehensive Analysis of US Academic Plastic Surgeons SO JOURNAL OF SURGICAL EDUCATION LA English DT Article DE academic practice; surgical training; research training; residency; h-index; postdoctoral research training ID INSTITUTES-OF-HEALTH; H-INDEX; RESEARCH PRODUCTIVITY; UNITED-STATES; IMPACT; RANK; SPECIALTIES; ASSOCIATION; DEPARTMENTS; PROMOTION AB INTRODUCTION: It is currently unknown whether formal research training has an influence on academic advancement in plastic surgery. The purpose of this study was to determine whether formal research training was associated with higher research productivity, academic rank, and procurement of extramural National Institutes of Health (NIH) funding in plastic surgery, comparing academic surgeons who completed said research training with those without. METHODS: This was a cross-sectional study of full-time academic plastic surgeons in the United States. The main predictor variable was formal research training, defined as completion of a postdoctoral research fellowship or attainment of a Doctor of Philosophy (PhD). The primary outcome was scientific productivity measured by the Hirsh-index (h-index, the number of publications, h that have at least h citations each). The secondary outcomes were academic rank and NIH funding. Descriptive, bivariate, and multiple regression statistics were computed. RESULTS: A total of 607 academic surgeons were identified from 94 Accreditation Council for Graduate Medical Education-accredited plastic surgery training programs. In all, 179 (29.5%) surgeons completed formal research training. The mean h-index was 11.7 +/- 9.9. And, 58 (9.6%) surgeons successfully procured NIH funding. The distribution of academic rank was the following: endowed professor (5.4%), professor (23.9%), associate professor (23.4%), assistant professor (46.0%), and instructor (1.3%). In a multiple regression analysis, completion of formal research training was significantly predictive of a higher h-index and successful procurement of NIH funding. CONCLUSION: Current evidence demonstrates that formal research training is associated with higher scientific productivity and increased likelihood of future NIH funding. (C) 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved. C1 [Lopez, Joseph; Ameri, Afshin; Susarla, Srinivas M.; Reddy, Sashank; Tong, J. W.; Lee, W. P. Andrew; Dorafshar, Amir] Johns Hopkins Univ Hosp, Dept Plast & Reconstruct Surg, Baltimore, MD 21287 USA. [Amini, Neda; Ahmed, Rizwan] Johns Hopkins Univ Hosp, Dept Gen Surg, Baltimore, MD 21287 USA. [Soni, Ashwin] Univ Washington, Med Ctr, Div Plast Surg, Seattle, WA 98195 USA. [May, James W., Jr.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Dorafshar, A (reprint author), Univ Maryland, Med Ctr, Johns Hopkins Hosp, Dept Plast Surg, 601 N,Caroline St, Baltimore, MD 21287 USA. EM adorafs1@jhmi.edu OI Lopez, Joseph/0000-0001-8723-6347; Susarla, Srinivas/0000-0003-0155-8260 NR 37 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 1931-7204 EI 1878-7452 J9 J SURG EDUC JI J. Surg. Educ. PD MAY-JUN PY 2016 VL 73 IS 3 BP 422 EP 428 DI 10.1016/j.jsurg.2015.12.001 PG 7 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA DK0PN UT WOS:000374614800011 PM 26796512 ER PT J AU Cadish, LA Fung, V Lane, FL Campbell, EG AF Cadish, Lauren A. Fung, Vicki Lane, Felicia L. Campbell, Eric G. TI Surgical Case Logging Habits and Attitudes: A Multispecialty Survey of Residents SO JOURNAL OF SURGICAL EDUCATION LA English DT Article DE case log; resident preparedness; ACGME AB OBJECTIVE: The Accreditation Council for Graduate Medical Education measures surgical residents' experience in the United States by mandating that residents log each procedure in which they have participated. This system is the primary mechanism by which breadth and depth of surgical training are. documented, and data are used for program accreditation and by individual program directors to assess resident preparedness. The study objective was to learn from residents across surgical specialties how this system is being used, and whether they believe these data are reliable. DESIGN: Investigators developed and administered a voluntary, 45-item survey. Resident demographic data, program details, logging behaviors, and attitudes were examined using descriptive statistics. Authors used multivariate logistic regression to assess respondent and program characteristics associated with logging habits. SETTING: The survey was administered at a large academic medical center. PARTICIPANTS: All general surgery, obstetrics and gynecology, orthopedics, urology, neurosurgery, otolaryngology, and plastic surgery residents were eligible. Of 126 surgical residents, 82 participated, yielding a response rate of 65%. RESULTS: Overall, 7.5% considered the case log system highly inaccurate, 28.8% somewhat inaccurate, 52.5% somewhat accurate, and 11.3% highly accurate. Nearly half (48.1%) use an incorrect metric to log their role as surgeon or assistant. Half logged monthly or less frequently. The longest time residents reported falling behind ranged from less than a week to more than a year, with about half (51.4%) reporting backlogs of 3 months or longer. Approximately two-thirds considered the system difficult to navigate (64.2%) and burdensome (68.8%). Departmental training and reminders to log were associated with high fidelity logging habits. CONCLUSIONS: Inconsistency of logging habits and perceived lack of accuracy raise concerns about use of the system for assessing surgical preparedness or accrediting training programs. Academic departments playing an active role may benefit from more reliable data to guide improvements in surgical training. (C) 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved. C1 [Cadish, Lauren A.; Lane, Felicia L.] Univ Calif Irvine, Med Ctr, Div Female Pelv Med & Reconstruct Surg, Dept Obstet & Gynecol, 101 City Dr,Bldg 56,Suite 800, Orange, CA 92868 USA. [Fung, Vicki; Campbell, Eric G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mongan Inst Hlth Policy, Boston, MA USA. [Fung, Vicki; Campbell, Eric G.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Cadish, LA (reprint author), Univ Calif Irvine, Med Ctr, Div Female Pelv Med & Reconstruct Surg, Dept Obstet & Gynecol, 101 City Dr,Bldg 56,Suite 800, Orange, CA 92868 USA. EM lcadish@uci.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-7204 EI 1878-7452 J9 J SURG EDUC JI J. Surg. Educ. PD MAY-JUN PY 2016 VL 73 IS 3 BP 474 EP 481 DI 10.1016/j.jsurg.2015.09.007 PG 8 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA DK0PN UT WOS:000374614800019 PM 27049679 ER PT J AU Goldberg, RB Temprosa, M Mele, L Orchard, T Mather, K Bray, G Horton, E Kitabchi, A Krakoff, J Marcovina, S Perreault, L White, N AF Goldberg, Ronald B. Temprosa, Marinella Mele, Lisa Orchard, Trevor Mather, Kieren Bray, George Horton, Edward Kitabchi, Abbas Krakoff, Jonathan Marcovina, Santica Perreault, Leigh White, Neil CA Diabet Prevention Program Res Grp TI Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the Diabetes Prevention Program SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Adiponectin; HDL; Lifestyle change; Metformin ID CARDIOVASCULAR RISK-FACTORS; LOW-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; INSULIN SENSITIVITY; ANTIGEN AB Objective. In addition to slowing diabetes development among participants in the Diabetes Prevention Program (DPP), intensive lifestyle change and metformin raised HDL-cholesterol (HDLC) compared to placebo treatment. We investigated the lifestyle and metabolic determinants as well as effects of biomarkers of inflammation, endothelial dysfunction and coagulation and their changes resulting from lifestyle and metformin interventions on the increase in HDL-C in the DPP. Methods. The effects of a 1 year period of intensive lifestyle change aimed at achieving 7% weight loss or metformin 850 mg twice daily versus placebo on HDL-C were assessed in 3070 participants with impaired glucose tolerance, and on HDL particle concentration (HDL-P) and size in a subgroup of 1645 individuals. Treatment-associated changes in lifestyle and metabolic factors as well as in novel biomarkers were investigated for their associations with change in HDL-C using multiple regression analysis. Results. After adjusting for BMI, insulin resistance, glycemia, dietary saturated fat, alcohol intake, physical activity and nine different biomarkers, only adiponectin accounted for the effect of intensive lifestyle change on HDL-C via an increase in large HDL-P. By contrast baseline and change in BMI and tissue plasminogen activator levels attenuated the effect of metformin on HDL-C, with adiponectin having no specific effect. Conclusion. While both lifestyle and metformin interventions used to prevent diabetes increase HDL-C, the mechanisms involved differ between the two treatments and may have consequences for future risk of cardiovascular disease. (C) 2016 Published by Elsevier Inc. C1 [Goldberg, Ronald B.] Univ Miami, Diabet Res Inst, 1450 NW 10th Ave,Suite 2054, Miami, FL 33136 USA. [Temprosa, Marinella; Mele, Lisa] George Washington Univ, Biostat Ctr, 6110 Executive Blvd,Suite 750, Rockville, MD 20852 USA. [Orchard, Trevor] Univ Pittsburgh, 3512 Fifth Ave, Pittsburgh, PA 15213 USA. [Mather, Kieren] Indiana Univ, Dept Med, 541 Clin Dr CL 365, Indianapolis, IN 46202 USA. [Bray, George] Louisiana State Univ, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Horton, Edward] Joslin Diabet Ctr, Sect Clin Behav & Outcomes Res, One Joslin Pl, Boston, MA 02215 USA. [Horton, Edward] Harvard Univ, Sch Med, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. [Kitabchi, Abbas] Univ Tennessee, Ctr Hlth Sci, Div Endocrinol, 920 Madison Ave Suite 300A, Memphis, TN 38163 USA. [Krakoff, Jonathan] NIDDKD, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. [Marcovina, Santica] Univ Washington, Northwest Lipid Res Labs, 401 Queen Anne Ave, North Seattle, WA 98109 USA. [Perreault, Leigh] Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Anschutz Med Campus,12801 E 17th Ave, Aurora, CO 80045 USA. [White, Neil] Washington Univ, Sch Med, 660 South Euclid Aye, St Louis, MO 63110 USA. RP Goldberg, RB (reprint author), George Washington Univ, Diabet Prevent Program, Coordinating Ctr, Biostat Ctr, 6110 Executive Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@bsc.gwu.edu OI orchard, trevor/0000-0001-9552-3215 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK048489] FX National Institute of Diabetes and Digestive and Kidney Diseases (DK048489) NR 31 TC 3 Z9 3 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD MAY PY 2016 VL 65 IS 5 BP 764 EP 775 DI 10.1016/j.metabol.2015.11.011 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK1ZI UT WOS:000374714000015 PM 27085783 ER PT J AU Howe, AS Buttenschon, HN Bani-Fatemi, A Maron, E Otowa, T Erhardt, A Binder, EB Gregersen, NO Mors, O Woldbye, DP Domschke, K Reif, A Shlik, J Koks, S Kawamura, Y Miyashita, A Kuwano, R Tokunaga, K Tanii, H Smoller, JW Sasaki, T Koszycki, D De Luca, V AF Howe, A. S. Buttenschon, H. N. Bani-Fatemi, A. Maron, E. Otowa, T. Erhardt, A. Binder, E. B. Gregersen, N. O. Mors, O. Woldbye, D. P. Domschke, K. Reif, A. Shlik, J. Koks, S. Kawamura, Y. Miyashita, A. Kuwano, R. Tokunaga, K. Tanii, H. Smoller, J. W. Sasaki, T. Koszycki, D. De Luca, V. TI Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways SO MOLECULAR PSYCHIATRY LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; SEROTONIN TRANSPORTER GENE; CHOLECYSTOKININ-B-RECEPTOR; GENDER-SPECIFIC ASSOCIATION; GENOME-WIDE ASSOCIATION; ENVIRONMENTAL RISK-FACTORS; NEUROTROPHIC-FACTOR GENE; CONVERTING-ENZYME ACE; ANXIETY DISORDERS; JAPANESE POPULATION AB The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.15-1.40, P = 2.49 x 10(-6)), rs11060369 (CC genotype: OR = 0.65, 95% CI: 0.53-0.79, P = 1.81 x 10(-5)) and COMT rs4680 (Val (G) allele: OR = 1.27, 95% CI: 1.14-1.42, P = 2.49 x 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR = 1.22, 95% CI: 1.07-1.38, P = 0.002), TPH1 rs1800532 (AA genotype: OR = 1.46, 95% CI: 1.14-1.89, P = 0.003) and HTR2A rs6313 (T allele: OR = 1.19, 95% CI: 1.07-1.33, P = 0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR = 1.21, 95% CI: 1.07-1.38, P = 0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD. C1 [Howe, A. S.; Bani-Fatemi, A.; De Luca, V.] Ctr Addict & Mental Hlth, Neurogenet Dept, 250 Coll St, Toronto, ON M5T 1R8, Canada. [Buttenschon, H. N.; Gregersen, N. O.] Aarhus Univ, Dept Clin Med, Translat Neuropsychiat Unit, Risskov, Denmark. [Buttenschon, H. N.; Gregersen, N. O.; Mors, O.] Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark. [Maron, E.] Univ London Imperial Coll Sci Technol & Med, Dept Neuropsychopharmacol & Mol Imaging, London, England. [Maron, E.] Univ Tartu, Dept Psychiat, Ulikooli 18, EE-50090 Tartu, Estonia. [Otowa, T.] Univ Tokyo, Grad Sch Med, Dept Neuropsychiat, Tokyo, Japan. [Erhardt, A.; Binder, E. B.] Max Planck Inst Psychiat, Munich, Germany. [Mors, O.] Aarhus Univ Hosp, Res Dept P, Risskov, Denmark. [Woldbye, D. P.] Univ Copenhagen, Dept Neurosci & Pharmacol, Lab Neuroplast, Copenhagen, Denmark. [Domschke, K.] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97070 Wurzburg, Germany. [Reif, A.] Goethe Univ Frankfurt, Dept Psychiat Psychosomat & Psychotherapy, D-60054 Frankfurt, Germany. [Shlik, J.] Univ Ottawa, Dept Psychiat, Ottawa, ON K1N 6N5, Canada. [Koks, S.] Univ Tartu, Dept Physiol, Ulikooli 18, EE-50090 Tartu, Estonia. [Kawamura, Y.; Miyashita, A.] Sakae Seijinkai Hosp, Dept Psychiat, Yokohama, Kanagawa, Japan. [Kuwano, R.] Niigata Univ, Brain Res Inst, Dept Mol Genet, Ctr Bioresources, Niigata, Japan. [Tokunaga, K.] Univ Tokyo, Grad Sch Med, Dept Human Genet, Tokyo, Japan. [Tanii, H.] Mie Univ, Brain Sci & Anim Model Res Ctr, Grad Sch Med, Dept Psychiat,Div Neurosci, Tsu, Mie 514, Japan. [Smoller, J. W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Sasaki, T.] Univ Tokyo, Grad Sch Educ, Lab Hlth Educ, Tokyo, Japan. [Koszycki, D.] Univ Ottawa, Fac Educ Counselling, Ottawa, ON, Canada. [Koszycki, D.] Univ Ottawa, Fac Med Psychiat, Ottawa, ON, Canada. [Koszycki, D.] Hop Montfort, Inst Rech, Ottawa, ON, Canada. [De Luca, V.] Ctr Addict & Mental Hlth, Dept Psychiat, Toronto, ON, Canada. RP Howe, AS; De Luca, V (reprint author), Ctr Addict & Mental Hlth, Neurogenet Dept, 250 Coll St, Toronto, ON M5T 1R8, Canada. EM aaron.howe@camh.ca; vincenzo.deluca@camh.ca RI Koks, Sulev/H-3655-2015; OI Koks, Sulev/0000-0001-6087-6643; Buttenschon, Henriette/0000-0003-3800-9169 FU Deutsche Forschungsgemeinschaft (DFG) project C02 [SFB-TRR-58]; Deutsche Forschungsgemeinschaft (DFG) project Z02 [SFB-TRR-58]; Ministry of Education, Culture, Sports, Science and Technology of Japan [17019029, 21300242] FX We thank the following authors for additional data (and assistance) provided in their respective studies: Professor J Deckert, Dr YK Kim, Dr C Blaya, Dr J Samochowiec, Professor PA Saiz, Dr K Mouri, Dr B Kim, Dr K Annerbrink, Dr M Cengiz, Dr G Karacetin, Dr J Hettema, Professor B. Bandelow, Dr C Hohoff, Dr C Fehr, Dr E Shimizu, Dr T Kanazawa, Professor Y Inada, Dr B Bayoglu, Professor J Costas, Professor X Estvill, Professor K Koido, Professor H Weber, Professor M Weissman, Professor R Subaran, Dr A Fyer, PRISME group of Denmark, Dr AS Kristensen, Dr P Koefoed, AG Wang and The Biobank of the Faroe Islands. Professor K Domschke was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB-TRR-58, project C02. Professor Reif was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB-TRR-58, project Z02. Professor T Sasaki was supported by Grants-in-Aid for Scientific Research on Priority Areas 'Comprehensive Genomics' and 'Applied Genomics' (no. 17019029; no. 21300242) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 165 TC 5 Z9 5 U1 6 U2 12 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 MAY PY 2016 VL 21 IS 5 BP 665 EP 679 DI 10.1038/mp.2015.138 PG 15 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DJ6LH UT WOS:000374324000013 PM 26390831 ER PT J AU Reis, SA Ghosh, B Hendricks, JA Szantai-Kis, DM Tork, L Ross, KN Lamb, J Read-Button, W Zheng, BX Wang, HT Salthouse, C Haggarty, SJ Mazitschek, R AF Reis, Surya A. Ghosh, Balaram Hendricks, J. Adam Szantai-Kis, D. Miklos Tork, Lisa Ross, Kenneth N. Lamb, Justin Read-Button, Willis Zheng, Baixue Wang, Hongtao Salthouse, Christopher Haggarty, Stephen J. Mazitschek, Ralph TI Light-controlled modulation of gene expression by chemical optoepigenetic probes SO NATURE CHEMICAL BIOLOGY LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; HDAC INHIBITORS; OPTICAL CONTROL; TRANSCRIPTION; PHARMACOLOGY; ACETYLATION AB Epigenetic gene regulation is a dynamic process orchestrated by chromatin-modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small-molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatiotemporal control. Here we present a generalizable approach, referred to as 'chemo-optical modulation of epigenetically regulated transcription' (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may be translated into new therapeutic strategies for diseases where conditional and selective epigenome modulation is required. C1 [Reis, Surya A.; Ghosh, Balaram; Haggarty, Stephen J.] Massachusetts Gen Hosp, Chem Neurobiol Lab, Boston, MA 02114 USA. [Reis, Surya A.; Ghosh, Balaram; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Reis, Surya A.; Ghosh, Balaram; Haggarty, Stephen J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Ghosh, Balaram; Hendricks, J. Adam; Szantai-Kis, D. Miklos; Tork, Lisa; Mazitschek, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Ross, Kenneth N.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Lamb, Justin; Read-Button, Willis; Zheng, Baixue] Genometry Inc, Cambridge, MA USA. [Wang, Hongtao; Salthouse, Christopher] Univ Massachusetts, Dept Elect & Comp Engn, Amherst, MA 01003 USA. [Wang, Hongtao; Salthouse, Christopher] Univ Massachusetts, Ctr Personalized Hlth Monitoring, Amherst, MA 01003 USA. [Haggarty, Stephen J.; Mazitschek, Ralph] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Ghosh, Balaram] BITS Pilani, Dept Pharm, Hyderabad Campus, Hyderabad, Andhra Pradesh, India. RP Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Chem Neurobiol Lab, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA.; Mazitschek, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. EM shaggarty@mgh.harvard.edu; rmazitschek@mgh.harvard.edu OI Szantai-Kis, D. Miklos/0000-0001-5958-5478; Haggarty, Stephen J./0000-0002-7872-168X FU US National Institutes of Health [R01NS088209, P50CA086355, R01DA028301, T32-CA079443]; Tau Consortium; Bluefield Consortium for Frontotemporal Dementia; Pitt-Hopkins Research Foundation FX We thank members of the Haggarty and Mazitschek laboratories and T. Pezeril for their constructive feedback throughout the project. We acknowledge financial support from the US National Institutes of Health (R01NS088209 R.M. and S.J.H., P50CA086355 R.M., R01DA028301 S.J.H., T32-CA079443 J.A.H.). S.J.H. is supported through funding from the Tau Consortium, Bluefield Consortium for Frontotemporal Dementia and Pitt-Hopkins Research Foundation. The computations in this paper were run on the Odyssey cluster supported by the Faculty of Arts and Sciences, Division of Science, Research Computing Group at Harvard University. We thank S. Johnston for acquiring the high-resolution mass spectra, and members of the Arduino development team and the open-source Maker Movement. NR 38 TC 6 Z9 6 U1 6 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD MAY PY 2016 VL 12 IS 5 BP 317 EP + DI 10.1038/NCHEMBIO.2042 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ6KY UT WOS:000374322800005 PM 26974814 ER PT J AU Zhang, YJ Gendron, TF Grima, JC Sasaguri, H Jansen-West, K Xu, YF Katzman, RB Gass, J Murray, ME Shinohara, M Lin, WL Garrett, A Stankowski, JN Daughrity, L Tong, JM Perkerson, EA Yue, M Chew, J Castanedes-Casey, M Kurti, A Wang, ZZS Liesinger, AM Baker, JD Jiang, J Lagier-Tourenne, C Edbauer, D Cleveland, DW Rademakers, R Boylan, KB Bu, GJ Link, CD Dickey, CA Rothstein, JD Dickson, DW Fryer, JD Petrucelli, L AF Zhang, Yong-Jie Gendron, Tania F. Grima, Jonathan C. Sasaguri, Hiroki Jansen-West, Karen Xu, Ya-Fei Katzman, Rebecca B. Gass, Jennifer Murray, Melissa E. Shinohara, Mitsuru Lin, Wen-Lang Garrett, Aliesha Stankowski, Jeannette N. Daughrity, Lillian Tong, Jimei Perkerson, Emilie A. Yue, Mei Chew, Jeannie Castanedes-Casey, Monica Kurti, Aishe Wang, Zizhao S. Liesinger, Amanda M. Baker, Jeremy D. Jiang, Jie Lagier-Tourenne, Clotilde Edbauer, Dieter Cleveland, Don W. Rademakers, Rosa Boylan, Kevin B. Bu, Guojun Link, Christopher D. Dickey, Chad A. Rothstein, Jeffrey D. Dickson, Dennis W. Fryer, John D. Petrucelli, Leonard TI C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins SO NATURE NEUROSCIENCE LA English DT Article ID DIPEPTIDE-REPEAT PROTEINS; AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT; FRONTOTEMPORAL DEMENTIA; DNA-REPAIR; RNA FOCI; ANTISENSE TRANSCRIPTS; SQSTM1 MUTATIONS; GGGGCC REPEAT; NEURONAL LOSS AB Neuronal inclusions of poly(GA), a protein unconventionally translated from G(4)C(2) repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology. C1 [Zhang, Yong-Jie; Gendron, Tania F.; Sasaguri, Hiroki; Jansen-West, Karen; Xu, Ya-Fei; Katzman, Rebecca B.; Gass, Jennifer; Murray, Melissa E.; Shinohara, Mitsuru; Lin, Wen-Lang; Garrett, Aliesha; Stankowski, Jeannette N.; Daughrity, Lillian; Tong, Jimei; Perkerson, Emilie A.; Yue, Mei; Chew, Jeannie; Castanedes-Casey, Monica; Kurti, Aishe; Wang, Zizhao S.; Liesinger, Amanda M.; Rademakers, Rosa; Bu, Guojun; Dickson, Dennis W.; Fryer, John D.; Petrucelli, Leonard] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Grima, Jonathan C.; Rothstein, Jeffrey D.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. [Grima, Jonathan C.; Rothstein, Jeffrey D.] Johns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21218 USA. [Grima, Jonathan C.; Rothstein, Jeffrey D.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21218 USA. [Chew, Jeannie; Fryer, John D.] Mayo Clin, Coll Med, Mayo Grad Sch, Neurobiol Dis Grad Program, Rochester, MN USA. [Baker, Jeremy D.; Dickey, Chad A.] Univ S Florida, Coll Med, Dept Mol Med, Byrd Alzheimers Inst, Tampa, FL USA. [Jiang, Jie; Cleveland, Don W.] Univ Calif San Diego, Ludwig Inst, La Jolla, CA 92093 USA. [Lagier-Tourenne, Clotilde] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Edbauer, Dieter] German Ctr Neurodegenerat Dis DZNE, Munich, Germany. [Edbauer, Dieter] Univ Munich, Inst Metab Biochem, Munich, Germany. [Edbauer, Dieter] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Cleveland, Don W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Boylan, Kevin B.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Link, Christopher D.] Univ Colorado, Inst Behav Genet, Integrat Physiol, Boulder, CO 80309 USA. RP Petrucelli, L (reprint author), Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. EM petrucelli.leonard@mayo.edu OI Murray, Melissa/0000-0001-7379-2545 FU US National Institutes of Health (NIH) National Institute on Aging [R01AG026251]; NIH National Institute of Neurological Disorders and Stroke [R21NS079807, R21NS089979, F32NS087842, R01NS080882, R01NS085207, U54NS091046, R01NS063964, R01NS077402, R21NS084528, P01NS084974, R01NS088689]; National Institute of Environmental Health Services [R01ES20395]; Department of Defense (ALSRP) [AL130125]; Mayo Clinic Foundation; Mayo Clinic Center for Individualized Medicine; Alzheimer's Association [NIRP-14-304425, NIRP-12-259289]; Amyotrophic Lateral Sclerosis Association; Robert Packard Center for ALS Research at Johns Hopkins; Target ALS; Brain Science Institute; Ludwig Institute for Cancer Research; European Union [617198]; National Science Foundation Graduate Research Fellowship Award; Thomas Shortman Training Fund Graduate Scholarship; Axol Science Scholarship FX We are grateful to all patients who agreed to donate post-mortem tissue. This work was supported by the US National Institutes of Health (NIH) National Institute on Aging (R01AG026251 (L.P.)); NIH National Institute of Neurological Disorders and Stroke (R21NS079807 (Y.-J.Z. and J.D.F.); R21NS089979 (T.F.G. and K.B.B.); F32NS087842 (J.J.); R01NS080882 (R.R.); R01NS085207 (J.D.R.); U54NS091046 (J.D.R.); R01NS063964 (L.P.); R01NS077402 (L.P.), R21NS084528 (L.P.); P01NS084974 (L.P., D.D., K.B.B. and R.R.); R01NS088689 (L.P.)); National Institute of Environmental Health Services (R01ES20395 (L.P.); Department of Defense (ALSRP AL130125 (L.P.)); Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Individualized Medicine (L.P. and K.B.B.); Alzheimer's Association (NIRP-14-304425 (Y.-J.Z.); NIRP-12-259289 (J.D.F.)); Amyotrophic Lateral Sclerosis Association (Y.-J.Z., T.F.G., K.B.B., D.W.C. and L.P.); Robert Packard Center for ALS Research at Johns Hopkins (J.D.R. and L.P.), Target ALS (C.L.-T., J.D.R. and L.P.); Brain Science Institute (J.D.R.); the Ludwig Institute for Cancer Research (D.W.C. and C.L.T.), and the European Union's Seventh Framework Programme (FP7/2014-2019 grant 617198 (D.E.)). J.C.G. is the recipient of a National Science Foundation Graduate Research Fellowship Award, a Thomas Shortman Training Fund Graduate Scholarship and an Axol Science Scholarship. NR 57 TC 18 Z9 18 U1 5 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAY PY 2016 VL 19 IS 5 BP 668 EP + DI 10.1038/nn.4272 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DK2RM UT WOS:000374762100006 PM 26998601 ER PT J AU Cosker, KE Fenstermacher, SJ Pazyra-Murphy, MF Elliott, HL Segal, RA AF Cosker, Katharina E. Fenstermacher, Sara J. Pazyra-Murphy, Maria F. Elliott, Hunter L. Segal, Rosalind A. TI The RNA-binding protein SFPQ orchestrates an RNA regulon to promote axon viability SO NATURE NEUROSCIENCE LA English DT Article ID NERVE GROWTH-FACTOR; MESSENGER-RNA; LOCAL TRANSLATION; MOLECULAR MOTORS; SPLICING FACTORS; GENE-REGULATION; COMPLEX; LOCALIZATION; NEURONS; PSF AB To achieve accurate spatiotemporal patterns of gene expression, RNA-binding proteins (RBPs) guide nuclear processing, intracellular trafficking and local translation of target mRNAs. In neurons, RBPs direct transport of target mRNAs to sites of translation in remote axons and dendrites. However, it is not known whether an individual RBP coordinately regulates multiple mRNAs within these morphologically complex cells. Here we identify SFPQ (splicing factor, poly-glutamine rich) as an RBP that binds and regulates multiple mRNAs in dorsal root ganglion sensory neurons and thereby promotes neurotrophin-dependent axonal viability. SFPQ acts in nuclei, cytoplasm and axons to regulate functionally related mRNAs essential for axon survival. Notably, SFPQ is required for coassembly of LaminB2 (Lmnb2) and Bclw (Bcl2l2) mRNAs in RNA granules and for axonal trafficking of these mRNAs. Together these data demonstrate that SFPQ orchestrates spatial gene expression of a newly identified RNA regulon essential for axonal viability. C1 [Cosker, Katharina E.; Fenstermacher, Sara J.; Pazyra-Murphy, Maria F.; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Cosker, Katharina E.; Fenstermacher, Sara J.; Pazyra-Murphy, Maria F.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Elliott, Hunter L.] Harvard Univ, Sch Med, Image & Data Anal Core, Boston, MA USA. RP Segal, RA (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA.; Segal, RA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM rosalind_segal@dfci.harvard.edu FU US National Institutes of Health [R01 NS050674, R01 MH091662, F31 NS077620]; Harvard/MIT Joint Research Program in Basic Neuroscience Grant; Harvard Mahoney; Harvard NeuroDiscovery Center; Alice and Joseph E. Brooks fund; Victoria Quan fund FX We thank members of the Segal laboratory, A. Eisner, M. McClintock and M. Greenberg for discussions, and G. McGregor (University of California, Irvine) for providing Bcl2l2-/- mice. This work was supported by US National Institutes of Health grants R01 NS050674 and R01 MH091662 to R.A.S. and F31 NS077620 to S.J.F.; Harvard/MIT Joint Research Program in Basic Neuroscience Grant to R.A.S. and M. Heiman; fellowships from the Harvard Mahoney, the Harvard NeuroDiscovery Center and the Alice and Joseph E. Brooks fund to K.E.C.; and a fellowship from the Victoria Quan fund to S.J.F. NR 50 TC 4 Z9 4 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAY PY 2016 VL 19 IS 5 BP 690 EP + DI 10.1038/nn.4280 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DK2RM UT WOS:000374762100008 PM 27019013 ER PT J AU Hayakawa, Y Sethi, N Sepulveda, AR Bass, AJ Wang, TC AF Hayakawa, Yoku Sethi, Nilay Sepulveda, Antonia R. Bass, Adam J. Wang, Timothy C. TI Oesophageal adenocarcinoma and gastric cancer: should we mind the gap? SO NATURE REVIEWS CANCER LA English DT Review ID HELICOBACTER-PYLORI INFECTION; STEM-CELL MARKER; BODY-MASS INDEX; POLYPEPTIDE-EXPRESSING METAPLASIA; LINEAGE-SURVIVAL ONCOGENES; HIGH-GRADE DYSPLASIA; PUMP INHIBITOR USE; BARRETTS-ESOPHAGUS; INTESTINAL METAPLASIA; GASTROESOPHAGEAL-REFLUX AB Over recent decades we have witnessed a shift in the anatomical distribution of gastric cancer (GC), which increasingly originates from the proximal stomach near the junction with the oesophagus. In parallel, there has been a dramatic rise in the incidence of oesophageal adenocarcinoma (OAC) in the lower oesophagus, which is associated with antecedent Barrett oesophagus (BO). In this context, there has been uncertainty regarding the characterization of adenocarcinomas spanning the area from the lower oesophagus to the distal stomach. Most relevant to this discussion is the distinction, if any, between OAC and intestinal-type GC of the proximal stomach. It is therefore timely to review our current understanding of OAC and intestinal-type GC, integrating advances from cell-of-origin studies and comprehensive genomic alteration analyses, ultimately enabling better insight into the relationship between these two cancers. C1 [Hayakawa, Yoku; Wang, Timothy C.] Columbia Univ Coll Phys & Surg, Div Digest & Liver Dis, 1130 St Nicholas Ave, New York, NY 10032 USA. [Hayakawa, Yoku; Wang, Timothy C.] Columbia Univ Coll Phys & Surg, Herbert Irving Canc Res Ctr, 1130 St Nicholas Ave, New York, NY 10032 USA. [Sethi, Nilay; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Sepulveda, Antonia R.] Columbia Univ Coll Phys & Surg, Dept Pathol, Div Clin Pathol & Cell Biol, 630 W 168th St, New York, NY 10032 USA. RP Wang, TC (reprint author), Columbia Univ Coll Phys & Surg, Div Digest & Liver Dis, 1130 St Nicholas Ave, New York, NY 10032 USA.; Wang, TC (reprint author), Columbia Univ Coll Phys & Surg, Herbert Irving Canc Res Ctr, 1130 St Nicholas Ave, New York, NY 10032 USA.; Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM adam_bass@dfci.harvard.edu; tcw21@columbia.edu NR 195 TC 5 Z9 5 U1 4 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAY PY 2016 VL 16 IS 5 BP 305 EP 318 DI 10.1038/nrc.2016.24 PG 14 WC Oncology SC Oncology GA DK2RV UT WOS:000374763000006 PM 27112208 ER PT J AU Clocchiatti, A Cora, E Zhang, Y Dotto, GP AF Clocchiatti, Andrea Cora, Elisa Zhang, Yosra Dotto, G. Paolo TI Sexual dimorphism in cancer SO NATURE REVIEWS CANCER LA English DT Review ID ESTROGEN-RECEPTOR-BETA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CELL LUNG-CANCER; EPITHELIAL OVARIAN-CANCER; CHRONIC MYELOID-LEUKEMIA; Y-CHROMOSOME GENES; ANDROGEN RECEPTOR; PROSTATE-CANCER; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA AB The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment. C1 [Clocchiatti, Andrea; Zhang, Yosra; Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Cora, Elisa; Zhang, Yosra; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. RP Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA.; Dotto, GP (reprint author), Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. EM paolo.dotto@unil.ch FU Swiss National Science Foundation [310030_156191/1]; US National Institutes of Health (NIH) [R01AR039190, R01AR064786]; European Research Council [26075083]; OncoSuisse [OCS-2922-02-2012]; AIRC-EU FP7 Marie Curie Fellowship - Italian Association for Cancer Research; European Union FP7 Marie Curie Program FX This work was supported by grants from Swiss National Science Foundation (310030_156191/1), US National Institutes of Health (NIH; R01AR039190; R01AR064786; the content not necessarily representing the official views of NIH), European Research Council (26075083) and OncoSuisse (OCS-2922-02-2012). A.C. is supported by an AIRC-EU FP7 Marie Curie Fellowship granted by the Italian Association for Cancer Research and the European Union FP7 Marie Curie Program. NR 189 TC 5 Z9 5 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAY PY 2016 VL 16 IS 5 BP 330 EP 339 DI 10.1038/nrc.2016.30 PG 10 WC Oncology SC Oncology GA DK2RV UT WOS:000374763000008 PM 27079803 ER PT J AU Ambroggio, L Test, M Metlay, JP Graf, TR Blosky, MA Macaluso, M Shah, SS AF Ambroggio, Lilliam Test, Matthew Metlay, Joshua P. Graf, Thomas R. Blosky, Mary Ann Macaluso, Maurizio Shah, Samir S. TI Beta-lactam versus beta- lactam/macrolide therapy in pediatric outpatient pneumonia SO PEDIATRIC PULMONOLOGY LA English DT Article DE pneumonia; child; pediatric; comparative effectiveness research; pneumonia bacterial; amoxicillin ID COMMUNITY-ACQUIRED-PNEUMONIA; RESISTANT STREPTOCOCCUS-PNEUMONIAE; MYCOPLASMA-PNEUMONIAE; PROPENSITY SCORES; ORAL AMOXICILLIN; CHILDREN OLDER; CLARITHROMYCIN; BACTEREMIA; GUIDELINES; MANAGEMENT AB ObjectiveThe objective was to evaluate the comparative effectiveness of beta-lactam monotherapy and beta- lactam/macrolide combination therapy in the outpatient management of children with community-acquired pneumonia (CAP). MethodsThis retrospective cohort study included children, ages 1-18 years, with CAP diagnosed between January 1, 2008 and January 31, 2010 during outpatient management in the Geisinger Health System. The primary exposure was receipt of beta-lactam monotherapy or beta-lactam/macrolide combination therapy. The primary outcome was treatment failure, defined as a follow-up visit within 14 days of diagnosis resulting in a change in antibiotic therapy. Logistic regression within a propensity score- restricted cohort was used to estimate the likelihood of treatment failure. ResultsOf 717 children in the analytical cohort, 570 (79.4%) received beta-lactam monotherapy and 147 (20.1%) received combination therapy. Of those who received combination therapy 58.2% of children were under 6 years of age. Treatment failure occurred in 55 (7.7%) children, including in 8.1% of monotherapy recipients, and 6.1% of combination therapy recipients. Treatment failure rates were highest in children 6-18 years receiving monotherapy (12.9%) and lowest in children 6-18 years receiving combination therapy (4.0%). Children 6-18 years of age who received combination therapy were less likely to fail treatment than those who received beta-lactam monotherapy (propensity-adjusted odds ratio, 0.51; 95% confidence interval, 0.28, 0.95). ConclusionChildren 6-18 years of age who received beta- lactam/macrolide combination therapy for CAP in the outpatient setting had lower odds of treatment failure compared with those who received beta-lactam monotherapy. Pediatr Pulmonol. 2016;51:541-548. (c) 2015 Wiley Periodicals, Inc. C1 [Ambroggio, Lilliam; Test, Matthew; Shah, Samir S.] Cincinnati Childrens Hosp Med Ctr, Div Hosp Med, Cincinnati, OH 45229 USA. [Ambroggio, Lilliam; Macaluso, Maurizio] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Ambroggio, Lilliam; Macaluso, Maurizio; Shah, Samir S.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Graf, Thomas R.] Geisinger Hlth Syst, Populat Hlth, Danville, PA USA. [Blosky, Mary Ann] Geisinger Hlth Syst, Ctr Hlth Res, Danville, PA USA. [Shah, Samir S.] Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. RP Ambroggio, L (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,ML 9016, Cincinnati, OH 45229 USA. EM Lilliam.Ambroggio@cchmc.org RI Macaluso, Maurizio/J-2076-2015; OI Macaluso, Maurizio/0000-0002-2977-9690; Ambroggio, Lilliam/0000-0002-6242-607X NR 36 TC 2 Z9 2 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD MAY PY 2016 VL 51 IS 5 BP 541 EP 548 DI 10.1002/ppul.23312 PG 8 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA DJ6ES UT WOS:000374303600014 PM 26367389 ER PT J AU Zhang, TW Dutton-Regester, K Brown, KM Hayward, NK AF Zhang, Tongwu Dutton-Regester, Ken Brown, Kevin M. Hayward, Nicholas K. TI The genomic landscape of cutaneous melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE exome sequencing; genomics; melanoma; mutation; ultraviolet radiation; driver gene ID TERT PROMOTER MUTATIONS; BASAL-CELL CARCINOMA; MALIGNANT-MELANOMA; SOMATIC MUTATIONS; FAMILIAL MELANOMA; WIDE ASSOCIATION; METASTATIC MELANOMA; SUSCEPTIBILITY LOCI; SEQUENCE VARIANTS; UVEAL MELANOMA AB Somatic mutation analysis of melanoma has been performed at the single gene level extensively over the past several decades. This has provided considerable insight into the critical pathways controlling melanoma initiation and progression. During the last 5yr, next-generation sequencing (NGS) has enabled even more comprehensive mutational screening at the level of multigene panels, exomes and genomes. These studies have uncovered many new and unexpected players in melanoma development. The recent landmark study from The Cancer Genome Atlas (TCGA) consortium describing the genomic architecture of 333 cutaneous melanomas provides the largest and broadest analysis to date on the somatic aberrations underlying melanoma genesis. It thus seems timely to review the mutational landscape of melanoma and highlight the key genes and cellular pathways that appear to drive this cancer. C1 [Zhang, Tongwu; Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dutton-Regester, Ken] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA. [Dutton-Regester, Ken] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dutton-Regester, Ken; Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Oncogen Lab, Herston, Qld, Australia. RP Hayward, NK (reprint author), QIMR Berghofer Med Res Inst, Oncogen Lab, Herston, Qld, Australia. EM nick.hayward@qimrberghofer.edu.au NR 122 TC 11 Z9 11 U1 4 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAY PY 2016 VL 29 IS 3 BP 266 EP 283 DI 10.1111/pcmr.12459 PG 18 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA DK1TH UT WOS:000374696700006 PM 26833684 ER PT J AU Thermenos, HW Juelich, RJ DiChiara, SR Mesholam-Gately, RI Woodberry, KA Wojcik, J Makris, N Keshavan, MS Whitfield-Gabrieli, S Woo, TUW Petryshen, TL Goldstein, JM Shenton, ME McCarley, RW Seidman, LJ AF Thermenos, Heidi W. Juelich, Richard J. DiChiara, Samantha R. Mesholam-Gately, Raquelle I. Woodberry, Kristen A. Wojcik, Joanne Makris, Nikos Keshavan, Matcheri S. Whitfield-Gabrieli, Susan Woo, Tsung-Ung W. Petryshen, Tracey L. Goldstein, Jill M. Shenton, Martha E. McCarley, Robert W. Seidman, Larry J. TI Hyperactivity of caudate, parahippocampal, and prefrontal regions during working memory in never-medicated persons at clinical high-risk for psychosis SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Psychosis; Prodrome; fMRI; Clinical high risk; Working memory ID MEDIAL TEMPORAL-LOBE; ULTRA-HIGH-RISK; ALTERED BRAIN ACTIVATION; SHORT-TERM-MEMORY; MENTAL STATE; BASAL GANGLIA; 1ST EPISODE; NEUROANATOMICAL ABNORMALITIES; HIPPOCAMPAL-FORMATION; ACTIVE MAINTENANCE AB Background: Deficits in working memory (WM) are a core feature of schizophrenia (SZ) and other psychotic disorders. We examined brain activity during WM in persons at clinical high risk (CHR) for psychosis. Methods: Thirty-seven CHR and 34 healthy control participants underwent functional MRI (fMRI) on a 3.0 T scanner while performing an N-back WM task. The sample included a sub-sample of CHR participants who had no lifetime history of treatment with psychotropic medications (n = 11). Data were analyzed using SPM8 (2-back > 0-back contrast). Pearson correlations between brain activity, symptoms, and WM performance were examined. Results: The total CHR group and medication-naive CHR sub-sample were comparable to controls in most demographic features and in N-back WM performance, but had significantly lower IQ. Relative to controls, medication naive CHR showed hyperactivity in the left parahippocampus (PHP) and the left caudate during performance of the N-back WM task. Relative to medication-exposed CHR, medication naive CHR exhibited hyperactivity in the left caudate and the right dorsolateral prefrontal cortex (DLPFC). DLPFC activity was significantly negatively correlated with WM performance. PHP, caudate and DLPFC activity correlated strongly with symptoms, but results did not withstand FDR-correction for multiple comparisons. When all CHR participants were combined (regardless of medication status), only trend-level PHP hyperactivity was observed in CHR relative to controls. Conclusions: Medication-naive CHR exhibit hyperactivity in regions that subserve WM. These regions are implicated in studies of schizophrenia and risk for psychosis. Results emphasize the importance of medication status in the interpretation of task - induced brain activity. (C) 2016 Elsevier B.V. All rights reserved. C1 [Thermenos, Heidi W.; Juelich, Richard J.; DiChiara, Samantha R.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Wojcik, Joanne; Keshavan, Matcheri S.; Woo, Tsung-Ung W.; Petryshen, Tracey L.; Goldstein, Jill M.; Shenton, Martha E.; McCarley, Robert W.; Seidman, Larry J.] Harvard Univ, Sch Med, Boston, MA USA. [Thermenos, Heidi W.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Wojcik, Joanne; Keshavan, Matcheri S.; Woo, Tsung-Ung W.; Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Div Publ Psychiat, Boston, MA 02215 USA. [Thermenos, Heidi W.; DiChiara, Samantha R.; Makris, Nikos; Petryshen, Tracey L.; Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Juelich, Richard J.] McLean Hosp, Dept Psychiat, 115 Mill St, Belmont, MA 02178 USA. [Whitfield-Gabrieli, Susan] MIT, McGovern Inst Brain Res, Poitras Ctr Affect Disorders Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Woo, Tsung-Ung W.] McLean Hosp, Lab Cellular Neuropathol, 115 Mill St, Belmont, MA 02178 USA. [Goldstein, Jill M.] Brigham & Womens Hosp, Dept Med, Dept Psychiat, Div Womens Hlth,Connors Ctr Womens Hlth & Gender, 75 Francis St, Boston, MA 02115 USA. [Shenton, Martha E.; McCarley, Robert W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Shenton, Martha E.; McCarley, Robert W.] VA Boston Healthcare Syst, Brockton, MA USA. RP Thermenos, HW (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,2nd Floor,Room 2602E,13th St, Charlestown, MA 02129 USA. EM hthermen@bidmc.harvard.edu FU NCRR NIH HHS [S10 RR023401, 1S10RR019307, 1S10RR023043, 1S10RR023401, M01 RR001032, M01RR01032, P41 RR014075, P41RR14075, S10 RR019307, S10 RR021110, S10 RR023043, S10RR021110, UL1 RR025758, UL1RR025758]; NIBIB NIH HHS [P41 EB015896, P41EB015896]; NIMH NIH HHS [K23 MH102358, P50 MH080272, P50MH080272, U01 MH081928, UO1 MH081928] NR 117 TC 0 Z9 0 U1 5 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAY PY 2016 VL 173 IS 1-2 BP 1 EP 12 DI 10.1016/j.schres.2016.02.023 PG 12 WC Psychiatry SC Psychiatry GA DK6SN UT WOS:000375055600001 PM 26965745 ER PT J AU Stagner, AM Jakobiec, FA Freitag, SK AF Stagner, Anna M. Jakobiec, Frederick A. Freitag, Suzanne K. TI Primary cutaneous extranodal marginal zone B-cell lymphoma of the eyelid skin: Diagnostic clues and distinction from other ocular adnexal diseases SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE eyelid; cutaneous; marginal zone; lymphoma; B cell; MALT ID T-CELL; MYCOSIS-FUNGOIDES; FOLLICULAR LYMPHOMA; INVOLVEMENT; CONJUNCTIVA; PAPULOSIS; ORBIT AB A 60-year-old man developed a rubbery thickening and erythema of his left lateral upper and lower eyelids and lateral canthus over several months. He was treated for an extended period of time for blepharitis and chalazia. Incisional biopsy eventually disclosed microscopically a hypercellular lymphoid population sparing the epidermis that surrounded adnexal structures and infiltrated between orbicularis muscle fibers. Immunohistochemically, the lesion was found to be composed of neoplastic, kappa-restricted B cells with an equal number of reactive T cells and small reactive follicles. The diagnosis was a primary cutaneous extranodal marginal zone B-cell lymphoma of the eyelid skin (EMZL). We review the distinguishing clinical, histopathologic, and immunohistochemical features of cutaneous EMZL and contrast those with EMZL of other ocular adnexal sites. Also offered is a differential diagnosis of cutaneous lymphomas of the eyelid skin, which are predominately T-cell lesions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Stagner, Anna M.; Jakobiec, Frederick A.; Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Suite 328,243 Charles St, Boston, MA 02114 USA. [Stagner, Anna M.; Jakobiec, Frederick A.; Freitag, Suzanne K.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Suite 328,243 Charles St, Boston, MA 02114 USA. EM Fred_jakobiec@meei.harvard.edu NR 23 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 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD MAY-JUN PY 2016 VL 61 IS 3 BP 333 EP 338 DI 10.1016/j.survophthal.2015.10.007 PG 6 WC Ophthalmology SC Ophthalmology GA DK0PT UT WOS:000374615400007 PM 26545575 ER PT J AU Jakobiec, FA Thanos, A Stagner, AM Grossniklaus, HE Proia, AD AF Jakobiec, Frederick A. Thanos, Aristomenis Stagner, Anna M. Grossniklaus, Hans E. Proia, Alan D. TI So-called massive retinal gliosis: A critical review and reappraisal SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE massive retinal gliosis; phthisis bulbi; astrocyte; Muller cell; retinal tumor ID GIANT-CELL ASTROCYTOMA; VASOPROLIFERATIVE TUMORS; CLINICOPATHOLOGIC CORRELATION; TUBEROUS SCLEROSIS; MALIGNANT-MELANOMA; CHOROIDAL MELANOMA; REACTIVE GLIOSIS; CILIARY BODY; EXPRESSION; PROLIFERATION AB Massive retinal gliosis, a nonneoplastic retinal glial proliferation, was first described in detail over 25 years ago, before the era of immunohistochemistry, in a series of 38 cases to which can be added 30 case reports or small series (no more than 3 cases) subsequently. We analyze a new series of 3 nontumoral intraretinal glioses and 15 cases of tumoral retinal gliosis, not all of which, strictly speaking, were massive. The data from this series are compared with the findings in previously published cases. Included are 2 cases of massive retinal gliosis diagnosed from evisceration specimens. In reviewing all published and current cases, we were able to establish 3 subgroups of retinal tumoral glioses rather than a single "massive" category: focal nodular gliosis, submassive gliosis, and massive gliosis. Among 43 reported cases, including the present series, but excluding the previous large series of 38 cases in which substantial clinical data were omitted, there were 19 men and 24 women. Their mean and median ages were 36.2 years and 36 years, respectively, with a range of 2 to 79 years. All lesions were composed of mitotically quiet, compact spindled fibrous astrocytes devoid of an Alcian blue-positive myxoid matrix. The most common associated ocular conditions were phthisis bulbi and congenital diseases or malformations. Histopathologically, all 3 tumoral categories were accompanied by progressively more extensive fibrous and osseous metaplasia of the pigment epithelium, the latter forming a clinically and diagnostically useful, almost continuous, outer rim of eggshell calcification in the sub massive and massive categories that should be detectable with appropriate imaging studies. In decreasing order of frequency, microcysts and macrocysts, vascular sclerosis, exudates, calcospherites, and Rosenthal fibers were observed among the proliferating fibrous astrocytes. Immunohistochemistry was positive for glial fibrillary acidic protein in all cases and nestin in most (an intermediate cytoplasmic filament typically restricted to embryonic and reparative neural tissue). The nonneoplastic nature of all categories of gliosis was confirmed by absent TP53 (tumor suppressor gene) dysregulation, Ki-67 negativity, and intact p16 expression (the protein product of the p16 tumor suppressor gene) in the overwhelming majority of cases. These findings indicate an intrinsic attempt to regulate and maintain a low level of glial cell proliferation that becomes unsuccessful as the disease evolves. The categories of tumoral proliferation appeared to constitute a spectrum. We conclude that focal nodular tumors encompass lesions previously called retinal vasoproliferative lesions, which display the same histopathologic and immunohistochemical findings as 3 major categories of retinal gliosis characterized herein. (C) 2016 Elsevier Inc. All rights reserved. C1 [Jakobiec, Frederick A.; Stagner, Anna M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol,Dept Ophthalmol, Boston, MA USA. [Jakobiec, Frederick A.; Thanos, Aristomenis; Stagner, Anna M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Grossniklaus, Hans E.] Emory Eye Ctr, Dept Ophthalmol, LF Montgomery Pathol Lab, Atlanta, GA USA. [Proia, Alan D.] Duke Univ, Dept Pathol, Durham, NC 27706 USA. [Proia, Alan D.] Duke Univ, Dept Ophthalmol, Durham, NC USA. RP Jakobiec, FA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Ophthalm Pathol Lab, 243 Charles St,Suite 328, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 76 TC 1 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD MAY-JUN PY 2016 VL 61 IS 3 BP 339 EP 356 DI 10.1016/j.survophthal.2015.12.002 PG 18 WC Ophthalmology SC Ophthalmology GA DK0PT UT WOS:000374615400008 PM 26703887 ER PT J AU Mason, SM Austin, SB Bakalar, JL Boynton-Jarrett, R Field, AE Gooding, HC Holsen, LM Jackson, B Neumark-Sztainer, D Sanchez, M Sogg, S Tanofsky-Kraff, M Rich-Edwards, JW AF Mason, Susan M. Austin, S. Bryn Bakalar, Jennifer L. Boynton-Jarrett, Renee Field, Alison E. Gooding, Holly C. Holsen, Laura M. Jackson, Benita Neumark-Sztainer, Dianne Sanchez, Mar Sogg, Stephanie Tanofsky-Kraff, Marian Rich-Edwards, Janet W. TI Child Maltreatment's Heavy Toll The Need for Trauma-Informed Obesity Prevention SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID GUT MICROBIOTA; STRESS; ABUSE; RISK; DEPRESSION; EXPOSURE; VIOLENCE; WEIGHT; HEALTH C1 [Mason, Susan M.; Neumark-Sztainer, Dianne] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Austin, S. Bryn; Field, Alison E.; Gooding, Holly C.] Harvard Univ, Boston Childrens Hosp, Div Adolescent & Young Adult Med, Sch Med, Boston, MA USA. [Austin, S. Bryn] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 665 Huntington Ave, Boston, MA 02115 USA. [Bakalar, Jennifer L.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Boynton-Jarrett, Renee] Boston Univ, Sch Med, Boston Med Ctr, Div Pediat, Boston, MA 02118 USA. [Holsen, Laura M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Holsen, Laura M.; Rich-Edwards, Janet W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Jackson, Benita] Smith Coll, Dept Psychol, Northampton, MA 01063 USA. [Sanchez, Mar] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Sanchez, Mar] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Sogg, Stephanie] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. [Sogg, Stephanie] Harvard Univ, Sch Med, Boston, MA USA. [Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dev Res Lab Eating & Weight Behav, Bethesda, MD 20814 USA. [Field, Alison E.; Rich-Edwards, Janet W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Mason, SM (reprint author), 1300 South 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM smmason@umn.edu OI Neumark-Sztainer, Dianne/0000-0001-9435-1669 FU Radcliffe Institute for Advanced Study FX We are grateful for the support of the Radcliffe Institute for Advanced Study, which funded the workshop at which this paper was conceived. NR 20 TC 0 Z9 0 U1 4 U2 6 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 MAY PY 2016 VL 50 IS 5 BP 646 EP 649 DI 10.1016/j.amepre.2015.11.004 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DJ5VJ UT WOS:000374277900012 PM 26689978 ER PT J AU EI-Jawahri, A Li, SL Antin, JH Spitzer, TR Armand, PA Koreth, J Nikiforow, S Ballen, KK Ho, VT Alyea, EP Dey, BR McAfee, SL Glotzbecker, BE Soiffer, RJ Cutler, CS Chen, YB AF EI-Jawahri, Areej Li, Shuli Antin, Joseph H. Spitzer, Thomas R. Armand, Philippe A. Koreth, John Nikiforow, Sarah Ballen, Karen K. Ho, Vincent T. Alyea, Edwin P. Dey, Bimalangshu R. McAfee, Steven L. Glotzbecker, Brett E. Soiffer, Robert J. Cutler, Corey S. Chen, Yi-Bin TI Improved Treatment-Related Mortality and Overall Survival of Patients with Grade IV Acute GVHD in the Modern Years SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE GVHD; Transplant-related mortality; Survival; Allogeneic HCT ID VERSUS-HOST-DISEASE; HEMATOPOIETIC-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; GRAFT; PROPHYLAXIS; INTENSITY; ANTIBODY; PENTOSTATIN; DACLIZUMAB; INFECTION AB The impact of advances in supportive care and hematopoietic stem cell transplantation (HSCT) practices on the outcomes of patients who develop grade III or IV acute graft-versus-host disease (GVHD) is unknown. We performed a retrospective analysis of 427 patients with overall grade III or IV acute GVHD treated at 2 partner institutions between 1997 and 2012. We compared treatment-related mortality (TRM) and overall survival (OS) in 2 cohorts based on the year of transplantation, 1997 to 2006 (n = 222) and 2007 to 2012 (n = 205), using multivariate analysis, adjusting for significant patient-, disease-, and transplantation-related factors. Recipient age, reduced-intensity conditioning, unrelated donor, and peripheral blood stem cell grafts in the patients with grade III or IV acute GVHD increased over time. In the unadjusted analysis, 12-month OS increased over time (30% in 1997 to 2006 versus 42% in 2007 to 2012; P = .003) reflecting a decrease in TRM (58% in 1997 to 2006 versus 38% in 2007 to 2012; P = .0002), and an increase in PFS (29% in 1997 to 2006 versus 43% in 2007 to 2012; P = .002). On multivariate analysis, the period of transplantation remained a significant predictor for OS (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54 to 0.94; P = .02), progression-free survival (PFS) (HR, 0.70; 95% CI, 0.52 to 0.94; P = .02), and TRM (HR, 0.57; 95% CI, 0.39 to 0.82; P = .002). In subgroup analysis, these differences were observed mainly in patients with grade IV acute GVHD. The outcomes of patients who develop overall grade III or IV acute GVHD after allogeneic HSCT has improved over time, with lower TRM and improved OS. This improvement in outcomes was seen primarily in patients with grade IV acute GVHD. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [EI-Jawahri, Areej; Spitzer, Thomas R.; Ballen, Karen K.; Dey, Bimalangshu R.; McAfee, Steven L.; Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [EI-Jawahri, Areej; Antin, Joseph H.; Spitzer, Thomas R.; Armand, Philippe A.; Koreth, John; Nikiforow, Sarah; Ballen, Karen K.; Ho, Vincent T.; Alyea, Edwin P.; Dey, Bimalangshu R.; McAfee, Steven L.; Glotzbecker, Brett E.; Soiffer, Robert J.; Cutler, Corey S.; Chen, Yi-Bin] Harvard Univ, Sch Med, Boston, MA USA. [Li, Shuli; Antin, Joseph H.; Armand, Philippe A.; Koreth, John; Nikiforow, Sarah; Ho, Vincent T.; Alyea, Edwin P.; Glotzbecker, Brett E.; Soiffer, Robert J.; Cutler, Corey S.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. RP EI-Jawahri, A (reprint author), Dept Hematol Oncol, Bone Marrow Transplant Program, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM ael-jawahri@partners.org NR 28 TC 2 Z9 2 U1 2 U2 2 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 MAY PY 2016 VL 22 IS 5 BP 910 EP 918 DI 10.1016/j.bbmt.2015.12.024 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DJ5VF UT WOS:000374277500019 ER PT J AU Braley, TJ Boudreau, EA AF Braley, Tiffany J. Boudreau, Eilis Ann TI Sleep Disorders in Multiple Sclerosis SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Obstructive sleep apnea; Restless leg syndrome; Insomnia; Fatigue; Multiple sclerosis ID RESTLESS LEGS SYNDROME; QUALITY-OF-LIFE; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; PERIODIC LIMB MOVEMENTS; FATIGUE IMPACT SCALE; HEART HEALTH; CLINICAL-PRACTICE; RISK-FACTOR; APNEA AB Recent studies suggest that individuals with multiple sclerosis (MS) are at increased risk for sleep disturbances and that sleep disturbances contribute to fatigue and other chronic symptoms in MS. Although fatigue occurs commonly in people with MS, this symptom is often attributed to MS-specific pathology. Consequently, sleep disorders are often unrecognized and untreated in this population. Timely diagnosis and treatment of sleep problems in MS offer a new opportunity to ameliorate some of the daytime fatigue experienced by patients with MS. To increase this opportunity, the practitioner should be comfortable performing basic screening for common sleep complaints among patients with MS. The objectives of this review are to summarize the latest relevant data on sleep disorders in MS and offer a helpful approach to the identification and workup of the most common sleep problems in this population. Unexplored research avenues and opportunities to address important questions at the interface of sleep and MS are also discussed. C1 [Braley, Tiffany J.] Univ Michigan, Dept Neurol, Multiple Sclerosis Ctr, 1500 E Med Ctr Dr,C728 Med Inn Bldg, Ann Arbor, MI USA. [Braley, Tiffany J.] Univ Michigan, Dept Neurol, Sleep Disorders Ctr, 1500 E Med Ctr Dr,C728 Med Inn Bldg, Ann Arbor, MI USA. [Boudreau, Eilis Ann] Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd L226, Portland, OR 97239 USA. [Boudreau, Eilis Ann] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, 3181 SW Sam Jackson Pk Rd L226, Portland, OR 97239 USA. [Boudreau, Eilis Ann] Portland VA Med Ctr, P3-ECOE,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. RP Boudreau, EA (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd L226, Portland, OR 97239 USA.; Boudreau, EA (reprint author), Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, 3181 SW Sam Jackson Pk Rd L226, Portland, OR 97239 USA.; Boudreau, EA (reprint author), Portland VA Med Ctr, P3-ECOE,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM tbraley@med.umich.edu; boudreau@ohsu.edu FU National Multiple Sclerosis Society; American Sleep Medicine Foundation; Michigan Translation and Commercialization (MTRAC) for Life Sciences Program; Biogen; Genzyme-Sanofi; Genentech-Roche FX Tiffany J. Braley receives grant support from the National Multiple Sclerosis Society, the American Sleep Medicine Foundation, and the Michigan Translation and Commercialization (MTRAC) for Life Sciences Program to conduct her research. She is principal investigator on a clinical trial that receives material support, but no financial support, from Biogen. She is site principal investigator for several industry-funded studies of MS immunotherapeutics at the University of Michigan (sponsors include Genzyme-Sanofi and Genentech-Roche) but receives no direct compensation for any of this work. NR 79 TC 4 Z9 4 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD MAY PY 2016 VL 16 IS 5 AR 50 DI 10.1007/s11910-016-0649-2 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DJ5NO UT WOS:000374255800009 PM 27068547 ER PT J AU Piquet, AL Cho, TA AF Piquet, Amanda L. Cho, Tracey A. TI The Clinical Approach to Encephalitis SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Encephalitis; Viral; Herpes; Arbovirus; Autoimmune; Paraneoplastic ID WEST-NILE-VIRUS; HERPES-SIMPLEX ENCEPHALITIS; VIRAL ENCEPHALITIS; INFECTION; DIAGNOSIS; DISEASE; MANIFESTATIONS; IMMUNOGLOBULIN; PATHOGENESIS; ETIOLOGIES AB Encephalitis has various etiologies, but viral infections and autoimmune disorders are the most commonly identified. Clinical signs, geographical clues, and diagnostic testing-including cerebrospinal fluid abnormalities and magnetic resonance imaging abnormalities-can be helpful in identifying the cause. Certain forms of encephalitis have specific treatments; hence, establishing a diagnosis rapidly and accurately is crucial. Here, we describe the clinical approach to diagnosing several common etiologies of encephalitis as well as treatment strategies. C1 [Piquet, Amanda L.; Cho, Tracey A.] Massachusetts Gen Hosp, Dept Neurol, Wang ACC 835,55 Fruit St, Boston, MA 02114 USA. [Piquet, Amanda L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Cho, TA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Wang ACC 835,55 Fruit St, Boston, MA 02114 USA. EM apiquet@partners.org; tcho@mgh.harvard.edu NR 40 TC 0 Z9 0 U1 7 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD MAY PY 2016 VL 16 IS 5 AR 45 DI 10.1007/s11910-016-0650-9 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DJ5NO UT WOS:000374255800010 PM 27021774 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Is Gleason Grade 5 Prostate Cancer Resistant to Conventional Androgen Deprivation Therapy? SO EUROPEAN UROLOGY LA English DT Editorial Material ID PHASE-III TRIAL; INCREASED SURVIVAL; RADIATION-THERAPY; RANDOMIZED-TRIAL; FOLLOW-UP; SUPPRESSION; CHEMOTHERAPY; RADIOTHERAPY; ENZALUTAMIDE; MITOXANTRONE C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, 75 Francis St, 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.; D'Amico, AV (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM adamico@partners.org NR 19 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2016 VL 69 IS 5 BP 761 EP 763 DI 10.1016/j.eururo.2015.08.057 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DJ4JR UT WOS:000374171700006 PM 26364550 ER PT J AU van den Bergh, RCN van Casteren, NJ van den Broeck, T Fordyce, ER Gietzmann, WKM Stewart, F MacLennan, S Dabestani, S Bellmunt, J Bolla, M Briers, E Cornford, P Joniau, S Mason, MD Matveev, V van der Poel, HG van der Kwast, TH Rouviere, O Wiegel, T Lam, TB Mottet, N AF van den Bergh, Roderick C. N. van Casteren, Niels J. van den Broeck, Thomas Fordyce, Eve R. Gietzmann, William K. M. Stewart, Fiona MacLennan, Steven Dabestani, Saeed Bellmunt, Joaquim Bolla, Michel Briers, Erik Cornford, Philip Joniau, Steven Mason, Malcolm D. Matveev, Vsevolod van der Poel, Henk G. van der Kwast, Theo H. Rouviere, Olivier Wiegel, Thomas Lam, Thomas B. Mottet, Nicolas TI Role of Hormonal Treatment in Prostate Cancer Patients with Nonmetastatic Disease Recurrence After Local Curative Treatment: A Systematic Review SO EUROPEAN UROLOGY LA English DT Review DE Prostate cancer; Hormonal; Therapy; Non-metastatic; Curative treatment; Recurrence; Systematic review; EAU Guidelines ID ANDROGEN-DEPRIVATION THERAPY; EXTERNAL-BEAM RADIOTHERAPY; RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; NATURAL-HISTORY; FAILURE; MEN; SURVIVAL; ANTIGEN; PREDICTORS AB Context: The relative benefits and harms of hormonal treatment (HT) versus no or deferred HT in patients with nonmetastatic prostate cancer (PCa) relapse after primary curative therapy are controversial. Objective: To assess the effectiveness of HT for nonmetastatic PCa relapse, prognostic factors for treatment outcome, timing of treatment, and the most effective treatment strategy to provide guidance for clinical practice. Evidence acquisition: A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library (search ended March 2015). Studies were critically appraised for risk of bias. The outcomes included overall and cancer-specific survival, metastasis-free survival, symptom-free survival, progression to castrate resistance, adverse events, and quality of life. Evidence synthesis: Of 9687 articles identified, 27 studies were eligible for inclusion (2 RCTs, 8 nonrandomised comparative studies, and 17 case series). The results suggest that only a subgroup of patients, especially those with high-risk disease, may benefit from early HT. The main predictors for unfavourable outcomes were shorter PSA doubling time (<6-12 mo) and higher Gleason score (>7). Early HT may be warranted for patients with high-risk disease. An intermittent HT strategy appears feasible. Most studies had a moderate to high risks of bias. Conclusions: HT for PCa relapse after primary therapy with curative intent should be reserved for patients at highest risk of progression and with a long life expectancy. The potential benefits of starting HT should be judiciously balanced against the associated harms. Patient summary: This article summarises the evidence on the benefits and harms of hormonal treatment in prostate cancer (PCa) patients in whom the disease has recurred following earlier curative treatment. We found that only a select group of patients with aggressive PCa and a fast rising prostate-specific antigen may benefit from early hormonal treatment (HT), whereas in others HT may be more harmful than beneficial. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [van den Bergh, Roderick C. N.] Univ Med Ctr, Dept Urol, Utrecht, Netherlands. [van Casteren, Niels J.] Ijsselland Hosp, Dept Urol, Capelle aan den IJssel, Netherlands. [van den Broeck, Thomas; Joniau, Steven] Univ Hosp Leuven, Dept Urol, Leuven, Belgium. [van den Broeck, Thomas] Katholieke Univ Leuven, Mol Endocrinol Lab, Leuven, Belgium. [Fordyce, Eve R.; Stewart, Fiona; MacLennan, Steven; Lam, Thomas B.] Univ Aberdeen, Acad Urol Unit, Aberdeen, Scotland. [Gietzmann, William K. M.; Lam, Thomas B.] Aberdeen Royal Infirm, Dept Urol, Aberdeen, Scotland. [Dabestani, Saeed] Skane Univ Hosp, Dept Urol, Malmo, Sweden. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Bolla, Michel] Ctr Hosp Univ Michallon, Dept Radiat Oncol, Grenoble, France. [Cornford, Philip] Royal Liverpool & Broadgreen Hosp NHS Trust, Liverpool, Merseyside, England. [Matveev, Vsevolod] Russian Acad Med Sci, Canc Res Ctr, Dept Oncourol, Moscow, Russia. [van der Poel, Henk G.] Netherlands Canc Inst, Dept Urol, Amsterdam, Netherlands. [van der Kwast, Theo H.] Erasmus MC, Dept Pathol, Rotterdam, Netherlands. [Rouviere, Olivier] Hop Edouard Herriot, Hosp Civils Lyon, Dept Radiol, Lyon, France. [Wiegel, Thomas] Univ Hosp Ulm, Dept Radiat Oncol, Ulm, Germany. [Mottet, Nicolas] Univ St Etienne, Dept Urol, North Hosp, CHU St Etienne, St Etienne, France. RP Mottet, N (reprint author), Univ St Etienne, Dept Urol, St Etienne, France. EM nicolas.mottet@chu-st-etienne.fr OI Van den Broeck, Thomas/0000-0002-7237-7160; Dabestani, Saeed/0000-0003-2240-1588; Rouviere, Olivier/0000-0002-0030-478X FU Takeda (France); Millennium; Ipsen; Nucletron; Takeda; Janssen; Sanofi; Astellas; Zeneca; Pierre Fabre; European Association of Urology; Bayer; Novartis; Amgen; Ferring; EDAP-TMS FX Nicolas Mottet certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Nicolas Mottet is a company consultant for Takeda (Millennium), Jansen, Ferring, Caprion, Ipsen, and Sanofi-Aventis. He receives company speaker honoraria from Pierre Fabre, Takeda, Astellas, Sanofi-Aventis, Jansen, and Ipsen. He participates in trials for Takeda (France), Millennium, and Astellas. He receives grants/research support from Takeda (France), Millennium, and Ipsen. He participates in trials for Sanofi. He receives honoraria or consultation fees from Nucletron and Takeda. He receives fellowships and travel grants from Janssen, Sanofi, Ipsen, Astellas, and Zeneca. He is a consultant for Bayer and Novartis. Joaquim Bellmunt is a company consultant for Janssen, Astellas, Pierre Fabre, Janssen, and Sanofi-Aventis. He participates in trials for Merck US. Michel Bolla receives company speaker honoraria from Astellas. He receives honoraria or consultation fees from Janssen. He receives fellowships and travel grants from Pierre Fabre. Erik Briers receives grants/research support from Ipsen, the European Association of Urology, and Bayer. He is an ex-officio board member of Europa UOMO. He is on the ethics committee and an advisory group member for REQUITE. He is a member of the European Congress of Radiology's Patient Advisory Group on Medical Imaging. He is a member of the Sceletal Care Academy and the European Medicine Agency's Patients/Consumers Working Party. Philip Cornford is a company consultant for Astellas, Jansen, and Ipsen. He receives company speaker honoraria from Ipsen. He participates in trials for Ferring and AstraZeneca. He receives fellowships and travel grants from Astellas. Steven Joniau receives company speaker honoraria and fellowship and travel grants from Novartis. He receives company speaker honoraria and fellowship and travel grants from Amgen. He is a company consultant for Bayer. He receives company speaker honoraria, fellowships, and travel grants from Ferring. Malcolm Mason is a company consultant for Bristol-Myers Squibb, Janssen, and Dendreon. He receives company speaker honoraria from Takeda. Vsevolod Matveev receives company speaker honoraria from Bayer Schering Pharma, Novartis, Pfizer, and Astra Zeneca. He participates in trials for Astellas, Pfizer, and Novartis. He receives company speaker honoraria from Sanofi and Astellas. Theo van der Kwast is a company consultant for HistoScanning, Waterloo, Belgium. Olivier Rouviere received a research grant from EDAP-TMS for the study presented in poster 970. He receives honoraria or consultation fees from Novartis. Thomas Wiegel receives company speaker honoraria from Astellas, Takeda, Hexal, Ipsen, Janssen-Cilac, and Ferring. Thomas B. Lam is a company consultant and receives company speaker honoraria from Pfizer, GSK, Astellas, and Ipsen. The remaining authors have nothing to disclose. NR 46 TC 5 Z9 5 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2016 VL 69 IS 5 BP 802 EP 820 DI 10.1016/j.eururo.2015.11.023 PG 19 WC Urology & Nephrology SC Urology & Nephrology GA DJ4JR UT WOS:000374171700015 PM 26691493 ER PT J AU Tannir, NM Jonasch, E Albiges, L Altinmakas, E Ng, CS Matin, SF Wang, XM Wang, X Qiao, W Lim, ZD Tamboli, P Rao, P Sircar, K Karam, JA McDermott, DF Wood, CG Choueiri, TK AF Tannir, Nizar M. Jonasch, Eric Albiges, Laurence Altinmakas, Emre Ng, Chaan S. Matin, Surena F. Wang, Xuemei Wang, Xuemei Qiao, Wei Lim, Zita Dubauskas Tamboli, Pheroze Rao, Priya Sircar, Kanishka Karam, Jose A. McDermott, David F. Wood, Christopher G. Choueiri, Toni K. TI Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial SO EUROPEAN UROLOGY LA English DT Article DE Renal cell carcinoma; Non-clear cell renal cell carcinoma; Sunitinib; Everolimus ID EXPANDED-ACCESS PROGRAM; INTERFERON-ALPHA; MAMMALIAN TARGET; SURVIVAL; EFFICACY; THERAPY; SAFETY; TEMSIROLIMUS; HISTOLOGIES; RAPAMYCIN AB Background: Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC). Objective: To conduct a randomized phase 2 trial comparing sunitinib and everolimus in non-clear cell RCC (non-ccRCC). Design, setting, and participants: Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression. Outcome measurement and statistical analysis: Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus. Results and limitations: Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p = 0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p = 0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p = 0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n = 49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p = 0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation. Conclusions: In this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC. Patient summary: This randomized phase 2 trial provides the first head-to-head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Tannir, Nizar M.; Jonasch, Eric; Lim, Zita Dubauskas] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Div Canc Med, Houston, TX 77030 USA. [Albiges, Laurence; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Altinmakas, Emre; Ng, Chaan S.] Univ Texas MD Anderson Canc Ctr, Diagnost Radiol, Houston, TX 77030 USA. [Matin, Surena F.; Karam, Jose A.; Wood, Christopher G.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Div Surg, Houston, TX 77030 USA. [Wang, Xuemei; Qiao, Wei] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Tamboli, Pheroze; Rao, Priya; Sircar, Kanishka] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Tannir, NM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Div Canc Med, Houston, TX 77030 USA. EM ntannir@mdanderson.org FU Novartis; NIH/NCI [P30CA016672]; Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence; Trust Family; Loker Pinard Funds for Kidney Cancer Research FX The trial was funded by Novartis, and supported by NIH/NCI award P30CA016672. The trial was also funded in part by the Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence, the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research for Toni K. Choueiri. Novartis had no role in the study design, data collection, analysis, interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. NR 30 TC 25 Z9 25 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2016 VL 69 IS 5 BP 866 EP 874 DI 10.1016/j.eururo.2015.10.049 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DJ4JR UT WOS:000374171700026 PM 26626617 ER PT J AU Bellmunt, J Kheoh, T Yu, MK Smith, MR Small, EJ Mulders, PFA Fizazi, K Rathkopf, DE Saad, F Scher, HI Taplin, ME Davis, ID Schrijvers, D Protheroe, A Molina, A De Porre, P Griffin, TW de Bono, JS Ryan, CJ Oudard, S AF Bellmunt, Joaquim Kheoh, Thian Yu, Margaret K. Smith, Matthew R. Small, Eric J. Mulders, Peter F. A. Fizazi, Karim Rathkopf, Dana E. Saad, Fred Scher, Howard I. Taplin, Mary-Ellen Davis, Ian D. Schrijvers, Dirk Protheroe, Andrew Molina, Arturo De Porre, Peter Griffin, Thomas W. de Bono, Johann S. Ryan, Charles J. Oudard, Stephane TI Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies SO EUROPEAN UROLOGY LA English DT Article DE Abiraterone acetate; Androgen receptor antagonists; Gonadotropin-releasing hormone; Prednisone; Prostate cancer ID SECONDARY HORMONAL-THERAPY; PLACEBO-CONTROLLED PHASE-3; DOCETAXEL CHEMOTHERAPY; INCREASED SURVIVAL; AUA GUIDELINE; DOUBLE-BLIND; ENZALUTAMIDE; PREDNISONE; MEN AB Background: The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Objective: To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity. Design, setting, and participants: Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naive mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist. Intervention: Patients were randomised to AA (1000 mg, orally once daily) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n = 1127 [94%]; COU-AA-302, n = 1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n = 78 [7%] COU-AA-302, n = 44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n = 1015 [85%]; COU-AA-302, n = 1078 [99%], 15.7 mo or 16.1 mo median duration, respectively). Outcome measurements and statistical analysis: Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic. Results and limitations: Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis. Conclusions: In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC. Patient summary: Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Bellmunt, Joaquim; Taplin, Mary-Ellen] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Kheoh, Thian] Janssen Res & Dev, San Diego, CA USA. [Yu, Margaret K.; Griffin, Thomas W.] Janssen Res & Dev, Los Angeles, CA USA. [Smith, Matthew R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Small, Eric J.; Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Mulders, Peter F. A.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Fizazi, Karim] Univ Paris 11, Inst Gustave Roussy, Villejuif, France. [Rathkopf, Dana E.; Scher, Howard I.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Rathkopf, Dana E.; Scher, Howard I.] Weill Cornell Med Coll, New York, NY USA. [Saad, Fred] Univ Montreal, Montreal, PQ, Canada. [Davis, Ian D.] Monash Univ, Clayton, Vic 3800, Australia. [Davis, Ian D.] Eastern Hlth, Melbourne, Vic, Australia. [Schrijvers, Dirk] ZNA Middelheim Oncol Clin, Med Oncol, Antwerp, Belgium. [Protheroe, Andrew] Churchill Hosp, Oxford OX3 7LJ, England. [Molina, Arturo] Janssen Res & Dev, Menlo Pk, CA USA. [De Porre, Peter] Janssen Res & Dev, Beerse, Belgium. [de Bono, Johann S.] Inst Canc Res, Sutton, Surrey, England. [de Bono, Johann S.] Royal Marsden Hosp, Sutton, Surrey, England. [Oudard, Stephane] Univ Paris 05, Georges Pompidou Hosp, Paris, France. RP Bellmunt, J (reprint author), Harvard Univ, Sch Med, Lank Ctr Genitourinary Oncol, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Joaquim_Bellmunt@dfci.harvard.edu FU Janssen Research Development; Janssen Global Services FX This work was supported by Janssen Research & Development (formerly Ortho Biotech Research & Development, unit of Cougar Biotechnology). Employees of Janssen Research & Development participated in trial design and oversight, data monitoring and collection, data analysis, data interpretation, and writing of the report. The study sponsor was involved in trial design and provided grants to trial sites, but had no involvement in the conduct of the trial. Analyses done by Janssen for this report were funded by Janssen Global Services. NR 26 TC 5 Z9 5 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2016 VL 69 IS 5 BP 924 EP 932 DI 10.1016/j.eururo.2015.10.021 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DJ4JR UT WOS:000374171700035 PM 26508309 ER PT J AU Villar, J Perez-Mendez, L Kacmarek, RM AF Villar, Jesus Perez-Mendez, Lina Kacmarek, Robert M. TI The Berlin definition met our needs: no SO INTENSIVE CARE MEDICINE LA English DT Editorial Material ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; ARDS; TRIAL; OUTCOMES C1 [Villar, Jesus; Perez-Mendez, Lina] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Barranco Ballena S-N,4th Floor,South Wing, Las Palmas Gran Canaria, Spain. [Villar, Jesus] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Li Ka Shing Knowledge Inst, Toronto, ON, Canada. [Perez-Mendez, Lina] Hosp Univ NS Candelaria, Res Unit, Santa Cruz De Tenerife, Spain. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesiol & Crit Care, Boston, MA 02115 USA. RP Villar, J (reprint author), Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Barranco Ballena S-N,4th Floor,South Wing, Las Palmas Gran Canaria, Spain. EM jesus.villar54@gmail.com NR 17 TC 2 Z9 2 U1 0 U2 2 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 MAY PY 2016 VL 42 IS 5 BP 648 EP 650 DI 10.1007/s00134-016-4242-6 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA DJ4LJ UT WOS:000374176700004 PM 27007104 ER PT J AU Thompson, BT Guerin, C Esteban, A AF Thompson, B. Taylor Guerin, Claude Esteban, Andres TI Should ARDS be renamed diffuse alveolar damage? SO INTENSIVE CARE MEDICINE LA English DT Editorial Material ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; AUTOPSY; BIOPSY C1 [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care, Dept Med, 55 Fruit St, Boston, MA 02114 USA. [Thompson, B. Taylor] Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. [Guerin, Claude] Hop Croix Rousse, Reanimat Med, F-69317 Lyon, France. [Guerin, Claude] IMRB INSERM 955 Eq13, Creteil, France. [Esteban, Andres] Hosp Univ Getafe, CIBER Enfermedades Resp, Getafe, Spain. RP Thompson, BT (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care, Dept Med, 55 Fruit St, Boston, MA 02114 USA.; Thompson, BT (reprint author), Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM tthompson1@partners.org NR 15 TC 1 Z9 1 U1 0 U2 3 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 MAY PY 2016 VL 42 IS 5 BP 653 EP 655 DI 10.1007/s00134-016-4296-5 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA DJ4LJ UT WOS:000374176700006 PM 26972901 ER PT J AU Sakr, Y Ferrer, R Reinhart, K Beale, R Rhodes, A Moreno, R Timsit, JF Brochard, L Thompson, BT Rezende, E Chiche, JD AF Sakr, Yasser Ferrer, Ricard Reinhart, Konrad Beale, Richard Rhodes, Andrew Moreno, Rui Timsit, Jean Francois Brochard, Laurent Thompson, B. Taylor Rezende, Ederlon Chiche, Jean Daniel CA IC-GLOSSARI Investigators ESICM Trials Grp TI The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study SO INTENSIVE CARE MEDICINE LA English DT Article DE Severe acute respiratory infections; Pneumonia; Outcome; Intensive care ID COMMUNITY-ACQUIRED PNEUMONIA; CRITICALLY-ILL PATIENTS; SEASONAL INFLUENZA VACCINE; DISTRESS-SYNDROME; CRITICAL ILLNESS; SEPSIS; METAANALYSIS; H1N1; UNIT; OUTCOMES AB In this prospective, multicenter, 14-day inception cohort study, we investigated the epidemiology, patterns of infections, and outcome in patients admitted to the intensive care unit (ICU) as a result of severe acute respiratory infections (SARIs). All patients admitted to one of 206 participating ICUs during two study weeks, one in November 2013 and the other in January 2014, were screened. SARI was defined as possible, probable, or microbiologically confirmed respiratory tract infection with recent onset dyspnea and/or fever. The primary outcome parameter was in-hospital mortality within 60 days of admission to the ICU. Among the 5550 patients admitted during the study periods, 663 (11.9 %) had SARI. On admission to the ICU, Gram-positive and Gram-negative bacteria were found in 29.6 and 26.2 % of SARI patients but rarely atypical bacteria (1.0 %); viruses were present in 7.7 % of patients. Organ failure occurred in 74.7 % of patients in the ICU, mostly respiratory (53.8 %), cardiovascular (44.5 %), and renal (44.6 %). ICU and in-hospital mortality rates in patients with SARI were 20.2 and 27.2 %, respectively. In multivariable analysis, older age, greater severity scores at ICU admission, and hematologic malignancy or liver disease were independently associated with an increased risk of in-hospital death, whereas influenza vaccination prior to ICU admission and adequate antibiotic administration on ICU admission were associated with a lower risk. Admission to the ICU for SARI is common and associated with high morbidity and mortality rates. We identified several risk factors for in-hospital death that may be useful for risk stratification in these patients. C1 [Sakr, Yasser; Reinhart, Konrad] Uniklinikum Jena, Dept Anesthesiol & Intens Care, Erlanger Allee 103, D-07743 Jena, Germany. [Ferrer, Ricard] Hosp Univ Vall DHebron, CIBER Enfermedades Resp, Dept Intens Care, Passeig Vall DHebron 119-129, Barcelona 08035, Spain. [Beale, Richard] Kings Hlth Partners, Westminster Bridge Rd, London SE1 7EH, England. [Rhodes, Andrew] St Georges Univ Hosp NHS Fdn Trust, Crit Care Directorate, London, England. [Moreno, Rui] Ctr Hosp Lisboa Cent, EPE, Hosp Sao Jos, Unidade Cuidados Intens Neurocrit,Intens Care Uni, Rua Jose Antonio Serrano,S, P-1150199 Lisbon, Portugal. [Timsit, Jean Francois] Paris Diderot Univ, Bichat Teaching Hosp Med & Infect Dis ICU, Med ICU, 46 Rue Henri Huchard, F-75018 Paris, France. [Brochard, Laurent] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Brochard, Laurent] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Thompson, B. Taylor] Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. [Rezende, Ederlon] IAMSPE, Serv Terapia Intens, Av Ibirapuera 981, BR-04028000 Sao Paulo, SP, Brazil. [Chiche, Jean Daniel] Paris Descartes Univ, Med Intens Care Unit, Paris, France. [Chiche, Jean Daniel] Hop Cochin, 27 Rue Faubourg St Jacques, F-75674 Paris, France. [Chiche, Jean Daniel] Cochin Inst, Dept Cell Biol & Host Pathogen Interact, 27 Rue Faubourg St Jacques, F-75679 Paris 14, France. [IC-GLOSSARI Investigators; ESICM Trials Grp] European Soc Intens Care ESICM, Rue Belliard 19, B-1040 Brussels, Belgium. RP Sakr, Y (reprint author), Uniklinikum Jena, Dept Anesthesiol & Intens Care, Erlanger Allee 103, D-07743 Jena, Germany. EM yasser.sakr@med.uni-jena.de RI Cortegiani, Andrea/H-4902-2016 OI Cortegiani, Andrea/0000-0003-1416-9993 FU European Society of Intensive Care Medicine (ESICM), Rue Belliard, Brussels, Belgium FX The study was supported by an unrestricted grant from the European Society of Intensive Care Medicine (ESICM), Rue Belliard, 19, 1040 Brussels, Belgium. NR 35 TC 3 Z9 3 U1 0 U2 0 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 MAY PY 2016 VL 42 IS 5 BP 817 EP 828 DI 10.1007/s00134-015-4206-2 PG 12 WC Critical Care Medicine SC General & Internal Medicine GA DJ4LJ UT WOS:000374176700033 PM 26880091 ER PT J AU Thompson, T Ranieri, VM AF Thompson, Taylor Ranieri, V. Marco TI Steroids are part of rescue therapy in ARDS patients with refractory hypoxemia: no SO INTENSIVE CARE MEDICINE LA English DT Editorial Material ID RESPIRATORY-DISTRESS-SYNDROME; CORTICOSTEROIDS; PNEUMONIA; FAILURE C1 [Thompson, Taylor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Pulm & Crit Care, 55 Fruit St, Boston, MA 02114 USA. [Ranieri, V. Marco] Univ Roma La Sapienza, Policlin Umberto I, Anesthesia & Crit Care Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy. RP Thompson, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Pulm & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM thompson.taylor@mgh.harvard.edu NR 15 TC 0 Z9 0 U1 1 U2 1 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 MAY PY 2016 VL 42 IS 5 BP 921 EP 923 DI 10.1007/s00134-016-4255-1 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA DJ4LJ UT WOS:000374176700048 ER PT J AU Sakr, Y Ferrer, R Reinhart, K Beale, R Rhodes, A Moreno, R Timsit, JF Brochard, L Thompson, BT Rezende, E Chiche, JD AF Sakr, Yasser Ferrer, Ricard Reinhart, Konrad Beale, Richard Rhodes, Andrew Moreno, Rui Timsit, Jean Francois Brochard, Laurent Thompson, B. Taylor Rezende, Ederlon Chiche, Jean Daniel CA IC-GLOSSARI Investigators ESICM Trials Grp TI The Intensive Care Global Study on Severe Acute Respiratory Infection (ICaEuroGLOSSARI): a multicenter, multinational, 14-day inception cohort study (vol 42, pg 817, 2016) SO INTENSIVE CARE MEDICINE LA English DT Correction C1 [Sakr, Yasser; Reinhart, Konrad] Uniklinikum Jena, Dept Anesthesiol & Intens Care, Erlanger Allee 103, D-07743 Jena, Germany. [Ferrer, Ricard] Hosp Univ Vall Hebron, CIBER Enfermedades Resp, Dept Intens Care, Passeig Vall dHebron 119-129, Barcelona 08035, Spain. [Beale, Richard] Kings Hlth Partners, Westminster Bridge Rd, London SE1 7EH, England. [Rhodes, Andrew] St Georges Univ Hosp NHS Fdn Trust, Crit Care Directorate, London, England. [Moreno, Rui] Hosp Sao Jos, EPE, Ctr Hosp Lisboa Cent, Unidade Cuidados Intens Neurocrit,Intens Care Uni, Rua Jose Antonio Serrano S, P-1150199 Lisbon, Portugal. [Timsit, Jean Francois] Paris Diderot Univ, Bichat Teaching Hosp Med & Infect Dis ICU, Med ICU, 46 Rue Henri Huchard, F-75018 Paris, France. [Brochard, Laurent] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Brochard, Laurent] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Thompson, B. Taylor] Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. [Rezende, Ederlon] IAMSPE, Serv Terapia Intens, Av Ibirapuera 981, BR-04028000 Sao Paulo, SP, Brazil. [Chiche, Jean Daniel] Paris Descartes Univ, Med Intens Care Unit, Paris, France. [Chiche, Jean Daniel] Hop Cochin, 27 Rue Faubourg St Jacques, F-75674 Paris, France. [Chiche, Jean Daniel] Cochin Inst, Dept Cell Biol, 27 Rue Faubourg St Jacques, F-75679 Paris 14, France. [Chiche, Jean Daniel] Cochin Inst, Host Pathogen Interact, 27 Rue Faubourg St Jacques, F-75679 Paris 14, France. RP Sakr, Y (reprint author), Uniklinikum Jena, Dept Anesthesiol & Intens Care, Erlanger Allee 103, D-07743 Jena, Germany. EM yasser.sakr@med.uni-jena.de 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 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD MAY PY 2016 VL 42 IS 5 BP 953 EP 953 DI 10.1007/s00134-016-4317-4 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA DJ4LJ UT WOS:000374176700060 PM 27038479 ER PT J AU Ryan, ET AF Ryan, Edward T. TI Troubling news from Asia about treating enteric fever: a coming storm SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID CONTROLLED-TRIAL; FEBRILE ILLNESS; OPEN-LABEL; NEPAL; GATIFLOXACIN C1 [Ryan, Edward T.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ryan, ET (reprint author), Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM etryan@mgh.harvard.edu NR 9 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD MAY PY 2016 VL 16 IS 5 BP 508 EP 509 DI 10.1016/S1473-3099(15)00542-3 PG 2 WC Infectious Diseases SC Infectious Diseases GA DJ5TL UT WOS:000374272900004 PM 26809814 ER PT J AU Karimkhani, C Wanga, V Coffeng, LE Naghavi, P Dellavalle, RP Naghavi, M AF Karimkhani, Chante Wanga, Valentine Coffeng, Luc E. Naghavi, Paria Dellavalle, Robert P. Naghavi, Mohsen TI Global burden of cutaneous leishmaniasis: a cross-sectional analysis from the Global Burden of Disease Study 2013 SO LANCET INFECTIOUS DISEASES LA English DT Article ID LIFE YEARS DALYS; INFECTION; INJURIES; ISFAHAN; IRAN AB Background High-quality epidemiological studies evaluating the burden of cutaneous leishmaniasis worldwide are lacking. We compared the burden of cutaneous leishmaniasis in each country to the overall global burden and assessed the equality of cutaneous leishmaniasis burden across different countries and regions. Methods Data were extracted from scientific literature, hospital sources, country reports, and WHO sources on the prevalence of sequalae of both acute and chronic cutaneous leishmaniasis. Prevalence data were combined with a disability weight to yield years lived with disability. Disability-adjusted life-years (DALYs) are a sum of the years lived with disability and years of life lost (or mortality, assumed to be zero). We compared DALYs due to cutaneous leishmaniasis for 152 countries using standard Z score analysis with Bonferroni correction (p<0.003) and generation of Lorenz curves with a Gini coefficient. Findings In 2013, the global mean age-standardised DALYs for cutaneous leishmaniasis was 0.58 per 100 000 people. Nine countries had significantly greater DALYs from cutaneous leishmaniasis than the mean: Afghanistan (87.0), Sudan (20.2), Syria (9.2), Yemen (6.2), Iraq (6.0), Burkina Faso (4.8), Bolivia (4.6), Haiti (4.1), and Peru (4.0). The Gini coefficient was 0.89. Andean Latin America, North Africa and Middle East, western sub-Saharan Africa, and south Asia had the highest DALYs from cutaneous leishmaniasis. Among males, Palestine had the highest incidence rates (616.2 cases per 100 000 people) followed by Afghanistan (566.4), Syria (357.1), and Nicaragua (354.8). Among females, Afghanistan had the highest incidence rates (623.9) followed by Syria (406.3), Palestine (222.1), and Nicaragua (180.8). Similar proportions of males and females had cutaneous leishmaniasis in most countries with a high incidence. Interpretation The burden from cutaneous leishmaniasis mainly falls on countries in Africa and the Middle East. Global and national data on the burden of cutaneous leishmaniasis disease are pivotal to promote field studies and initiate behavioural change. C1 [Karimkhani, Chante] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Wanga, Valentine; Coffeng, Luc E.; Naghavi, Paria; Naghavi, Mohsen] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Coffeng, Luc E.] Erasmus MC Univ Med Ctr Rotterdam, Dept Publ Hlth, Ca Rotterdam, Netherlands. [Dellavalle, Robert P.] Univ Colorado, Dept Dermatol, Anschutz Med Campus, Aurora, CO USA. [Dellavalle, Robert P.] Eastern Colorado Hlth Care Syst, Dermatol Serv, US Dept Vet Affairs, Denver, CO USA. [Dellavalle, Robert P.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. RP Karimkhani, C (reprint author), Univ Hosp Case Western Med Ctr, Dept Med, 408 W St Clair Ave,Unit 317, Cleveland, OH 44113 USA. EM ck2525@caa.columbia.edu OI Naghavi, Paria/0000-0002-8908-7952 FU Bill & Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 31 TC 6 Z9 7 U1 5 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD MAY PY 2016 VL 16 IS 5 BP 584 EP 591 DI 10.1016/S1473-3099(16)00003-7 PG 8 WC Infectious Diseases SC Infectious Diseases GA DJ5TL UT WOS:000374272900029 PM 26879176 ER PT J AU Engelhart, AE Adamala, KP Szostak, JW AF Engelhart, Aaron E. Adamala, Katarzyna P. Szostak, Jack W. TI A simple physical mechanism enables homeostasis in primitive cells SO NATURE CHEMISTRY LA English DT Article ID PRIMER EXTENSION; MODEL PROTOCELLS; VESICLES; RNA; COMPETITION; ACIDS AB The emergence of homeostatic mechanisms that enable maintenance of an intracellular steady state during growth was critical to the advent of cellular life. Here, we show that concentration-dependent reversible binding of short oligonucleotides, of both specific and random sequence, can modulate ribozyme activity. In both cases, catalysis is inhibited at high concentrations, and dilution activates the ribozyme via inhibitor dissociation, thus maintaining near-constant ribozyme specific activity throughout protocell growth. To mimic the result of RNA synthesis within non-growing protocells, we co-encapsulated high concentrations of ribozyme and oligonucleotides within fatty acid vesicles, and ribozyme activity was inhibited. Following vesicle growth, the resulting internal dilution produced ribozyme activation. This simple physical system enables a primitive homeostatic behaviour: the maintenance of constant ribozyme activity per unit volume during protocell volume changes. We suggest that such systems, wherein short oligonucleotides reversibly inhibit functional RNAs, could have preceded sophisticated modern RNA regulatory mechanisms, such as those involving miRNAs. C1 [Engelhart, Aaron E.; Adamala, Katarzyna P.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Engelhart, Aaron E.; Adamala, Katarzyna P.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Adamala, Katarzyna P.] MIT Media Lab, 77 Massachusetts Ave,E14-E15, Cambridge, MA 02139 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu OI Adamala, Kate/0000-0003-1066-7207 FU NASA [NNX11AD56G]; Simons Foundation [290363]; Massachusetts General Hospital Executive Committee on Research FX The authors thank K.A. Bjorkbom, T. Walton, N. Kamat, C. Hentrich, L. Jin and other Szostak laboratory members for discussions. This work was supported in part by NASA Exobiology grant NNX11AD56G to J.W.S. and a grant (290363) from the Simons Foundation to J.W.S. A.E.E. was supported by an appointment to the NASA Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA, and by a Tosteson Fellowship from the Massachusetts General Hospital Executive Committee on Research. J.W.S. is an Investigator of the Howard Hughes Medical Institute. NR 19 TC 3 Z9 3 U1 10 U2 25 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 MAY PY 2016 VL 8 IS 5 BP 448 EP 453 DI 10.1038/NCHEM.2475 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA DJ9LD UT WOS:000374534100012 PM 27102678 ER PT J AU Yang, Y Wang, J Shigematsu, H Xu, WM Shih, WM Rothman, JE Lin, CX AF Yang, Yang Wang, Jing Shigematsu, Hideki Xu, Weiming Shih, William M. Rothman, James E. Lin, Chenxiang TI Self-assembly of size-controlled liposomes on DNA nanotemplates SO NATURE CHEMISTRY LA English DT Article ID DETERGENT MIXED MICELLES; VESICLE FORMATION; NANOSCALE SHAPES; OCTYL GLUCOSIDE; GENE DELIVERY; ANCHORED DNA; FOLDING DNA; NANOSTRUCTURES; UNILAMELLAR; PHOSPHATIDYLCHOLINE AB Artificial lipid-bilayer membranes are valuable tools for the study of membrane structure and dynamics. For applications such as the study of vesicular transport and drug delivery, there is a pressing need for artificial vesicles with controlled size. However, controlling vesicle size and shape with nanometre precision is challenging, and approaches to achieve this can be heavily affected by lipid composition. Here, we present a bio-inspired templating method to generate highly monodispersed sub-100-nm unilamellar vesicles, where liposome self-assembly was nucleated and confined inside rigid DNA nanotemplates. Using this method, we produce homogeneous liposomes with four distinct predefined sizes. We also show that the method can be used with a variety of lipid compositions and probe the mechanism of templated liposome formation by capturing key intermediates during membrane self-assembly. The DNA nanotemplating strategy represents a conceptually novel way to guide lipid bilayer formation and could be generalized to engineer complex membrane/protein structures with nanoscale precision. C1 [Yang, Yang; Wang, Jing; Xu, Weiming; Rothman, James E.; Lin, Chenxiang] Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06520 USA. [Yang, Yang; Wang, Jing; Xu, Weiming; Rothman, James E.; Lin, Chenxiang] Yale Univ, Nanobiol Inst, West Haven, CT 06516 USA. [Shigematsu, Hideki] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06250 USA. [Shih, William M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Shih, William M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Shih, William M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Shigematsu, Hideki] RIKEN Ctr Life Sci Technol, Div Struct & Synthet Biol, Yokohama, Kanagawa 2300045, Japan. RP Rothman, JE; Lin, CX (reprint author), Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06520 USA.; Rothman, JE; Lin, CX (reprint author), Yale Univ, Nanobiol Inst, West Haven, CT 06516 USA.; Shih, WM (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA.; Shih, WM (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Shih, WM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM william_shih@dfci.harvard.edu; james.rothman@yale.edu; chenxiang.lin@yale.edu RI Shigematsu, Hideki/E-1052-2017; OI Shigematsu, Hideki/0000-0003-3951-8651; Lin, Chenxiang/0000-0001-7041-1946; Yang, Yang/0000-0002-2630-6062 FU National Institutes of Health (NIH) [DP2-GM114830]; NIH [R21-GM109466, R01-DK027044, DP2-OD004641]; Yale University; Army Research Office MURI grant [W911NF-12-1-0420]; National Science Foundation [1317694]; Wyss Institute for Biologically Inspired Engineering Faculty Award FX The authors thank P.D. Ellis for designing the DNA rings used for placing lipid seeds at different angles and for proofreading the manuscript, and F. Sigworth for providing cryo-electron micrographs of extruded liposomes. This work is supported by a National Institutes of Health (NIH) Director's New Innovator Award (DP2-GM114830), an NIH grant (R21-GM109466) and a Yale University faculty startup fund to C.L., an NIH grant to J.E.R. (R01-DK027044) and an NIH Director's New Innovator Award (DP2-OD004641), an Army Research Office MURI grant (W911NF-12-1-0420), National Science Foundation Expeditions Grant (1317694) and a Wyss Institute for Biologically Inspired Engineering Faculty Award to W.M.S. NR 50 TC 14 Z9 14 U1 18 U2 65 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 MAY PY 2016 VL 8 IS 5 BP 476 EP 483 DI 10.1038/NCHEM.2472 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DJ9LD UT WOS:000374534100016 PM 27102682 ER PT J AU Tsai, SQ Joung, JK AF Tsai, Shengdar Q. Joung, J. Keith TI Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases SO NATURE REVIEWS GENETICS LA English DT Review ID OFF-TARGET CLEAVAGE; RNA-GUIDED ENDONUCLEASE; ZINC-FINGER NUCLEASES; DNA-CLEAVAGE; HUMAN-CELLS; STEM-CELLS; GENE KNOCKOUT; ENGINEERED NUCLEASES; CRISPR/CAS9 SYSTEMS; EDITING SPECIFICITY AB CRISPR-Cas9 RNA-guided nucleases are a transformative technology for biology, genetics and medicine owing to the simplicity with which they can be programmed to cleave specific DNA target sites in living cells and organisms. However, to translate these powerful molecular tools into safe, effective clinical applications, it is of crucial importance to carefully define and improve their genome-wide specificities. Here, we outline our state-of-the-art understanding of target DNA recognition and cleavage by CRISPR-Cas9 nucleases, methods to determine and improve their specificities, and key considerations for how to evaluate and reduce off-target effects for research and therapeutic applications. C1 [Tsai, Shengdar Q.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, 149 13th St, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 149 13th St, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Tsai, SQ; Joung, JK (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, 149 13th St, Charlestown, MA 02129 USA. EM shengdar@gmail.com; jjoung@mgh.harvard.edu FU US National Institutes of Health (NIH) [DP1GM105378]; Jim and Ann Orr Massachusetts General Hospital (MGH) Research Scholar Award; MGH Tosteson Award FX J.K.J. is supported by the US National Institutes of Health (NIH) Director's Pioneer Award (DP1GM105378) and by the Jim and Ann Orr Massachusetts General Hospital (MGH) Research Scholar Award. SQT is supported by an MGH Tosteson Award. NR 94 TC 21 Z9 21 U1 17 U2 69 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 MAY PY 2016 VL 17 IS 5 BP 300 EP 312 DI 10.1038/nrg.2016.28 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DJ4ZK UT WOS:000374216400011 PM 27087594 ER PT J AU Mai, CL Ahmed, Z Maze, A Noorulla, F Yaster, M AF Mai, Christine L. Ahmed, Zulfiqar Maze, Aubrey Noorulla, Fatima Yaster, Myron TI Pediatric transport medicine and the dawn of the pediatric anesthesiology and critical care medicine subspecialty: an interview with pioneer Dr. Alvin Hackel SO PEDIATRIC ANESTHESIA LA English DT Article DE Alvin Hackel; pediatric anesthesia; transportation of patients; incubators; infant; credentialing; facility regulation and control ID VENTILATION; ENVIRONMENT; CALIFORNIA AB Dr. Alvin Al' Hackel (1932-) Professor Emeritus of Anesthesiology, Perioperative and Pain Medicine, and Pediatrics at the Stanford University School of Medicine, has been an influential pioneer in shaping the scope and practice of pediatric anesthesia. His leadership helped to formally define the subspecialty of pediatric anesthesiology (who is a pediatric anesthesiologist?') and the importance of specialization and regionalization of expertise in both patient transport and perioperative care. His enduring impact on pediatric anesthesia and critical care practice was recognized in 2006 by the American Academy of Pediatrics when it bestowed upon him the profession's highest lifetime achievement award, the Robert M. Smith Award. Of his many contributions, Dr. Hackel identifies his early involvement in the development of pediatric transport medicine as well as the subspecialty of pediatric anesthesiology as his defining contribution. Based on a series of interviews held with Dr. Hackel between 2009 and 2014, this article reviews the early development of transportation medicine and the remarkable career of a pioneering pediatric anesthesiologist. C1 [Mai, Christine L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Mai, Christine L.] Massachusetts Eye & Ear Infirm, Dept Anesthesia, Boston, MA 02114 USA. [Ahmed, Zulfiqar] Wayne State Univ, Anesthesia Associates Ann Arbor, Detroit, MI USA. [Maze, Aubrey] Valley Anesthesiol & Pain Consultants, Phoenix, AZ USA. [Noorulla, Fatima] Wayne State Univ, Sch Med, Detroit, MI USA. [Yaster, Myron] Johns Hopkins Univ, Dept Anesthesiol, Baltimore, MD USA. [Yaster, Myron] Johns Hopkins Univ, Dept Crit Care Med, Baltimore, MD USA. [Yaster, Myron] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. RP Mai, CL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM cmai1@partners.org NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 EI 1460-9592 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD MAY PY 2016 VL 26 IS 5 BP 475 EP 480 DI 10.1111/pan.12880 PG 6 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA DJ1ZN UT WOS:000374003600003 PM 26992643 ER PT J AU Koh, KA Bharel, M Henderson, DC AF Koh, Katherine A. Bharel, Monica Henderson, David C. TI Nutrition for homeless populations: shelters and soup kitchens as opportunities for intervention SO PUBLIC HEALTH NUTRITION LA English DT Article DE Homeless; Nutrition; Shelters; Soup kitchens ID OBESITY AB Nutrition is a daily challenge for the homeless population in America. Homeless individuals suffer from a high prevalence of diseases related to poor diet, yet there has been little public health effort to improve nutrition in this population. Shelters and soup kitchens may have an untapped potential to impact food access, choice and quality. We offer ideas for intervention and lessons learned from ten shelters and soup kitchens around Greater Boston, MA, USA. By advancing food quality, education and policies in shelters and soup kitchens, the homeless population can be given an opportunity to restore its nutrition and health. C1 [Koh, Katherine A.; Henderson, David C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Koh, Katherine A.; Henderson, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Bharel, Monica] Massachusetts Dept Publ Hlth, Boston, MA USA. [Henderson, David C.] Massachusetts Gen Hosp, Freedom Trail Clin, Boston, MA 02114 USA. RP Koh, KA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Koh, KA (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM kakoh@post.harvard.edu NR 11 TC 0 Z9 0 U1 8 U2 12 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD MAY PY 2016 VL 19 IS 7 BP 1312 EP 1314 DI 10.1017/S1368980015002682 PG 3 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA DJ5IX UT WOS:000374241700019 PM 26434381 ER PT J AU Yamasaki, A Mise, Y Mise, Y Lee, JE Aloia, TA Katz, MH Chang, GJ Lillemoe, KD Raut, CP Conrad, C AF Yamasaki, Alisa Mise, Yoshihiro Mise, Yoko Lee, Jeffrey E. Aloia, Thomas A. Katz, Matthew H. Chang, George J. Lillemoe, Keith D. Raut, Chandrajit P. Conrad, Claudius TI Musical preference correlates closely to professional roles and specialties in operating room: A multicenter cross-sectional cohort study with 672 participants SO SURGERY LA English DT Article ID BACKGROUND MUSIC; PERFORMANCE; PROPOFOL; PERSONALITY; RECOVERY; SURGEONS AB Background. It is unclear whether music preferences and perceptions in the operating room (OR) differ by demographic and professional factors and how an improved understanding of these potential differences can be leveraged to enhance team dynamics and the OR work environment. Currently, there is limited knowledge regarding the impact of music on OR team concentration and communication. Methods. This study was a multicenter, cross-sectional study of 282 preoperative patients and 390 providers attending physicians, residents, and nurses in anesthesiology and surgery. Patient and provider responses were measured using a newly developed questionnaire. Results. Patients who highly enjoyed music felt music alleviated stress and enhanced concentration and communication and favored use of music in the OR. The genres favored most by patients were rock music (32%), classical music (28%), and top 40 hits (26 %). All providers reported a high frequency of use of music during the operation. Nurses and residents were more likely than attendings to report high enjoyment of music in the OR (P < .02). Surgeons and anesthesiologists had high median scores for enjoyment of music and low median scores for music as distraction. Anesthesiologists preferred classical and jazz/blues at lower volumes compared with surgeons, who favored top 40 music at higher noise pressure levels. Patients and providers perceived music to improve provider concentration and team communication; nurses held the most positive views. Conclusion. Musical preferences and perceptions of the effect of music in the OR differ by both professional status and specialty and provide insight into broader team dynamics that could be leveraged potentially to optimize the OR environment. C1 [Yamasaki, Alisa] Harvard Univ, Sch Med, Boston, MA USA. [Mise, Yoshihiro; Mise, Yoko] Tokyo Univ Hosp, Tokyo 113, Japan. [Lee, Jeffrey E.; Aloia, Thomas A.; Katz, Matthew H.; Chang, George J.; Conrad, Claudius] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Raut, Chandrajit P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Conrad, C (reprint author), Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Surg Oncol Hepatopancreatobiliary Surg, 1400 Pressler,Unit 1484, Houston, TX 77030 USA. EM cconrad1@mdanderson.org NR 23 TC 2 Z9 2 U1 6 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAY PY 2016 VL 159 IS 5 BP 1260 EP 1268 DI 10.1016/j.surg.2015.10.031 PG 9 WC Surgery SC Surgery GA DJ4WI UT WOS:000374208400003 PM 26706609 ER PT J AU Lo-Ciganic, WH Gellad, WF Gordon, AJ Cochran, G Zemaitis, MA Cathers, T Kelley, D Donohue, JM AF Lo-Ciganic, Wei-Hsuan Gellad, Walid F. Gordon, Adam J. Cochran, Gerald Zemaitis, Michael A. Cathers, Terri Kelley, David Donohue, Julie M. TI Association between trajectories of buprenorphine treatment and emergency department and in-patient utilization SO ADDICTION LA English DT Article DE Buprenorphine; group-based trajectory models; Medicaid; opioid agonist therapy; Opioid use disorders; trajectories; treatment duration; treatment patterns ID OFFICE-BASED TREATMENT; PRESCRIPTION OPIOID DEPENDENCE; HEALTH-CARE-SYSTEM; MEDICATION-ADHERENCE; MAINTENANCE THERAPY; AGONIST TREATMENT; USE DISORDER; HOSPITALIZATION; METHADONE; NONADHERENCE AB Background and aimsUncertainty about optimal treatment duration for buprenorphine opioid agonist therapy may lead to substantial variation in provider and payer decision-making regarding treatment course. We aimed to identify distinct trajectories of buprenorphine use and examine outcomes associated with these trajectories to guide health system interventions regarding treatment length. DesignRetrospective cohort study. SettingUS Pennsylvania Medicaid. PatientsA total of 10945 enrollees aged 18-64years initiating buprenorphine treatment between 2007 and 2012. MeasurementsGroup-based trajectory models were used to identify trajectories based on monthly proportion of days covered with buprenorphine in the 12months post-treatment initiation. We used separate multivariable Cox proportional hazard models to examine associations between trajectories and time to first all-cause hospitalization and emergency department (ED) visit within 12months after the first-year treatment. FindingsSix trajectories [Bayesian information criterion (BIC)=-86246.70] were identified: 24.9% discontinued buprenorphine <3months, 18.7% discontinued between 3 and 5months, 12.4% discontinued between 5 and 8months, 13.3% discontinued >8months, 9.5% refilled intermittently and 21.2% refilled persistently for 12months. Persistent refill trajectories were associated with an 18% lower risk of all-cause hospitalizations [hazard ratio (HR)=0.82, 95% confidence interval (CI)=0.70-0.95] and 14% lower risk of ED visits (HR=0.86, 95% CI=0.78-0.95) in the subsequent year, compared with those discontinuing between 3 and 5months. ConclusionsSix distinct buprenorphine treatment trajectories were identified in this population-based low-income Medicaid cohort in Pennsylvania, USA. There appears to be an association between persistent use of buprenorphine for 12months and lower risk of all-cause hospitalizations/emergency department visits. C1 [Lo-Ciganic, Wei-Hsuan] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Drachman Hall,Room 307E,1295 N Martin Ave, Tucson, AZ 85719 USA. [Lo-Ciganic, Wei-Hsuan; Gellad, Walid F.; Gordon, Adam J.; Cochran, Gerald; Zemaitis, Michael A.; Donohue, Julie M.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Hlth Policy Inst, Pittsburgh, PA USA. [Gellad, Walid F.; Gordon, Adam J.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Gellad, Walid F.; Gordon, Adam J.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Cochran, Gerald] Univ Pittsburgh, Sch Social Work, Pittsburgh, PA 15260 USA. [Zemaitis, Michael A.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Cathers, Terri; Kelley, David] Penn Dept Human Serv, Harrisburg, PA USA. [Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA USA. RP Lo-Ciganic, WH (reprint author), Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Drachman Hall,Room 307E,1295 N Martin Ave, Tucson, AZ 85719 USA. EM lociganic@pharmacy.arizona.edu OI Donohue, Julie/0000-0003-2418-6017 FU University of Pittsburgh Health Policy Institute, Center for Pharmaceutical Policy and Prescribing; Pennsylvania Department of Human Services; University of Pittsburgh; VA HSR&D Career Development Award FX We thank Dr. Bobby Jones for his assistance on performing group-based trajectory models. W.-H.L.-C. was funded by a post-doctoral fellowship through the University of Pittsburgh Health Policy Institute, Center for Pharmaceutical Policy and Prescribing. This work was supported in part by an intergovernmental agreement between the Pennsylvania Department of Human Services and the University of Pittsburgh. W.F.G. was supported by a VA HSR&D Career Development Award. NR 58 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD MAY PY 2016 VL 111 IS 5 BP 892 EP 902 DI 10.1111/add.13270 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DJ3HO UT WOS:000374095600019 PM 26662858 ER PT J AU Sidani, JE Shensa, A Shiffman, S Switzer, GE Primack, BA AF Sidani, J. E. Shensa, A. Shiffman, S. Switzer, G. E. Primack, B. A. TI Public health implications of waterpipe tobacco use in the United States warrant initial steps towards assessing dependence SO ADDICTION LA English DT Letter ID INTERMITTENT SMOKERS; PUFF TOPOGRAPHY; YOUNG-ADULTS; SMOKING; EXPOSURE C1 [Sidani, J. E.; Shensa, A.; Primack, B. A.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med,UPMC Montefiore Hosp, Pittsburgh, PA 15213 USA. [Sidani, J. E.; Shensa, A.; Primack, B. A.] Univ Pittsburgh, Ctr Res Media Technol & Hlth, Pittsburgh, PA USA. [Shiffman, S.] Pinney Associates, Pittsburgh, PA USA. [Switzer, G. E.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Switzer, G. E.] Univ Pittsburgh, Dept Med Psychiat Clin & Translat Sci, Pittsburgh, PA USA. [Primack, B. A.] Univ Pittsburgh, Sch Med, Dept Pediat, Div Adolescent Med, Pittsburgh, PA 15261 USA. RP Sidani, JE (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med,UPMC Montefiore Hosp, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [R21 CA185767, R01 CA140150] NR 16 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD MAY PY 2016 VL 111 IS 5 BP 937 EP 938 DI 10.1111/add.13316 PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DJ3HO UT WOS:000374095600024 PM 26987303 ER PT J AU Becker, KD Fischer, S Smith, GT Miller, JD AF Becker, Kendra Davis Fischer, Sarah Smith, Gregory T. Miller, Joshua D. TI The influence of negative urgency, attentional bias, and emotional dimensions on palatable food consumption SO APPETITE LA English DT Article DE Stroop; Food; Negative urgency; Arousal; Valence ID EATING-DISORDERS; STROOP INTERFERENCE; RESTRAINED EATERS; BULIMIA-NERVOSA; MODEL; IMPULSIVITY; METAANALYSIS; BEHAVIOR; ANGER; STRESS AB We tested a theoretical model concerning the role of attentional bias and negative affect in food consumption that offers important advances. We hypothesized that the effects of negative affect manipulations on food consumption vary as a function of trait levels of negative urgency (NU; tendency to act impulsively when distressed), and attentional bias and that the roles of emotional arousal and negative emotional valence differ and should be studied separately. 190 undergraduate women were randomly assigned to either an anger or neutral mood condition. Women in both conditions completed the Food Stroop, in which the presentation of food and neutral words were counterbalanced. After the task, participants were given the opportunity to eat mandarin oranges and/or chocolate candy while the experimenter was out of the room. The type and quantity of food consumed was counted after the participant departed. As hypothesized, the roles of emotional arousal and valence differed and the effect of the induced emotion was moderated by NU. Women high in NU who experienced emotional arousal were more likely to eat candy and consumed more candy than other women. Emotional valence had no effect on candy consumption. Neither increases in emotional arousal or emotional valence influenced attentional bias to food cues. Attentional bias was also unrelated to food consumption. The impact of negative mood inductions on palatable food consumption appears to operate through emotional arousal and not negative emotional valence, and it may operate primarily for women high in NU. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Becker, Kendra Davis; Miller, Joshua D.] Univ Georgia, Athens, GA 30602 USA. [Fischer, Sarah] George Mason Univ, Fairfax, VA 22030 USA. [Smith, Gregory T.] Univ Kentucky, Lexington, KY 40506 USA. RP Becker, KD (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 2 Longfellow Pl,Suite 200, Boston, MA 02114 USA. EM krbecker@mgh.harvard.edu NR 66 TC 0 Z9 0 U1 8 U2 18 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD MAY 1 PY 2016 VL 100 BP 236 EP 243 DI 10.1016/j.appet.2016.02.019 PG 8 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA DJ0BK UT WOS:000373866200028 PM 26877214 ER PT J AU Tegou, E Magana, M Katsogridaki, AE Ioannidis, A Raptis, V Jordan, S Chatzipanagiotou, S Chatzandroulis, S Ornelas, C Tegos, GP AF Tegou, Evangelia Magana, Maria Katsogridaki, Alexandra Eleni Ioannidis, Anastasios Raptis, Vasilios Jordan, Sheldon Chatzipanagiotou, Stylianos Chatzandroulis, Stavros Ornelas, Catia Tegos, George P. TI Terms of endearment: Bacteria meet graphene nanosurfaces SO BIOMATERIALS LA English DT Review DE Graphene; Carbon allotropes; Nanosurfaces; Antimicrobial resistance; Biocompatible therapeutics; Biosensing ID WALLED CARBON NANOTUBES; DIAMOND-LIKE CARBON; DEXTRAN FUNCTIONALIZED GRAPHENE; FULLERENE WATER SUSPENSIONS; ATOMIC-FORCE MICROSCOPY; CONTROLLED DRUG-RELEASE; ANTIBACTERIAL ACTIVITY; ANTIMICROBIAL ACTIVITY; ESCHERICHIA-COLI; IN-VIVO AB Microbial multidrug resistance poses serious risks in returning the human species into the pre-antibiotic era if it remains unsolved. While conventional research approaches to combat infectious diseases have been inadequate, nanomaterials are a promising alternative for the development of sound antimicrobial countermeasures. Graphene, a two-dimensional ultra-thin nanomaterial, possesses excellent electronic and biocompatibility properties, which position it in the biotechnology forefront for diverse applications in biosensing, therapeutics, diagnostics, drug delivery and device development. Yet, several questions remain unanswered. For instance, the way these nanosurfaces interact with the microbial entities is poorly understood. The mechanistic elucidation of this interface seems critical to determine the feasibility of applications under development. Are graphene derivatives appropriate materials to design potent antimicrobial agents, vehicles or effective diagnostic microsensors? Has the partition of major microbial resistance phenotypic determinants been sufficiently investigated? Can toxicity become a limiting factor? Are we getting closer to clinical implementation? To facilitate research conducive to answer such questions, this review describes the features of the graphene bacterial interaction. An overview on paradigms of graphene microbial interactions is expected to shed light on the range of materials available, and identify possible applications, serving the ultimate goal to develop deeper understanding and collective conscience for the true capabilities of this nanomaterial platform. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Tegou, Evangelia; Raptis, Vasilios; Chatzandroulis, Stavros] Natl Ctr Sci Res Demokritos, Inst Nanosci & Nanotechnol, Athens 15310, Greece. [Magana, Maria; Katsogridaki, Alexandra Eleni; Ioannidis, Anastasios; Chatzipanagiotou, Stylianos] Aeginit Hosp, Athens Med Sch, Dept Clin Microbiol, Athens, Greece. [Ioannidis, Anastasios] Univ Peloponnese, Fac Human Movement & Qual Life Sci, Dept Nursing, Sparta, Greece. [Jordan, Sheldon] Peptineo, 5901 Indian Sch Rd NE, Albuquerque, NM 87110 USA. [Ornelas, Catia] Univ Estadual Campinas, Inst Chem, UNICAMP, BR-13083970 Campinas, SP, Brazil. [Tegos, George P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Tegos, George P.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Tegos, GP (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM gtegos@mgh.harvard.edu RI Ornelas, Catia/H-4606-2011; OI Ornelas, Catia/0000-0001-8020-9776; Chatzipanagiotou, Stylianos/0000-0002-1251-8355; Jordan, Sheldon/0000-0002-4559-0919; Raptis, Vasilios/0000-0002-2276-8374 FU Greek State Scholarships Foundation (IKY grant) under the IKY fellowships of excellence for postgraduate studies in Greece-Siemens program [2013/22056]; Sao Paulo Research Foundation (FAPESP) [2013/11519-7]; Greek Public Benefit Foundation "Lilian Voudouri" [2014/272] FX This work was partially funded by the Greek State Scholarships Foundation (IKY grant #2013/22056) under the IKY fellowships of excellence for postgraduate studies in Greece-Siemens program (to ET). Financial support for CO has been provided by Sao Paulo Research Foundation (FAPESP, grant #2013/11519-7). MM was financially supported by scholarship from the Greek Public Benefit Foundation "Lilian Voudouri" (grant#2014/272). NR 299 TC 4 Z9 4 U1 55 U2 136 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD MAY PY 2016 VL 89 BP 38 EP 55 DI 10.1016/j.biomaterials.2016.02.030 PG 18 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DJ2YY UT WOS:000374072500004 PM 26946404 ER PT J AU Ren, XY Tu, V Bischoff, D Weisgerber, DW Lewis, MS Yamaguchi, DT Miller, TA Harley, BAC Lee, JC AF Ren, Xiaoyan Tu, Victor Bischoff, David Weisgerber, Daniel W. Lewis, Michael S. Yamaguchi, Dean T. Miller, Timothy A. Harley, Brendan A. C. Lee, Justine C. TI Nanoparticulate mineralized collagen scaffolds induce in vivo bone regeneration independent of progenitor cell loading or exogenous growth factor stimulation SO BIOMATERIALS LA English DT Article DE Bone regeneration; Biomimetic material; Nanoparticulate mineralization ID MESENCHYMAL STEM-CELLS; OSTEOGENIC DIFFERENTIATION; MORPHOGENETIC PROTEINS; SIGNALING PATHWAYS; CROSS-LINKING; DEFECT MODEL; GAG SCAFFOLD; FAMILY; RHBMP-2; FUSION AB Current strategies for skeletal regeneration often require co-delivery of scaffold technologies, growth factors, and cellular material. However, isolation and expansion of stem cells can be time consuming, costly, and requires an additional procedure for harvest. Further, the introduction of supraphysiologic doses of growth factors may result in untoward clinical side effects, warranting pursuit of alternative methods for stimulating osteogenesis. In this work, we describe a nanoparticulate mineralized collagen glycosaminoglycan scaffold that induces healing of critical-sized rabbit cranial defects without addition of expanded stem cells or exogenous growth factors. We demonstrate that the mechanism of osteogenic induction corresponds to an increase in canonical BMP receptor signalling secondary to autogenous production of BMP-2 and -9 early and BMP-4 later during differentiation. Thus, nanoparticulate mineralized collagen glycosaminoglycan scaffolds may provide a novel growth factor-free and ex vivo progenitor cell culture-free implantable method for bone regeneration. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ren, Xiaoyan; Tu, Victor; Miller, Timothy A.; Lee, Justine C.] Univ Calif Los Angeles, David Geffen Sch Med, Div Plast & Reconstruct Surg, 200 UCLA Med Plaza,Suite 465, Los Angeles, CA 90095 USA. [Ren, Xiaoyan; Tu, Victor; Miller, Timothy A.; Lee, Justine C.] Greater Los Angeles VA Healthcare Syst, Div Plast & Reconstruct Surg, Los Angeles, CA 90073 USA. [Ren, Xiaoyan; Tu, Victor; Bischoff, David; Yamaguchi, Dean T.; Lee, Justine C.] Greater Los Angeles VA Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Weisgerber, Daniel W.; Harley, Brendan A. C.] Univ Illinois, Inst Genom Biol, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Lewis, Michael S.] Greater Los Angeles VA Healthcare Syst, Dept Pathol, Los Angeles, CA 90073 USA. RP Lee, JC (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Plast & Reconstruct Surg, 200 UCLA Med Plaza,Suite 465, Los Angeles, CA 90095 USA. EM justine@ucla.edu OI Harley, Brendan/0000-0001-5458-154X FU US Department of Veterans Affairs [IK2 BX002442-01A2, 1I01BX001367-01A2]; Aramont Foundation; Jean Perkins Foundation; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [R21 AR063331]; AO Foundation, Switzerland [S-14-54H]; National Science Foundation (NSF) IGERT: Training the Next Generation of Researchers in Cellular & Molecular Mechanics and BioNanotechnology [0965918] FX This work was supported by the US Department of Veterans Affairs under award numbers IK2 BX002442-01A2 (JCL) and 1I01BX001367-01A2 (TAM), the Aramont Foundation (TAM), and the Jean Perkins Foundation (JCL). Research reported in this publication was also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R21 AR063331 (BACH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by project number S-14-54H by AO Foundation, Switzerland (BACH). DWW was funded at UIUC from National Science Foundation (NSF) Grant 0965918 IGERT: Training the Next Generation of Researchers in Cellular & Molecular Mechanics and BioNanotechnology. NR 48 TC 3 Z9 3 U1 9 U2 39 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD MAY PY 2016 VL 89 BP 67 EP 78 DI 10.1016/j.biomaterials.2016.02.020 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DJ2YY UT WOS:000374072500006 PM 26950166 ER PT J AU Hotta, R Cheng, LS Graham, HK Nagy, N Belkind-Gerson, J Mattheolabakis, G Amiji, MM Goldstein, AM AF Hotta, Ryo Cheng, Lily S. Graham, Hannah K. Nagy, Nandor Belkind-Gerson, Jaime Mattheolabakis, George Amiji, Mansoor M. Goldstein, Allan M. TI Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo SO BIOMATERIALS LA English DT Article DE Enteric neuropathies; Cell therapy; Serotonin; 5-HT4 receptor agonist; Liposomal nanoparticles; Thermosensitive hydrogel ID PLURONIC F-127 GELS; SYSTEM STEM-CELLS; NERVOUS-SYSTEM; NEURONS; RELEASE; GUT; SEROTONIN; DRUG; RAT; DISORDERS AB Cell therapy offers an innovative approach for treating enteric neuropathies. Postnatal gut-derived enteric neural stem/progenitor cells (ENSCs) represent a potential autologous source, but have a limited capacity for proliferation and neuronal differentiation. Since serotonin (5-HT) promotes enteric neuronal growth during embryonic development, we hypothesized that serotonin receptor agonism would augment growth of neurons from transplanted ENSCs. Postnatal ENSCs were isolated from 2 to 4 week-old mouse colon and cultured with 5-HT4 receptor agonist (RS67506)-loaded liposomal nano particles. ENSCs were co-cultured with mouse colon explants in the presence of RS67506-loaded (n = 3) or empty nanoparticles (n = 3). ENSCs were also transplanted into mouse rectum in vivo with RS67506-loaded (n = 8) or blank nanoparticles (n = 4) confined in a thermosensitive hydrogel, Pluronic F-127. Neuronal density and proliferation were analyzed immunohistochemically. Cultured ENSCs gave rise to significantly more neurons in the presence of RS67506-loaded nanoparticles. Similarly, colon explants had significantly increased neuronal density when RS67506-loaded nanoparticles were present. Finally, following in vivo cell delivery, co-transplantation of ENSCs with 5-HT4 receptor agonist-loaded nano particles led to significantly increased neuronal density and proliferation. We conclude that optimization of postnatal ENSCs can support their use in cell-based therapies for neurointestinal diseases. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Hotta, Ryo; Cheng, Lily S.; Graham, Hannah K.; Nagy, Nandor; Goldstein, Allan M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA USA. [Cheng, Lily S.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Nagy, Nandor] Semmelweis Univ, Fac Med, Dept Anat Histol & Embryol, H-1085 Budapest, Hungary. [Belkind-Gerson, Jaime] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mattheolabakis, George; Amiji, Mansoor M.] Northeastern Univ, Bouve Coll Hlth Sci, Sch Pharm, Dept Pharmaceut Sci, Boston, MA USA. RP Goldstein, AM (reprint author), Massachusetts Gen Hosp, Warren 1153, Boston, MA 02114 USA. EM agoldstein@partners.org FU Tosteson Fund for Medical Discovery at Massachusetts General Hospital; REACHirschsprung Foundation; Ethicon Surgical Research Fellowship Award from Society of University Surgeons; National Institutes of Health [R01DK103785] FX RH is supported by grants from the Tosteson Fund for Medical Discovery at Massachusetts General Hospital and from the REACHirschsprung Foundation. LC is supported by an Ethicon Surgical Research Fellowship Award from the Society of University Surgeons. AMG is supported by the National Institutes of Health (R01DK103785). NR 64 TC 4 Z9 4 U1 5 U2 32 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD MAY PY 2016 VL 88 BP 1 EP 11 DI 10.1016/j.biomaterials.2016.02.016 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DJ4SW UT WOS:000374199300001 PM 26922325 ER PT J AU Rugge, M Genta, RM Graham, DY Di Mario, F Coelho, LGV Kim, N Malfertheiner, P Sugano, K Tsukanov, V Correa, P AF Rugge, Massimo Genta, Robert M. Graham, David Y. Di Mario, Francesco Coelho, Luiz Gonzaga Vaz Kim, Nayoung Malfertheiner, Peter Sugano, Kentaro Tsukanov, Vladislav Correa, Pelayo TI Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment SO GUT LA English DT Article ID HELICOBACTER-PYLORI INFECTION; CHRONIC ATROPHIC GASTRITIS; INTESTINAL METAPLASIA; EPITHELIAL-DYSPLASIA; PRECANCEROUS LESIONS; MAGNIFYING ENDOSCOPY; MALT LYMPHOMA; CLASSIFICATION; MANAGEMENT; OLGA C1 [Rugge, Massimo] Univ Padua, Dept Med DIMED, Pathol & Cytopathol Unit, Padua, Italy. [Rugge, Massimo] Tumor Registry Veneto Reg, Padua, Italy. [Genta, Robert M.] Miraca Life Sci Res Inst, Irving, TX USA. [Genta, Robert M.] Univ Texas Southwestern Med Sch, Dallas, TX USA. [Graham, David Y.] Michael E De Bakey Vet Affairs Med Ctr, Dept Med, Houston, TX USA. [Graham, David Y.] Baylor Coll Med, Houston, TX 77030 USA. [Di Mario, Francesco] Univ Parma, Dept Clin & Expt Med, I-43100 Parma, Italy. [Coelho, Luiz Gonzaga Vaz] Univ Fed Minas Gerais, Inst Alfa Gastroenterol, Belo Horizonte, MG, Brazil. [Kim, Nayoung] Seoul Natl Univ, Bundang Hosp, Dept Internal Med, Songnam, Gyeonggi Do, South Korea. [Malfertheiner, Peter] Univ Med Ctr Magdeburg, Otto Von Guericke Univ, Dept Gastroenterol Hepatol & Infect Dis, Magdeburg, Germany. [Sugano, Kentaro] Jichi Med Univ, Dept Med, Shimotsuke, Tochigi, Japan. [Tsukanov, Vladislav] Russian Acad Med Sci, State Sci Med Res Inst, Northern Problems Siberian Div, Krasnoyarsk, Russia. [Correa, Pelayo] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Rugge, M (reprint author), Univ Padua, Surg Pathol & Cytopathol Unit, Dept Med DIMED, Via A Gabelli 61, I-35121 Padua, Italy. EM massimo.rugge@unipd.it RI Rugge, Massimo/K-7525-2016; Tsukanov, Vladislav/E-6638-2015 FU Italian Association for Cancer Research (AIRC) [6421]; Healthy Stomach Initiative (HSI) FX This work was partly supported by a grant from the Italian Association for Cancer Research (AIRC Regional grant 2008 N. 6421). This study was conducted under the cooperative auspices of the Healthy Stomach Initiative (HSI). NR 50 TC 3 Z9 3 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD MAY PY 2016 VL 65 IS 5 BP 721 EP + DI 10.1136/gutjnl-2015-310846 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ3QA UT WOS:000374119400001 PM 26927528 ER PT J AU Tulic, MK Vivinus-Nebot, M Rekima, A Medeiros, SR Bonnart, C Shi, HN Walker, A Dainese, R Boyer, J Vergnolle, N Piche, T Verhasselt, V AF Tulic, Meri K. Vivinus-Nebot, Mylene Rekima, Akila Medeiros, Samara Rabelo Bonnart, Chrystelle Shi, Haining Walker, Allan Dainese, Raffaella Boyer, Julien Vergnolle, Nathalie Piche, Thierry Verhasselt, Valerie TI Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction SO GUT LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; PROTEASE-ACTIVATED RECEPTOR-2; ORAL TOLERANCE; DERMATOPHAGOIDES-PTERONYSSINUS; MUC2 MUCIN; DISEASE; INFLAMMATION; DER-P-1; ASTHMA; RESPONSES AB Background Abnormal gut barrier function is the basis of gut inflammatory disease. It is known that house dust mite (HDM) aero-allergens induce inflammation in respiratory mucosa. We have recently reported allergen from Dermatophagoides pteronyssinus (Der p1) to be present in rodent gut. Objective To examine whether Der p1 is present in human gut and to assess its effect on gut barrier function and inflammation. Design Colonic biopsies, gut fluid, serum and stool were collected from healthy adults during endoscopy. Der p1 was measured by ELISA. Effect of HDM was assessed on gut permeability, tight-junction and mucin expression, and cytokine production, in presence or absence of cysteine protease inhibitors or serine protease inhibitors. In vivo effect of HDM was examined in mice given oral HDM or protease-neutralised HDM. Role of HDM in low-grade inflammation was studied in patients with IBS. Results HDM Der p1 was detected in the human gut. In colonic biopsies from healthy patients, HDM increased epithelial permeability (p< 0.001), reduced expression of tight-junction proteins and mucus barrier. These effects were associated with increased tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 production and were abolished by cysteine-protease inhibitor (p< 0.01). HDM effects did not require Th2 immunity. Results were confirmed in vivo in mice. In patients with IBS, HDM further deteriorated gut barrier function, induced TNF-alpha but failed to induce IL-10 secretion (p< 0.001). Conclusions HDM, a ubiquitous environmental factor, is present in the human gut where it directly affects gut function through its proteolytic activity. HDM may be an important trigger of gut dysfunction and warrants further investigation. C1 [Tulic, Meri K.; Vivinus-Nebot, Mylene; Rekima, Akila; Medeiros, Samara Rabelo; Dainese, Raffaella; Boyer, Julien; Piche, Thierry; Verhasselt, Valerie] Univ Nice Sophia Antipolis, EA Immune Tolerance TIM 6302, F-06189 Nice, France. [Tulic, Meri K.; Verhasselt, Valerie] Worldwide Univ Network, Int Inflammat In FLAME Network, New York, NY USA. [Vivinus-Nebot, Mylene] Univ Nice Sophia Antipolis, CHU Nice, Dept Immunol, Hop Archet 1, F-06189 Nice, France. [Medeiros, Samara Rabelo] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Inst Ciencias Biol, Belo Horizonte, MG, Brazil. [Bonnart, Chrystelle; Vergnolle, Nathalie] INSERM, CPTP, U1043, Toulouse, France. [Bonnart, Chrystelle; Vergnolle, Nathalie] CNRS, U5282, Toulouse, France. [Bonnart, Chrystelle; Vergnolle, Nathalie] Univ Toulouse, Site Paul Sabatier UPS, Toulouse, France. [Shi, Haining; Walker, Allan] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Charlestown, MA USA. [Dainese, Raffaella; Boyer, Julien; Piche, Thierry] Univ Nice Sophia Antipolis, CHU Nice, Hop Archet 2, Dept Gastroenterol & Nutr, F-06189 Nice, France. RP Tulic, MK; Verhasselt, V (reprint author), Univ Nice Sophia Antipolis, EA Immune Tolerance TIM 6302, Hop Archet 1, Route St Antoine Ginestiere BP3079, F-06202 Nice 03, France. EM meri.tulic@unice.fr; valerie.verhasselt@unice.fr RI BONNART, Chrystelle/A-1309-2011; Tulic, Meri/P-6613-2016 FU ITMO IHP-CMN; Institut National de la Sante et Recherche Medicale (INSERM); Universite de Nice Sophia-Antipolis; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) FX This work was supported by ITMO IHP-CMN funding, Institut National de la Sante et Recherche Medicale (INSERM) and the Universite de Nice Sophia-Antipolis. SRM was financed by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) scholarship while in France. NR 43 TC 3 Z9 4 U1 3 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD MAY PY 2016 VL 65 IS 5 BP 757 EP 766 DI 10.1136/gutjnl-2015-310523 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ3QA UT WOS:000374119400009 PM 26646935 ER PT J AU Chen, ST Burgin, S Soroka, MT AF Chen, Steven T. Burgin, Susan Soroka, Margaret T. TI A cross-sectional survey on the attitudes, perceptions, and motivations of patients who volunteer to teach dermatology to medical students SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Letter ID MELANOMA C1 [Chen, Steven T.; Burgin, Susan] Beth Israel Deaconess Med Ctr, Dept Dermatol, Boston, MA 02215 USA. [Soroka, Margaret T.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Steven T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA USA. RP Chen, ST (reprint author), Beth Israel Deaconess Med Ctr, Dept Dermatol, Boston, MA 02215 USA.; Chen, ST (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA USA. EM stchen@partners.org 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 0011-9059 EI 1365-4632 J9 INT J DERMATOL JI Int. J. Dermatol. PD MAY PY 2016 VL 55 IS 5 BP E317 EP E320 DI 10.1111/ijd.13151 PG 4 WC Dermatology SC Dermatology GA DJ1ZQ UT WOS:000374003900019 PM 26694766 ER PT J AU Afolabi, K Ali, S Gahtan, V Gorji, R Li, FH Nussmeier, NA AF Afolabi, Kola Ali, Sameer Gahtan, Vivian Gorji, Reza Li, Fenghua Nussmeier, Nancy A. TI Postoperative conversion disorder SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Editorial Material DE Anesthesia; General; Conversion disorder; Postoperative complications AB Conversion disorder is a psychiatric disorder in which psychological stress causes neurologic deficits. A 28-year-old female surgical patient had uneventful general anesthesia and emergence but developed conversion disorder 1 hour postoperatively. She reported difficulty speaking, right-hand numbness and weakness, and right-leg paralysis. Neurologic examination and imaging revealed no neuronal damage, herniation, hemorrhage, or stroke. The patient mentioned failing examinations the day before surgery and discontinuing her prescribed antidepressant medication, leading us to diagnose conversion disorder, with eventual confirmation by neuroimaging and follow-up examinations. (C) 2016 Elsevier Inc. All rights reserved. C1 [Afolabi, Kola; Gorji, Reza; Li, Fenghua; Nussmeier, Nancy A.] SUNY Upstate Med Univ, Dept Anesthesiol, Syracuse, NY 13210 USA. [Ali, Sameer] SUNY Upstate Med Univ, Dept Neurol, Syracuse, NY 13210 USA. [Gahtan, Vivian] SUNY Upstate Med Univ, Dept Surg, Div Vasc Surg & Endovasc Serv, Syracuse, NY 13210 USA. RP Nussmeier, NA (reprint author), SUNY Upstate Med Univ, Dept Anesthesiol, Syracuse, NY 13210 USA.; Nussmeier, NA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Gray Bgelow 441, Boston, MA 02114 USA. EM nnussmeier@partners.org NR 10 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 EI 1873-4529 J9 J CLIN ANESTH JI J. Clin. Anesth. PD MAY PY 2016 VL 30 BP 21 EP 23 DI 10.1016/j.jclinane.2015.12.002 PG 3 WC Anesthesiology SC Anesthesiology GA DJ1MF UT WOS:000373966200008 PM 27041258 ER PT J AU Zhao, J Yu, WF Tong, CY Xie, ZC Sun, JZ Zhou, SF Liu, H Meng, LZ AF Zhao, Jing Yu, Weifeng Tong, Chuanyao Xie, Zhongcong Sun, Jianzhong Zhou, Shao Feng Liu, Hong Meng, Lingzhong TI Adopting the American anesthesia oral examination in China: value and roadblocks SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE ABA oral examination; Adoption in China; Anesthesia training and certification; Value; Roadblocks; Pragmatic approach ID VALIDITY AB The quality and standardized training and certification of young physicians is key to the quality of health care in the future. In contrast to the American system, there is no nationwide and standardized oral examination in the training and certification process for anesthesiologists in China. The adoptability of the American anesthesia oral examination in China, as well as potential roadblocks, has not been specifically discussed. In this commentary, we share our experience of introducing the American oral examination to an audience of Chinese anesthesiologists and propose a pragmatic approach for adopting the anesthesia oral examination in China. This initiative has the potential to reform the current anesthesia training and certification process and improve the quality of anesthetic care in China. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zhao, Jing] Beijing Union Med Coll Hosp, Dept Anesthesiol, Beijing, Peoples R China. [Yu, Weifeng] Eastern Hepatobiliary Surg Hosp, Dept Anesthesiol, Shanghai, Peoples R China. [Yu, Weifeng] Renji Hosp, Dept Anesthesiol, Shanghai, Peoples R China. [Tong, Chuanyao] Wake Forest Baptist Med Ctr, Dept Anesthesiol, Winston Salem, NC USA. [Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Boston, MA USA. [Sun, Jianzhong] Thomas Jefferson Univ & Hosp, Dept Anesthesiol, Philadelphia, PA USA. [Zhou, Shao Feng] Univ Texas Hlth Sci Ctr Houston, Dept Anesthesiol, Houston, TX 77030 USA. [Liu, Hong] Univ Calif Davis Hlth Syst, Dept Anesthesiol & Pain Med, Sacramento, CA USA. [Meng, Lingzhong] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, 500 Parnassus Ave,Box 0648, San Francisco, CA 94143 USA. RP Meng, LZ (reprint author), Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, 500 Parnassus Ave,Box 0648, San Francisco, CA 94143 USA. EM zhaojing1009@aliyun.com; ywf808@yeah.net; cyt970@yahoo.com; zxie@hms.harvard.edu; jian-zhong.sun@jefferson.edu; Shao.Feng.Zhou@uth.tmc.edu; hong.liu@ucdmc.ucdavis.edu; lingzhong.meng@ucsf.edu FU Medtronic FX We thank Zhenmeng Wang, MD, PhD (Eastern Hepatobiliary Surgery Hospital, Shanghai, China) and Jianxia Meng, MD (Peking Union Medical College Hospital, Beijing, China) for their assistance in workshop coordination and survey distribution/collection. We thank the Chinese Association of Anesthesiologists (CAA) and the ICAA for providing the resources. We thank Covidien Healthcare International Trading (Shanghai) Co. Ltd. (now affiliated with Medtronic) for sponsoring the workshop. NR 5 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 EI 1873-4529 J9 J CLIN ANESTH JI J. Clin. Anesth. PD MAY PY 2016 VL 30 BP 42 EP 45 DI 10.1016/j.jclinane.2015.12.047 PG 4 WC Anesthesiology SC Anesthesiology GA DJ1MF UT WOS:000373966200012 PM 27041262 ER PT J AU Tsai, AC Wolfe, WR Kumbakumba, E Kawuma, A Hunt, PW Martin, JN Bangsberg, DR Weiser, SD AF Tsai, Alexander C. Wolfe, William R. Kumbakumba, Elias Kawuma, Annet Hunt, Peter W. Martin, Jeffrey N. Bangsberg, David R. Weiser, Sheri D. TI Prospective Study of the Mental Health Consequences of Sexual Violence Among Women Living With HIV in Rural Uganda SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE HIV; domestic violence; rape; Uganda; depressive disorder ID INTIMATE-PARTNER VIOLENCE; SUB-SAHARAN AFRICA; STRESSFUL LIFE EVENTS; QUALITY-OF-LIFE; CD4 CELL COUNT; SURVEY MOS-HIV; DAR-ES-SALAAM; MEDICAL OUTCOMES; DEPRESSIVE SYMPTOMS; DOMESTIC VIOLENCE AB The association between sexual violence and depression is well known, but the temporal aspects of the association have not been well established. We analyzed data from a cohort of 173 HIV-positive women in rural Uganda who were interviewed every 3 months for a median of 1.8 years of follow-up. The method of generalized estimating equations (GEE) was used to model the marginal expectation of depression symptom severity (Hopkins Symptom Checklist for Depression), mental health-related quality of life (MOS-HIV Mental Health Summary), and heavy drinking (Alcohol Use Disorders Identification Test) as a function of self-reported forced-sex victimization in the 3 months prior to interview. Estimates were adjusted for variables known to confound the association between victimization and mental health status. To assess any potential reciprocal relationships, we reversed the temporal ordering of the exposures and outcomes and refitted similar GEE models. In multivariable analyses, victimization was associated with greater depression symptom severity (b = 0.17; 95% CI = [0.02, 0.33]) and lower mental health-related quality of life (b = -5.65; 95% CI = [-9.34, -1.96]), as well as increased risks for probable depression (adjusted relative risk [ARR] = 1.58; 95% CI = [1.01, 2.49) and heavy drinking (ARR = 3.99; 95% CI = [1.84, 8.63]). We did not find strong evidence of a reciprocal relationship. Our findings suggest that forced sex is associated with adverse mental health outcomes among HIV-positive women in rural Uganda. Given the substantial mental health-related impacts of victimization, effective health sector responses are needed. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.; Kumbakumba, Elias; Kawuma, Annet; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Tsai, Alexander C.] Harvard Univ, Sch Med, Psychiat, Boston, MA USA. [Wolfe, William R.] Univ Calif San Francisco, Psychiat, San Francisco, CA 94143 USA. [Hunt, Peter W.; Weiser, Sheri D.] Univ Calif San Francisco, Med Residence, San Francisco, CA 94143 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Epidemiol & Biostat Residence, San Francisco, CA 94143 USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Health, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Med, Boston, MA USA. [Bangsberg, David R.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Health, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU U.S. National Institutes of Health [R01MH054907, P30A1027763]; [K23MH096620]; [K24MH087227]; [K23MH079713] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Uganda AIDS Rural Treatment Outcomes study is funded by U.S. National Institutes of Health R01MH054907 and P30A1027763. The authors also acknowledge additional salary support through K23MH096620, K24MH087227, and K23MH079713. NR 112 TC 3 Z9 3 U1 6 U2 8 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 MAY PY 2016 VL 31 IS 8 BP 1531 EP 1553 DI 10.1177/0886260514567966 PG 23 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA DJ1FO UT WOS:000373948900008 PM 25586914 ER PT J AU Eichinger, JK Miller, LR Hartshorn, T Li, XN Warner, JJP Higgins, LD AF Eichinger, Josef K. Miller, Lindsay R. Hartshorn, Timothy Li, Xinning Warner, Jon J. P. Higgins, Laurence D. TI Evaluation of satisfaction and durability after hemiarthroplasty and total shoulder arthroplasty in a cohort of patients aged 50 years or younger: an analysis of discordance of patient satisfaction and implant survival SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Shoulder arthroplasty; young patients; patient satisfaction; implant survival ID PRIMARY GLENOHUMERAL OSTEOARTHRITIS; ROTATOR CUFF TEARS; QUALITY-OF-LIFE; FOLLOW-UP; NEER HEMIARTHROPLASTY; GLENOID COMPONENT; REPLACEMENT; MOTION; ARTHRITIS; OLD AB Background: Shoulder arthroplasty in individuals aged 50 years or younger reportedly leads to worse outcomes than in older patients. Current methods of determining survivorship may be inadequate and may not reflect actual patient definitions of satisfaction. The purpose of this study is to evaluate and contrast the survival of patient satisfaction and implant survival in the youngest reported patients undergoing either a primary hemiarthroplasty (HA) or total shoulder arthroplasty (TSA) using a third-generation stemmed prosthesis. Methods: Outcomes in 71 patients aged 50 years or younger who were treated with primary HA or TSA were evaluated for patient satisfaction and implant survival rates. Patient satisfaction survival was based on yes or no answers to 2 binary questions regarding willingness to undergo surgery again and whether surgery improved the patient's shoulder. Results: The Kaplan-Meier patient satisfaction survival rates at 5 years were 71.6% (95% confidence interval [ CI], 46%-87%) for HAs and 95% (95% CI, 81%-99%) for TSAs. Multivariable regression analysis implicated postoperative pain as the primary causative factor for failure of patient satisfaction in all patients. In contrast, the implant survival rates at 5 years were 89% (95% CI, 69%-96%) for HAs and 95% (CI, 85%-100%) for TSAs. Conclusions: Patients aged 50 years or younger who undergo shoulder arthroplasty have declining rates of self-reported satisfaction despite high implant survival rates, and this finding highlights the discordance between patient satisfaction and implant survival. Primary TSA outperforms HA in both implant survival and patient satisfaction survival rates at short-term follow-up. Future studies and registries must incorporate measurements of patient satisfaction and not just revision rates to truly interpret outcomes. Level of evidence: Level III, Retrospective Cohort Design, Treatment Study. Published by Elsevier Inc. on behalf of Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Eichinger, Josef K.] Madigan Army Med Ctr, Orthopaed Serv, 9040 Fitzsimmons Dr, Tacoma, WA 98431 USA. [Miller, Lindsay R.; Higgins, Laurence D.] Brigham & Womens Hosp, Dept Orthoped Surg, Sports Med & Shoulder Serv, 75 Francis St, Boston, MA 02115 USA. [Hartshorn, Timothy] Beach Cities Orthoped & Sports Med, Manhattan Beach, CA USA. [Li, Xinning] Boston Univ, Sch Med, Dept Orthopaed Surg, Boston, MA 02118 USA. [Warner, Jon J. P.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Shoulder Serv, Boston, MA 02114 USA. RP Eichinger, JK (reprint author), Madigan Army Med Ctr, Orthopaed Serv, 9040 Fitzsimmons Dr, Tacoma, WA 98431 USA. EM joe.eichinger@gmail.com OI Eichinger, Josef/0000-0001-8563-7307 NR 47 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2016 VL 25 IS 5 BP 772 EP 780 DI 10.1016/j.jse.2015.09.028 PG 9 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DJ3PI UT WOS:000374117400014 PM 26700556 ER PT J AU Lubberts, B Janssen, S Mellema, J Ring, D AF Lubberts, Bart Janssen, Stein Mellema, Jos Ring, David TI Quantitative 3-dimensional computed tomography analysis of olecranon fractures SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Computed tomography; quantitative; olecranon; fracture; Mayo classification ID ELBOW AB Hypothesis/Background: Olecranon fractures have variable size of the proximal fragment, patterns of fragmentation, and subluxation of the ulnohumeral joint that might be better understood and categorized on the basis of quantitative 3-dimensional computed tomography analysis. Mayo type I fractures are undisplaced, Mayo type II are displaced and stable, and Mayo type III are displaced and unstable. The last is categorized into anterior and posterior dislocations. The purpose of this study was to further clarify fracture morphology between Mayo type I, II, and III fractures. Methods: Three-dimensional models were created for a consecutive series of 78 patients with olecranon fractures that were evaluated with computed tomography. We determined the total number of fracture fragments, the volume and articular surface area of each fracture fragment, and the degree of displacement of the most proximal olecranon fracture fragment. Results: Displaced olecranon fractures were more comminuted than nondisplaced fractures (P=.02). Displaced fractures without ulnohumeral subluxation were smallest in terms of both volume (P<.001) and articular surface involvement (P<.001) of the most proximal olecranon fracture fragment. There was no difference in average displacement of the proximal fragment between displaced fractures with and without ulnohumeral subluxation (P=.74). Anterior olecranon fracture-dislocations created more displaced (P=.04) and smaller proximal fragments than posterior fracture-dislocations (P=.005), with comparable fragmentation on average (P=.60). Discussion/Conclusion: The ability to quantify volume, articular surface area, displacement, and fragmentation using quantitative 3-dimensional computed tomography should be considered when increased knowledge of fracture morphology and fracture patterns might be useful. Level of evidence: Basic Science Study; Anatomy; Imaging (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Lubberts, Bart; Janssen, Stein; Mellema, Jos; Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, Boston, MA USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Suite 1-114AC MC R1800, Austin, TX 78723 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Suite 1-114AC MC R1800, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu OI Ring, David/0000-0002-6506-4879 FU Skeletal Dynamics; Biomet FX David C. Ring has received study-specific grants from Skeletal Dynamics and Biomet. He is a consultant for Wright Medical, Skeletal Dynamics, and Acumed. He receives honoraria from AO North America and AO International. He receives royalties from Wright Medical, Biomet, and Skeletal Dynamics. He has stock options in Illuminos. All the other authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article. NR 17 TC 1 Z9 1 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 MAY PY 2016 VL 25 IS 5 BP 831 EP 836 DI 10.1016/j.jse.2015.10.002 PG 6 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DJ3PI UT WOS:000374117400022 PM 26711473 ER PT J AU Wanner, M Sakamoto, FH Avram, MM Anderson, RR AF Wanner, Molly Sakamoto, Fernanda H. Avram, Mathew M. Anderson, R. Rox TI Immediate skin responses to laser and light treatments Warning endpoints: How to avoid side effects SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE adverse effects; endpoint; laser; light; skin; warning ID PULSED-DYE-LASER; ND-YAG LASER; SWITCHED RUBY-LASER; PORT-WINE STAINS; INTENSE ULTRASOUND THERAPY; DYNAMIC COOLING DEVICE; SHAM-CONTROLLED TRIAL; CARBON-DIOXIDE LASER; 1450-NM DIODE-LASER; 755 NM ALEXANDRITE AB Lasers are versatile, commonly used treatment tools in dermatology. While it is tempting to follow manufacturer's guidelines or other "recipes'' for laser treatment, this approach alone can be a recipe for disaster. Specific and immediate skin responses or endpoints exist and are clinically useful because they correlate with underlying mechanisms that are either desirable (ie, therapeutic), undesirable (ie, warning signs of injury or side effects), or incidental. The observation of clinical endpoints is a safe and reliable guide for appropriate treatment. This article presents the warning endpoints during specific dermatologic laser treatments, and the accompanying article presents the therapeutic endpoints, their underlying mechanisms, and the utility of these endpoints. C1 [Wanner, Molly; Sakamoto, Fernanda H.; Avram, Mathew M.; Anderson, R. Rox] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA USA. [Sakamoto, Fernanda H.; Avram, Mathew M.; Anderson, R. Rox] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. RP Wanner, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Ste 200, Boston, MA 02114 USA. EM mwanner@partners.org NR 115 TC 0 Z9 0 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP 807 EP 819 DI 10.1016/j.jaad.2015.06.025 PG 13 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100012 PM 27085227 ER PT J AU Wanner, M Sakamoto, FH Avram, MM Chan, HH Alam, M Tannous, Z Anderson, RR AF Wanner, Molly Sakamoto, Fernanda H. Avram, Mathew M. Chan, Henry H. Alam, Murad Tannous, Zeina Anderson, R. Rox TI Immediate skin responses to laser and light treatments Therapeutic endpoints: How to obtain efficacy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE endpoint; immediate skin responses; laser; light; skin; therapeutic ID PULSED-DYE-LASER; Q-SWITCHED RUBY; PORT-WINE STAINS; ND-YAG LASER; ASSISTED HAIR REMOVAL; ALUMINUM-GARNET LASER; 800-NM DIODE-LASER; 755 NM ALEXANDRITE; GUINEA-PIG SKIN; IN-VIVO AB Clinical endpoints are immediate or early tissue reactions that occur during laser treatment. They can guide the laser surgeon in delivering safe and effective laser treatment. Some endpoints act as warning signs of injury to the skin; others can indicate a therapeutic response. The first article in this series reviewed undesirable and warning endpoints, and this article focuses on desirable and therapeutic endpoints and their underlying mechanisms in laser surgery. We will also review treatments without clinical endpoints. C1 [Wanner, Molly; Sakamoto, Fernanda H.; Avram, Mathew M.; Anderson, R. Rox] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Sakamoto, Fernanda H.; Avram, Mathew M.; Anderson, R. Rox] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. [Chan, Henry H.] Univ Hong Kong, Dept Med, Pokfulam, Hong Kong, Peoples R China. [Alam, Murad] Northwestern Univ, Dept Dermatol, Chicago, IL 60611 USA. [Tannous, Zeina] Lebanese Amer Univ, Sch Med, Beirut, Lebanon. RP Wanner, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Ste 200, Boston, MA 02114 USA. EM mwanner@partners.org RI Chan, Henry Hin Lee/L-2267-2013 FU Allergan; Cutera; CynoSure; Solta; Syneron; Access Business Group; Zeltiq; Regeneron; Basis Medical Technologies; Lumenis; McGraw-Hill; Quanta System; Ulthera; Cytrellis; Venus Concept; OptMed [PD-100-002] FX Massachusetts General Hospital receives royalties from laser companies, but none are related to this manuscript. Dr Avram is on the advisory board of and is a consultant for Zeltiq, a consultant for Kythera, and an investigator for Cutera. Dr Chan receives honoraria, equipment, stock, or other financial benefits from the following companies: Allergan, Cutera, CynoSure, Solta, Syneron, Access Business Group, Zeltiq, Regeneron, Basis Medical Technologies, Lumenis, McGraw-Hill, Quanta System, Ulthera, Cytrellis, and Venus Concept. Dr Alam received a grant (PD-100-002) from OptMed paid to his employer, Northwestern University, royalties from Elsevier, and has a consulting relationship with Amway. NR 87 TC 0 Z9 0 U1 6 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP 821 EP 833 DI 10.1016/j.jaad.2015.06.026 PG 13 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100013 PM 27085228 ER PT J AU Strober, BE Bissonnette, R Fiorentino, D Kimball, AB Naldi, L Shear, NH Goyal, K Fakharzadeh, S Calabro, S Langholff, W You, Y Galindo, C Lee, S Lebwohl, MG AF Strober, Bruce E. Bissonnette, Robert Fiorentino, David Kimball, Alexa B. Naldi, Luigi Shear, Neil H. Goyal, Kavitha Fakharzadeh, Steven Calabro, Stephen Langholff, Wayne You, Yin Galindo, Claudia Lee, Seina Lebwohl, Mark G. TI Comparative effectiveness of biologic agents for the treatment of psoriasis in a real-world setting: Results from a large, prospective, observational study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE adalimumab; biologic; BSA; DLQI; effectiveness; efficacy; etanercept; infliximab; PGA; PSOLAR; Psoriasis Longitudinal Assessment and Registry; ustekinumab ID TO-SEVERE PSORIASIS; RANDOMIZED CONTROLLED-TRIAL; SEVERE PLAQUE PSORIASIS; QUALITY-OF-LIFE; PATIENT-REPORTED OUTCOMES; PHASE-III TRIAL; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; DISEASE-BASED REGISTRY; DOUBLE-BLIND; SYSTEMIC TREATMENTS AB Background: Comparing effectiveness of biologics in real-world settings will help inform treatment decisions. Objectives: We sought to compare therapeutic responses among patients initiating infliximab, adalimumab, or etanercept versus ustekinumab during the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Methods: Proportions of patients achieving a Physician Global Assessment score of clear (0)/minimal (1) and mean decrease in percentage of body surface area with psoriasis were evaluated at 6 and 12 months. Adjusted logistic regression (Physician Global Assessment score 0/1) and analysis of covariance (percentage of body surface area with psoriasis) were performed to determine treatment factors associated with effectiveness. Results: Of 2541 new users on registry, 2076 had efficacy data: ustekinumab (n = 1041), infliximab (n = 116), adalimumab (n = 662), and etanercept (n = 257). Patients receiving tumor necrosis factor-alpha(-alpha) inhibitors were significantly less likely to achieve Physician Global Assessment score 0/1 versus ustekinumab (infliximab [odds ratio {OR} 0.396, P < .0001], adalimumab [OR 0.686, P =.0012], etanercept [OR 0.554, P =.0003] at 6 months and infliximab [OR 0.449, P =.0040] at 12 months). Mean decrease in percentage of body surface area with psoriasis was significantly greater for ustekinumab versus adalimumab (point estimate 1.833, P =.0020) and etanercept (point estimate 3.419, P < .0001) at 6 months and versus infliximab (point estimate 3.945, P =.0005) and etanercept (point estimate 2.778, P =.0007) at 12 months. Limitations: Treatment selection bias and limited data for doing adjustments are limitations. Conclusions: In PSOLAR, effectiveness of ustekinumab was significantly better versus all 3 tumor necrosis factor-a inhibitors studied for the majority of comparisons at 6 and 12 months. C1 [Strober, Bruce E.] Univ Connecticut, Ctr Hlth, 21 S Rd,Second Floor, Farmington, CT 06032 USA. [Strober, Bruce E.] Prob Med Res, Waterloo, ON, Canada. [Bissonnette, Robert] Innovaderm Res Inc, Montreal, PQ, Canada. [Fiorentino, David] Stanford Univ, Dept Dermatol, Stanford, CA 94305 USA. [Kimball, Alexa B.] Harvard Univ, Sch Med, Dept Dermatol, Cambridge, MA 02138 USA. [Kimball, Alexa B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Naldi, Luigi] Azienda Osped Papa Giovanni XIII, Ctr Studi Grp Italiano Studi Epidemiol Dermatol G, Bergamo, Italy. [Shear, Neil H.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Goyal, Kavitha; Fakharzadeh, Steven; Calabro, Stephen; Galindo, Claudia] Janssen Sci Affairs LLC, Los Angeles, CA USA. [Langholff, Wayne; You, Yin] Janssen Res & Dev LLC, Los Angeles, CA USA. [Lee, Seina] Janssen Hlth Econ & Outcomes Res, Horsham, PA USA. [Lebwohl, Mark G.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Strober, BE (reprint author), Univ Connecticut, Ctr Hlth, 21 S Rd,Second Floor, Farmington, CT 06032 USA. EM strober@uchc.edu RI Naldi, Luigi/K-6343-2016 OI Naldi, Luigi/0000-0002-3160-2835 FU Janssen Scientific Affairs, LLC FX This study was sponsored by Janssen Scientific Affairs, LLC (clincialtrials.gov: NCT00508547). NR 37 TC 4 Z9 4 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP 851 EP + DI 10.1016/j.jaad.2015.12.017 PG 15 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100016 PM 26853180 ER PT J AU Gibson, JF Huang, J Liu, KJ Carlson, KR Foss, F Choi, J Edelson, R Hussong, JW Mohl, R Hill, S Girardi, M AF Gibson, Juliet F. Huang, Jing Liu, Kristina J. Carlson, Kacie R. Foss, Francine Choi, Jaehyuk Edelson, Richard Hussong, Jerry W. Mohl, Ramsey Hill, Sally Girardi, Michael TI Cutaneous T-cell lymphoma (CTCL): Current practices in blood assessment and the utility of T-cell receptor (TCR)-V beta chain restriction SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE cutaneous T-cell lymphoma; flow cytometry; mycosis fungoides; peripheral blood analysis; Sezary syndrome; T-cell receptor-V beta ID V-BETA ANTIBODIES; SEZARY-SYNDROME; PERIPHERAL-BLOOD; MYCOSIS-FUNGOIDES; FLOW-CYTOMETRY; INVOLVEMENT; LYMPHOCYTES; EXPRESSION; DISORDERS; RELEVANCE AB Background: Accurate quantification of malignant cells in the peripheral blood of patients with cutaneous T-cell lymphoma is important for early detection, prognosis, and monitoring disease burden. Objective: We sought to determine the spectrum of current clinical practices; critically evaluate elements of current International Society for Cutaneous Lymphomas (ISCL) B-1 and B-2 staging criteria; and assess the potential role of T-cell receptor-V beta analysis by flow cytometry. Methods: We assessed current clinical practices by survey, and performed a retrospective analysis of 161 patients evaluated at Yale (2011-2014) to compare the sensitivity, specificity, positive predictive value, and negative predictive value of parameters for ISCL B2 staging. Results: There was heterogeneity in clinical practices among institutions. ISCL B1 criteria did not capture 5 Yale cohort cases with immunophenotypic abnormalities that later progressed. T-cell receptor-V beta testing was more specific than polymerase chain reaction and aided diagnosis in detecting clonality, but was of limited benefit in quantification of tumor burden. Limitations: Because of limited follow-up involving a single center, further investigation will be necessary to conclude whether our proposed diagnostic algorithm is of general clinical benefit. Conclusion: We propose further study of modified B-1 criteria: CD4/CD8 ratio 5 or greater, % CD4(+) CD26(-) 20% or greater, or % CD4(+) CD7(-) 20% or greater, with evidence of clonality. T-cell receptor-V beta testing should be considered in future diagnostic and staging algorithms. C1 [Gibson, Juliet F.; Carlson, Kacie R.; Choi, Jaehyuk; Edelson, Richard; Girardi, Michael] Yale Univ, Sch Med, Dept Dermatol, 333 Cedar St,POB 208059, New Haven, CT 06520 USA. [Foss, Francine] Yale Univ, Sch Med, Dept Hematol & Oncol, New Haven, CT 06520 USA. [Huang, Jing] New York Presbyterian Hosp, Dept Dermatol, Weill Cornell Med Ctr, New York, NY USA. [Liu, Kristina J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Cambridge, MA 02138 USA. [Hussong, Jerry W.; Mohl, Ramsey; Hill, Sally] Univ Utah, ARUP Labs, Dept Pathol, Salt Lake City, UT 84112 USA. RP Girardi, M (reprint author), Yale Univ, Sch Med, Dept Dermatol, 333 Cedar St,POB 208059, New Haven, CT 06520 USA. EM michael.girardi@yale.edu FU Yale SPORE in Skin Cancer from National Institutes of Health/National Cancer Institute [1P50CA121974] FX Supported by Yale SPORE in Skin Cancer (grant # 1P50CA121974 from National Institutes of Health/National Cancer Institute). NR 26 TC 2 Z9 2 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP 870 EP 877 DI 10.1016/j.jaad.2015.12.018 PG 8 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100018 PM 26874819 ER PT J AU Haedersdal, M Erlendsson, AM Paasch, U Anderson, RR AF Haedersdal, Merete Erlendsson, Andres M. Paasch, Uwe Anderson, R. Rox TI Translational medicine in the field of ablative fractional laser (AFXL)-assisted drug delivery: A critical review from basics to current clinical status SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE ablative fractional laser; cutaneous; drug delivery; laser; laser-assisted drug delivery; topical administration; transcutaneous ID CARBON-DIOXIDE LASER; ERBIUM-YAG LASER; ASSISTED PHOTODYNAMIC THERAPY; ORGAN TRANSPLANT RECIPIENTS; ENHANCE SKIN PERMEATION; BASAL-CELL CARCINOMA; 12-MONTH FOLLOW-UP; TRANSDERMAL DELIVERY; METHYL AMINOLEVULINATE; HISTOLOGICAL CHARACTERIZATION AB Background: Ablative fractional lasers enhance uptake of topical therapeutics and the concept of fractional laser-assisted drug delivery has now been taken into clinical practice. Objectives: We systematically reviewed preclinical data and clinical evidence for fractional lasers to enhance drug uptake and improve clinical efficacy. Methods: We searched PubMed and Embase databases; 34 articles met the inclusion criteria. Studies were categorized into experimental preclinical studies and clinical trials, the latter graded according to level of evidence. Results: All preclinical trials (n = 16) documented enhanced topical drug uptake into skin after ablative fractional laser treatment. Clinical evidence encompassed 18 studies, of which 9 were randomized controlled trials and 2 were controlled trials, examining neoplastic lesions, photodamaged skin, scars, onychomycosis, and topical anesthetics. The highest level of evidence was reached for actinic keratoses treated with methylaminolevulinate for photodynamic therapy (level IB, 5 randomized controlled trials), substantiating superior and long-lasting efficacy versus conventional photodynamic therapy. No adverse events were reported, but ablative fractional laser-assisted drug delivery implies risks of systemic drug absorption, especially when performed over large skin areas. Conclusions: Fractional laser-assisted drug delivery is beneficial in enhancing preclinical and clinical outcomes for certain skin conditions. C1 [Haedersdal, Merete; Erlendsson, Andres M.] Univ Copenhagen, Bispebjerg Hosp, Dept Dermatol, DK-1168 Copenhagen, Denmark. [Haedersdal, Merete; Erlendsson, Andres M.; Anderson, R. Rox] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02138 USA. [Paasch, Uwe] Univ Leipzig, Dept Dermatol, D-04109 Leipzig, Germany. [Paasch, Uwe] Univ Leipzig, Dept Venereol, D-04109 Leipzig, Germany. [Paasch, Uwe] Univ Leipzig, Dept Allergol, D-04109 Leipzig, Germany. RP Haedersdal, M (reprint author), Bispebjerg Hosp, Dept Dermatol, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark. EM mhaedersdal@dadlnet.dk NR 89 TC 5 Z9 5 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP 981 EP 1004 DI 10.1016/j.jaad.2015.12.008 PG 24 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100030 PM 26936299 ER PT J AU Chen, C Mikailov, A Kroshinsky, D AF Chen, Chen (Amy) Mikailov, Anar Kroshinsky, Daniela TI A widespread eruption with sloughing SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material C1 [Chen, Chen (Amy); Kroshinsky, Daniela] Harvard Univ, Sch Med, Boston, MA USA. [Mikailov, Anar; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM dkroshinsky@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP E87 EP E88 DI 10.1016/j.jaad.2015.10.017 PG 2 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100001 PM 27085244 ER PT J AU Kim, JB Ejiofor, JI Yammine, M Camuso, JM Walsh, CW Ando, M Melnitchouk, SI Rawn, JD Leacche, M MacGillivray, TE Cohn, LH Byrne, JG Sundt, TM AF Kim, Joon Bum Ejiofor, Julius I. Yammine, Maroun Camuso, Janice M. Walsh, Conor W. Ando, Masahiko Melnitchouk, Serguei I. Rawn, James D. Leacche, Marzia MacGillivray, Thomas E. Cohn, Lawrence H. Byrne, John G. Sundt, Thoralf M. TI Are homografts superior to conventional prosthetic valves in the setting of infective endocarditis involving the aortic valve? SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE Infective endocarditis; surgery; valve replacement; homograft; prognosis ID SURGICAL-TREATMENT; ACTIVE ENDOCARDITIS; CLINICAL-OUTCOMES; ROOT REPLACEMENT; GUIDELINES; EXPERIENCE; ALLOGRAFTS; MORTALITY; SURVIVAL; SURGERY AB Background: Surgical dogma suggests that homografts should be used preferentially, compared with conventional xenograft or mechanical prostheses, in the setting of infective endocarditis (IE), because they have greater resistance to infection. However, comparative data that support this notion are limited. Methods: From the prospective databases of 2 tertiary academic centers, we identified 304 consecutive adult patients (age >= 17 years) who underwent surgery for active IE involving the aortic valve (AV), in the period 2002 to 2014. Short-and long-term outcomes were evaluated using propensity scores and inverse-probability weighting to adjust for selection bias. Results: Homografts, and xenograft and mechanical prostheses, were used in 86 (28.3%), 139 (45.7%), and 79 (26.0%) patients, respectively. Homografts were more often used in the setting of prosthetic valve endocarditis (58.1% vs 28.8%, P = .002) and methicillin-resistant Staphylococcus (25.6% vs 12.1%, P = .002), compared with conventional prostheses. Early mortality occurred in 17 (19.8%) in the homograft group, and 20 (9.2%) in the conventional group (P = .019). During follow-up (median: 29.4 months; interquartile-range: 4.7-72.6 months), 60 (19.7%) patients died, and 23 (7.7%) experienced reinfection, with no significant differences in survival (P = .23) or freedom from reinfection rates (P = .65) according to the types of prostheses implanted. After adjustments for baseline characteristics, using propensity-score analyses, use of a homograft did not significantly affect early death (odds ratio 1.61; 95% confidence interval [CI], 0.73-3.40, P = .23), overall death (hazard ratio 1.10; 95% CI, 0.62-1.94, P = .75), or reinfection (hazard ratio 1.04; 95% CI, 0.49-2.18, P = .93). Conclusions: No significant benefit to use of homografts was demonstrable with regard to resistance to reinfection in the setting of IE. The choice among prosthetic options should be based on technical and patient-specific factors. Lack of availability of homografts should not impede appropriate surgical intervention. C1 [Kim, Joon Bum; Camuso, Janice M.; Ando, Masahiko; Melnitchouk, Serguei I.; MacGillivray, Thomas E.; Sundt, Thoralf M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg, Boston, MA USA. [Kim, Joon Bum] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Thorac & Cardiovasc Surg, Seoul, South Korea. [Ejiofor, Julius I.; Yammine, Maroun; Rawn, James D.; Leacche, Marzia; Cohn, Lawrence H.; Byrne, John G.] Harvard Univ, Brigham & Womens Hosp, Med Sch, Div Cardiac Surg, Boston, MA 02115 USA. [Walsh, Conor W.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Sundt, TM (reprint author), Massachusetts Gen Hosp, Cox 652,55 Fruit St, Boston, MA 02114 USA. EM tsundt@partners.org OI Kim, Joon Bum/0000-0001-5801-2395 FU American Association for Thoracic Surgery (AATS) FX The American Association for Thoracic Surgery (AATS) provided funding for this research to Joon Bum Kim, who is the 63rd AATS Graham Foundation Travelling Fellow. NR 28 TC 5 Z9 5 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD MAY PY 2016 VL 151 IS 5 BP 1239 EP 1246 DI 10.1016/j.jtcvs.2015.12.061 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DJ3PO UT WOS:000374118100007 PM 26936004 ER PT J AU Sundt, TM AF Sundt, Thoralf M. TI Setting the benchmark SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Sundt, Thoralf M.] Massachusetts Gen Hosp, Div Cardiac Surg, 55 Fruit St, Boston, MA 02114 USA. RP Sundt, TM (reprint author), Massachusetts Gen Hosp, Div Cardiac Surg, 55 Fruit St, Boston, MA 02114 USA. EM tsundt@mgh.harvard.edu NR 1 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 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD MAY PY 2016 VL 151 IS 5 BP 1339 EP 1339 DI 10.1016/j.jtcvs.2016.03.005 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DJ3PO UT WOS:000374118100026 PM 27085614 ER PT J AU Bambouskova, M Polakovicova, I Halova, I Goel, G Draberova, L Bugajev, V Doan, A Utekal, P Gardet, A Xavier, RJ Draber, P AF Bambouskova, Monika Polakovicova, Iva Halova, Ivana Goel, Gautam Draberova, Lubica Bugajev, Viktor Doan, Aivi Utekal, Pavol Gardet, Agnes Xavier, Ramnik J. Draber, Petr TI New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FC-EPSILON-RI; T-CELL-ACTIVATION; BASOPHILIC LEUKEMIA-CELLS; MAST-CELL; IMMUNOGLOBULIN-E; TYROSINE KINASE; LIPID RAFTS; MONOCLONAL-ANTIBODY; NEGATIVE REGULATION; MEDIATOR RELEASE AB Aggregation of the high-affinity receptor for IgE (Fc epsilon RI) in mast cells initiates activation events that lead to degranulation and release of inflammatory mediators. To better understand the signaling pathways and genes involved in mast cell activation, we developed a high-throughput mast cell degranulation assay suitable for RNA interference experiments using lentivirus-based short hairpin RNA (shRNA) delivery. We tested 432 shRNAs specific for 144 selected genes for effects on Fc epsilon RI-mediated mast cell degranulation and identified 15 potential regulators. In further studies, we focused on galectin-3 (Gal3), identified in this study as a negative regulator of mast cell degranulation. Fc epsilon RI-activated cells with Gal3 knockdown exhibited upregulated tyrosine phosphorylation of spleen tyrosine kinase and several other signal transduction molecules and enhanced calcium response. We show that Gal3 promotes internalization of IgE-Fc epsilon RI complexes; this may be related to our finding that Gal3 is a positive regulator of Fc epsilon RI ubiquitination. Furthermore, we found that Gal3 facilitates mast cell adhesion and motility on fibronectin but negatively regulates antigen-induced chemotaxis. The combined data indicate that Gal3 is involved in both positive and negative regulation of Fc epsilon RI-mediated signaling events in mast cells. C1 [Bambouskova, Monika; Polakovicova, Iva; Halova, Ivana; Draberova, Lubica; Bugajev, Viktor; Utekal, Pavol; Draber, Petr] Acad Sci Czech Republic, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic. [Goel, Gautam; Doan, Aivi; Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Goel, Gautam; Doan, Aivi; Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Goel, Gautam; Doan, Aivi; Gardet, Agnes; Xavier, Ramnik J.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Draber, P (reprint author), Acad Sci Czech Republic, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic. EM draberpe@img.cas.cz RI Halova, Ivana/G-3512-2014 OI Halova, Ivana/0000-0003-3078-7986 FU HHS \ National Institutes of Health (NIH) [DK43351]; Crohn's and Colitis Foundation of America (CCFA); Czech Science Foundation [P302/12/G101]; Prirodovedecka Fakulta, Univerzita Karlova (Faculty of Science, Charles University); Leona M. and Harry B. Helmsley Charitable Trust (Helmsley Charitable Trust) FX This work, including the efforts of Ramnik Xavier, was funded by HHS vertical bar National Institutes of Health (NIH) (DK43351). This work, including the efforts of Ramnik Xavier, was funded by Crohn's and Colitis Foundation of America (CCFA). This work, including the efforts of Petr Draber, was funded by Czech Science Foundation (P302/12/G101). This work, including the efforts of Monika Bambouskova and Iva Polakovicova, was funded by Prirodovedecka Fakulta, Univerzita Karlova (Faculty of Science, Charles University). This work, including the efforts of Ramnik Xavier, was funded by Leona M. and Harry B. Helmsley Charitable Trust (Helmsley Charitable Trust). NR 79 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2016 VL 36 IS 9 BP 1366 EP 1382 DI 10.1128/MCB.00064-16 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3MZ UT WOS:000374110900005 PM 26929198 ER PT J AU Nasti, TH Cochran, JB Tsuruta, Y Yusuf, N McKay, KM Athar, M Timares, L Elmets, CA AF Nasti, Tahseen H. Cochran, J. Barry Tsuruta, Yuko Yusuf, Nabiha McKay, Kristopher M. Athar, Mohammad Timares, Laura Elmets, Craig A. TI A murine model for the development of melanocytic nevi and their progression to melanoma SO MOLECULAR CARCINOGENESIS LA English DT Article DE carcinogenesis; melanocyte; nevi; Ras ID CELL-CYCLE ARREST; ULTRAVIOLET-RADIATION; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; TUMOR PROMOTION; KNOCKOUT MICE; GROWTH-FACTOR; MOUSE MODEL; IN-VIVO; SKIN AB Acquired melanocytic nevi are commonly found in sun exposed and unexposed human skin, but the potential for their transformation into invasive melanoma is not clear. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Nevi develop due to DNA damage initiated by dimethylbenz(a) anthracene (DMBA) followed by chronic promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Dysplastic pigmented skin lesions appeared in 7-9wk with 100% penetrance. Nests of melanocytic cells appeared in a subset of skin draining lymph nodes (dLN) by 25wk, but not in age matched controls. Immunohistochemistry, real-time PCR, and flow cytometric analyses confirmed their melanocytic origin. Transformed cells were present in a subset of nevi and dLNs, which exhibited anchorage-independent growth, tumor development, and metastasis in nude mice. Approximately 50% of the cell lines contained H-Ras mutations and lost tumor suppressor p16(Ink4a) expression. While most studies of melanoma focus on tumor progression in transgenic mouse models where the mutations are present from birth, our model permits investigation of acquired mutations at the earliest stages of nevus initiation and promotion of nevus cell transformation. This robust nevus/melanoma model may prove useful for identifying genetic loci associated with nevus formation, novel oncogenic pathways, tumor targets for immune-prevention, screening therapeutics, and elucidating mechanisms of immune surveillance and immune evasion. (c) 2015 The Authors. Molecular Carcinogenesis, published by Wiley Periodicals, Inc. C1 [Nasti, Tahseen H.; Cochran, J. Barry; Tsuruta, Yuko; Yusuf, Nabiha; McKay, Kristopher M.; Athar, Mohammad; Timares, Laura; Elmets, Craig A.] Univ Alabama Birmingham, Sch Med, Dept Dermatol, Birmingham, AL USA. [Tsuruta, Yuko; Yusuf, Nabiha; Athar, Mohammad; Timares, Laura; Elmets, Craig A.] Univ Alabama Birmingham, Skin Dis Res Ctr, Sch Med, Birmingham, AL USA. [Yusuf, Nabiha; Timares, Laura; Elmets, Craig A.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Timares, L (reprint author), Univ Alabama Birmingham, Dept Dermatol, 1720 2nd Ave S, Birmingham, AL 35294 USA. FU UAB Skin Diseases Research Center Core [P30 AR05094]; NIH NCI [R01 CA138988]; Heflin Center Genomic Core and Cancer Center Core [P30CA13148-40]; UAB Comprehensive Flow Cytometry Core of the Rheumatic Diseases Core Center [P30AR048311, P30AI27667] FX Grant sponsor: UAB Skin Diseases Research Center Core; Grant number: P30 AR05094; Grant sponsor: NIH NCI; Grant number: R01 CA138988; Grant sponsor: Heflin Center Genomic Core and Cancer Center Core; Grant number: P30CA13148-40; Grant sponsor: UAB Comprehensive Flow Cytometry Core of the Rheumatic Diseases Core Center; Grant numbers: P30AR048311; P30AI27667 NR 58 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2016 VL 55 IS 5 BP 646 EP 658 DI 10.1002/mc.22310 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA DJ3IA UT WOS:000374096800020 PM 25788145 ER PT J AU Belstrom, D Holmstrup, P Fiehn, NE Rosing, K Bardow, A Paster, BJ Pedersen, AML AF Belstrom, D. Holmstrup, P. Fiehn, N-E Rosing, K. Bardow, A. Paster, B. J. Pedersen, A. M. Lynge TI Bacterial composition in whole saliva from patients with severe hyposalivation - a case-control study SO ORAL DISEASES LA English DT Article DE saliva; hyposalivation; Human Oral Microbe Identification using Next Generation Sequencing; bacteria; dental caries ID DENTAL-CARIES; FLOW-RATES; MICROBIOME; DIVERSITY; HEALTH; PERIODONTITIS; PREVALENCE; SECRETION; PROFILES; LESSONS AB ObjectiveThe purpose of this study was to compare the microbiota of stimulated whole saliva samples from patients with severe hyposalivation to samples from individuals with normal whole saliva flow rates. It was hypothesized that the two groups differ with regard to salivary bacterial profiles. MethodsThis cross-sectional study included 36 participants (24 females and 12 males, mean age 58.5years) with severe hyposalivation and 36 gender-, age-, and geographically matched participants with normal salivary secretion from the Danish Health Examination Survey (DANHES). The microbiota of stimulated whole saliva samples was characterized by HOMINGS. ResultsThe two groups had comparable caries experience measured by decayed, missed, filled surfaces/teeth and decayed, missed, filled root surfaces as well as active caries lesions. In addition, no single probe target was present with a significant difference in frequency or proportional presence between groups. Furthermore, data reduction by principal component analysis and correspondence analysis showed comparable bacterial community profiles between groups. ConclusionsThe results indicate that the salivary bacterial profiles of patients with severe hyposalivation do not differ from those of individuals with normal salivary secretion, when there are virtually no untreated active caries lesions present in the oral cavity. C1 [Belstrom, D.; Holmstrup, P.; Rosing, K.] Univ Copenhagen, Fac Hlth & Med Sci, Periodontol Oral Microbiol & Community Dent, Dept Odontol,Sect 1, Noerre Alle 20, DK-2200 Copenhagen N, Denmark. [Fiehn, N-E] Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark. [Bardow, A.; Pedersen, A. M. Lynge] Univ Copenhagen, Fac Hlth & Med Sci, Oral Med Clin Oral Physiol Oral Anat & Pathol, Dept Odontol,Sect 1, Copenhagen, Denmark. [Paster, B. J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, B. J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. RP Belstrom, D (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Periodontol Oral Microbiol & Community Dent, Dept Odontol,Sect 1, Noerre Alle 20, DK-2200 Copenhagen N, Denmark. EM dbel@sund.ku.dk FU Danish Dental Association; Danish Foundation of Mutual Efforts in Dental Care; Trygfonden; Simon Spies Foundation FX The authors wish to thank Dr. Nikolai Kirkby from Copenhagen University Hospital, Rigshospitalet, for assistance with DNA isolation and Alexis Kokaras from the Forsyth Institute for laboratory assistance. The authors declare no conflict of interest. This study was supported by funding from the Danish Dental Association, the Danish Foundation of Mutual Efforts in Dental Care, Trygfonden, and the Simon Spies Foundation. NR 35 TC 0 Z9 0 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD MAY PY 2016 VL 22 IS 4 BP 330 EP 337 DI 10.1111/odi.12452 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DJ2PH UT WOS:000374046600014 PM 26824889 ER PT J AU Moole, H Jaeger, A Bechtold, ML Forcione, D Taneja, D Puli, SR AF Moole, Harsha Jaeger, Amy Bechtold, Matthew L. Forcione, David Taneja, Deepak Puli, Srinivas R. TI Success of Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management A Meta-Analysis and Systematic Review SO PANCREAS LA English DT Article DE extracorporeal shock wave lithotripsy; chronic pancreatitis; meta-analysis; systematic review ID DUCT STONES; LONG-TERM; ENDOSCOPIC TREATMENT; CLINICAL-OUTCOMES; FOLLOW-UP; METAANALYSIS; CALCULI; TRIALS; PAIN; DISINTEGRATION AB Objectives: This is a meta-analysis and systematic review to assess the overall utility and safety of Extracorporeal shock wave lithotripsy (ESWL) in chronic calcific pancreatitis. Primary outcomes are pain relief, narcotic usage, ductal clearance, quality of life, and pancreatic exocrine and endocrine function. Methods: Studies involving ESWL in chronic calcific pancreatitis with main pancreatic duct stones greater than 5 mm and patients that failed conservative pain management were included. Fixed and random effects models were used to calculate the pooled proportions. Results: Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data were extracted from 27 studies (N = 3189) which met the inclusion criterion. The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85-54.56) and mild to moderate pain at follow-up was 33.43% (95% CI, 31.40-35.50). Quality of life improved in 88.21% (95% CI, 85.43-90.73) and complete ductal clearance was 70.69% (95% CI, 68.97-72.38) in the pooled patients. Conclusions: The ESWL is an effective and safe management option in patients with chronic calcific pancreatitis patients with main pancreatic duct stone size greater than 5 mm who did not get adequate pain relief with conservative management. C1 [Moole, Harsha; Jaeger, Amy] Univ Illinois, Coll Med Peoria, Div Gen Internal Med, Peoria, IL 61637 USA. [Bechtold, Matthew L.] Univ Missouri, Div Gastroenterol & Hepatol, Columbia, MO USA. [Forcione, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Intervent Endoscopy Serv,Gastrointestinal Unit, Boston, MA 02115 USA. [Taneja, Deepak] St Francis Med Ctr, Dept Med, Div Pulm Med, Peoria, IL USA. [Puli, Srinivas R.] Univ Illinois, Coll Med Peoria, Div Gastroenterol & Hepatol, Peoria, IL 61656 USA. RP Moole, H (reprint author), Univ Illinois, Coll Med Peoria, Dept Internal Med, 530 NE Glen Oak Ave, Peoria, IL 61637 USA. EM harsha1778@yahoo.co.in NR 51 TC 2 Z9 2 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD MAY-JUN PY 2016 VL 45 IS 5 BP 651 EP 658 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ5QU UT WOS:000374265700004 PM 26580454 ER PT J AU Gutzmer, K Ludwig-Barron, NT Wyatt, GE Hamilton, AB Stockman, JK AF Gutzmer, Kyle Ludwig-Barron, Natasha T. Wyatt, Gail E. Hamilton, Alison B. Stockman, Jamila K. TI "Come on Baby. You Know I Love You": African American Women's Experiences of Communication with Male Partners and Disclosure in the Context of Unwanted Sex SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Unwanted sex; Partner communication; Disclosure; African American women ID INTIMATE PARTNER; HELP-SEEKING; DATING PARTNERS; VIOLENCE; COERCION; HEALTH; ASSAULT; MEN; VICTIMIZATION; BEHAVIOR AB We examined African American women's experiences of communication with their male intimate partners a couple of hours before and after an incident of unwanted sex. We also examined women's experiences of disclosure following an incident of unwanted sex. Semi-structured qualitative interviews were conducted with a community-based sample of sexually active African American women (n = 19) reporting at least one incident of sexual coercion (i.e., being pressured into unwanted sex without consent) by an intimate male partner since the age of 18. Our analysis was guided by "the sexual division of power" from Connell's (1987) theory of gender and power. Data were analyzed inductively by examining the interviews for common themes in the following domains: communication before the unwanted sex, communication after the unwanted sex, and disclosure to others. Men pressured partners for unwanted sex through verbal and non-verbal tactics, ranging from pestering and blunt requests for sex to verbal bullying and violence. Many women responded by clearly saying no. However, many women also described eventually ceasing to resist their partners and engaging in unwanted sex. After the unwanted sex, men actively and passively avoided discussing the incident. Although many women discussed the unwanted sex with family and friends, less women disclosed to trained professionals. In some cases, women did not discuss the incident with anyone at all. These findings indicate that, when addressing sexual violence against women, there is a need to target men as well as the norms of masculinity that underpin physical and sexual violence against women. C1 [Gutzmer, Kyle] Univ Calif San Diego, Dept Family Med & Publ Hlth, 9500 Gilman Dr,MC 0507, La Jolla, CA 92093 USA. [Gutzmer, Kyle] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Ludwig-Barron, Natasha T.; Stockman, Jamila K.] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, 9500 Gilman Dr,MC 0507, La Jolla, CA 92093 USA. [Wyatt, Gail E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Hamilton, Alison B.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Stockman, JK (reprint author), Univ Calif San Diego, Dept Med, Div Global Publ Hlth, 9500 Gilman Dr,MC 0507, La Jolla, CA 92093 USA. EM jstockman@ucsd.edu FU National Institute of Mental Health [R25MH080665, R25MH080664]; National Institute on Drug Abuse [K01DA031593]; National Institute on Minority Health and Health Disparities [L60MD003701]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD077891] FX We gratefully acknowledge the contributions of study participants and study staff to this research. This study was supported by the National Institute of Mental Health (Grant #R25MH080665 and Grant #R25MH080664), the National Institute on Drug Abuse (Grant #K01DA031593), the National Institute on Minority Health and Health Disparities (Grant#L60MD003701), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant #R01HD077891). The views expressed are those of the authors and not necessarily those of the National Institutes of Health. NR 42 TC 0 Z9 0 U1 5 U2 11 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 MAY PY 2016 VL 45 IS 4 BP 807 EP 819 DI 10.1007/s10508-015-0688-9 PG 13 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA DI6WH UT WOS:000373640400011 PM 26892099 ER PT J AU Mierau, SB Patrizi, A Hensch, TK Fagiolini, M AF Mierau, Susanna B. Patrizi, Annarita Hensch, Takao K. Fagiolini, Michela TI Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Development; GluN2A; GluN2B; Parvalbumin; Rett syndrome; Visual cortex ID CRITICAL PERIOD PLASTICITY; RETT-SYNDROME; NMDA RECEPTORS; GABAERGIC INTERNEURONS; TRANSCRIPTIONAL REPRESSION; VISUAL-CORTEX; MOUSE MODEL; MICE; SUBUNIT; PHOSPHORYLATION AB BACKGROUND: Early postnatal experience shapes N-methyl-D-aspartate receptor (NMDAR) subunit composition and kinetics at excitatory synapses onto pyramidal cells; however, little is known about NMDAR maturation onto inhibitory interneurons. METHODS: We combined whole-cell patch clamp recordings (n = 440) of NMDAR-mediated currents from layer-4-to-layer-2/3 synapses onto pyramidal and green fluorescent protein labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30, and 45 postnatal days) with array tomography three-dimensional reconstructions of NMDAR subunits GluN2A-and GluN2B-positive synapses onto PV cells. RESULTS: We show that the trajectory of the NMDAR subunit switch is slower in PV interneurons than in excitatory pyramidal cells in visual cortex. Notably, this differential time course is reversed in the absence of methyl-CpG-binding protein, MECP2, the molecular basis for cognitive decline in Rett syndrome and some cases of autism. Additional genetic reduction of GluN2A subunits, which prevents regression of vision in Mecp2-knockout mice, specifically rescues the accelerated NMDAR maturation in PV cells. CONCLUSIONS: We demonstrate 1) the time course of NMDAR maturation is cell-type specific, and 2) a new cell-type specific role for Mecp2 in the development of NMDAR subunit composition. Reducing GluN2A expression in Mecp2-knockout mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus, circuit-based therapies targeting NMDAR subunit composition on PV cells may provide novel treatments for Rett syndrome. C1 [Mierau, Susanna B.; Patrizi, Annarita; Hensch, Takao K.; Fagiolini, Michela] Harvard Univ, Sch Med, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, 300 Longwood Ave, Boston, MA 02115 USA. [Mierau, Susanna B.] Massachusetts Gen Hosp, Dept Neurol, Lurie Ctr Autism, Boston, MA 02114 USA. [Hensch, Takao K.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. RP Fagiolini, M (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, 300 Longwood Ave, Boston, MA 02115 USA. EM michela.fagiolini@childrens.harvard.edu FU National Institutes of Health National Research Service Award (T32); Nancy Lurie Marks Foundation; International Rett Syndrome Foundation FX This work was supported by the National Institutes of Health National Research Service Award (T32), Nancy Lurie Marks Foundation, and International Rett Syndrome Foundation. NR 43 TC 5 Z9 5 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2016 VL 79 IS 9 BP 746 EP 754 DI 10.1016/j.biopsych.2015.05.018 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DI7IX UT WOS:000373674000015 PM 26185009 ER PT J AU Reed, SD Newton, KM Larson, JC Booth-LaForce, C Woods, NF Landis, CA Tolentino, E Carpenter, JS Freeman, EW Joffe, H Anawalt, BD Guthrie, KA AF Reed, S. D. Newton, K. M. Larson, J. C. Booth-LaForce, C. Woods, N. F. Landis, C. A. Tolentino, E. Carpenter, J. S. Freeman, E. W. Joffe, H. Anawalt, B. D. Guthrie, K. A. TI Daily salivary cortisol patterns in midlife women with hot flashes SO CLINICAL ENDOCRINOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MENOPAUSAL TRANSITION; VASOMOTOR SYMPTOMS; SOCIOECONOMIC-STATUS; URINARY CORTISOL; CHRONIC STRESS; EFFICACY; IMPACT; ACTIVATION; DURATION AB ObjectiveDiurnal salivary cortisol patterns in healthy adults are well established but have not been studied in midlife women with hot flashes. We hypothesized that frequent hot flashes areassociated with aberrant cortisol patterns similar to sleep-deficient individuals. DesignCross-sectional. ParticipantsA total of 306 women, ages 40-62, randomized to a behavioural intervention for hot flashes. MeasurementsBaseline comparisons of cortisol geometric means (nmol/l) from four daily time points averaged over two consecutive days plus other calculated cortisol measures were made between groups defined by baseline: (i) mean daily hot flash frequency tertile (55, N=103; >55-88, N=103; >88, N=100) and (ii) selected characteristics. Repeated-measures linear regression models of log-transformed cortisol evaluated group differences, adjusting for covariates. ResultsWomen were 67% White and 24% African American, with 76 (SD 39) hot flashes per day. Salivary cortisol geometric means (nmol/l) among all women were as follows: 750 (SD 448) total, 86 (SD 56) wake, 100 (SD 75) wake +30min, 37 (SD 33) early afternoon and 16 (SD 18) bedtime. Wake+30-minute values showed an 18% median rise from wake values (interquartile range -24 to 96%), and means varied by hot flash frequency tertile, from lowest to highest: 114(SD 73), 103 (SD 65) and 86 (SD 78), respectively, P=0003. Beside the early afternoon value (P=002), cortisol values did not vary by hot flash frequency. ConclusionTaken together, these findings suggest that high frequency of moderate-to-severe hot flashes may be associated with subtle abnormalities in cortisol concentrations - a pattern consistent with chronic sleep disturbance. C1 [Reed, S. D.] Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Reed, S. D.] Univ Washington, Sch Med, Dept Epidemiol, Seattle, WA 98195 USA. [Newton, K. M.] Grp Hlth Res Inst, Seattle, WA USA. [Larson, J. C.; Guthrie, K. A.] Fred Hutchinson Canc Res Ctr, Data Coordinating Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Booth-LaForce, C.; Woods, N. F.; Landis, C. A.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Tolentino, E.] Univ Washington, Lab Testing Serv, Seattle, WA 98195 USA. [Carpenter, J. S.] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. [Freeman, E. W.] Perelman Sch Med, Dept Obstet & Gynecol, Philadelphia, PA USA. [Freeman, E. W.] Perelman Sch Med, Dept Psychiat, Philadelphia, PA USA. [Joffe, H.] Harvard Univ, Brigham & Womens Hosp, Dept Psychiat, Sch Med, Boston, MA 02115 USA. [Joffe, H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Anawalt, B. D.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Reed, SD (reprint author), Univ Washington, Dept Obstet & Gynecol, Epidemiol, 325 9th Ave,Box 359865, Seattle, WA 98104 USA. EM reeds@u.washington.edu FU National Institute of Aging (NIA); Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Center for Complementary and Alternative Medicine (NCCAM); Office of Research and Women's Health (ORWH); NIA [U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700]; Indiana Clinical and Translational Sciences Institute; National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award [UL1 RR025761] FX This study was supported by a co-operative agreement issued by the National Institute of Aging (NIA), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Research and Women's Health (ORWH), and grants U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699 and U01AG032700 from the NIA and an administrative supplement for the Seattle site U01 AG032682. At the Indiana University site, the project was funded in part with support from the Indiana Clinical and Translational Sciences Institute, grant UL1 RR025761 from the National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award. NR 35 TC 2 Z9 2 U1 0 U2 4 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 MAY PY 2016 VL 84 IS 5 BP 672 EP 679 DI 10.1111/cen.12995 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DI8GV UT WOS:000373740400005 PM 26663024 ER PT J AU Janssen, SJ Hermanussen, HH Guitton, TG van den Bekerom, MPJ van Deurzen, DFP Ring, D AF Janssen, Stein J. Hermanussen, Hugo H. Guitton, Thierry G. van den Bekerom, Michel P. J. van Deurzen, Derek F. P. Ring, David TI Greater Tuberosity Fractures: Does Fracture Assessment and Treatment Recommendation Vary Based on Imaging Modality? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TIBIAL PLATEAU FRACTURES; PROXIMAL HUMERUS; DECISION-MAKING; CT-SCAN; CLASSIFICATION; RELIABILITY AB Background For greater tuberosity fractures, 5-mm displacement is a commonly used threshold for recommending surgery; however, it is unclear if displacement can be assessed with this degree of precision and reliability using plain radiographs. It also is unclear if CT images provide additional information that might change decision making. Question/Purposes We asked: (1) Does interobserver agreement for assessment of the amount and direction of fracture-fragment displacement vary based on imaging modality (radiographs only; 2-dimensional [2-D] CT images and radiographs; and 3-dimensional [3-D] and 2-D CT images and radiographs)? (2) Does the likelihood of recommending surgery vary based on imaging modality? (3) Does the level of confidence regarding the decision for treatment vary based on imaging modality? Methods We invited 791 orthopaedic surgeons to complete a survey on greater tuberosity fractures. One hundred eighty (23%) responded and were randomized on a 1:1:1 basis in one of the three imaging modality groups and evaluated the same set of 22 fractures. We described age, sex, mechanism of injury, days between injury and imaging, and that patients had no comorbidities or signs of neurovascular damage for every case. One hundred sixty-four of the 180 respondents completed the study and there was an imbalance in noncompletion between the three groups (two of 67 [3.0%] in the radiograph only group; nine of 57 [16%] in the 2-D CT and radiograph group; and five of 56 [8.9%] in the 3-D CT, 2-D CT, and radiograph group; p = 0.043 by Fisher's exact test). Participants assessed amount (in millimeters) and direction (posterosuperior/posteroinferior/anterosuperior/anteroinferior/no displacement) of displacement; recommended treatment (surgical or nonoperative); and indicated their level of confidence regarding the recommended treatment on a scale from 0 to 10 for every case. Overall recommendation for treatment was expressed as a surgery score per surgeon by dividing the amount of cases they would operate on by the total number of cases (n = 22) and presented as a percentage. Confidence regarding the decision for treatment was calculated by averaging the confidence score per surgeon, ranging from 0 to 10. We compared interobserver agreement using kappa for categorical variables and intraclass correlation (ICC) for continuous variables. We used multivariable linear regression to assess difference in surgery score and confidence level between imaging groups, controlling for surgeon characteristics. Results Interobserver agreement for assessment of amount (radiographs: ICC, 0.55, 2-D CT + radiographs ICC, 0.53, 3-D CT + 2-D CT + radiographs ICC, 0.57; p values on all comparisons > 0.7) and direction (radiographs: kappa, 0.30, 2-D CT + radiographs kappa, 0.43, 3-D CT + 2-D CT + radiographs kappa, 0.40; p values for all comparisons > 0.096) of displacement did not vary by imaging modality. 2-D CT and radiographs (beta regression coefficient [beta], 3.1; p = 0.253) and 3-D CT, 2-D CT and radiographs (beta, 1.6; p = 0.561) did not result in a difference in recommendation for surgery compared with radiographs alone. 2-D CT and radiographs (beta, 0.40; p = 0.021) and 3-D CT, 2-D CT and radiographs (beta, 0.44; p = 0.011) were associated with slightly higher levels of confidence compared with radiographs alone. Conclusions Imaging modality, with the numbers evaluated, does not influence interobserver agreement of greater tuberosity fracture assessment, nor did it influence the recommendation for surgical treatment. However, surgeons did feel slightly more confident about their treatment recommendation when assessing CT images with radiographs compared with radiographs alone. Our results therefore suggest no additional value of CT scans for assessment of greater tuberosity fractures when displacement seems to be minimal on plain radiographs. CT scans could be helpful in borderline cases, or in case other fractures can be expected (eg, an occult surgical neck fracture). C1 [Janssen, Stein J.; Hermanussen, Hugo H.; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Hand Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. [Guitton, Thierry G.] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van den Bekerom, Michel P. J.; van Deurzen, Derek F. P.] Onze Lieve Vrouw Hosp, Shoulder & Elbow Unit, Dept Orthopaed Surg, Amsterdam, Netherlands. RP Ring, D (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Hand Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org FU Wright Medical (Memphis, TN, USA); Skeletal Dynamics (Miami, FL, USA); Biomet (Warsaw, IN, USA); AO North America (Paoli, PA, USA); AO International (Dubendorf, Switzerland); Anna Foundation (The Netherlands); Marco Polo Fund (The Netherlands); Groningen University Fund (The Netherlands) FX One of the authors (DR) certifies that he, or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount less than USD 10,000 from Wright Medical (Memphis, TN, USA); an amount less than USD 10,000 from Skeletal Dynamics (Miami, FL, USA); an amount less than USD 10,000 from Biomet (Warsaw, IN, USA); an amount less than USD 10,000 from AO North America (Paoli, PA, USA); and an amount less than USD 10,000 from AO International (Dubendorf, Switzerland). One of the authors (HHH) certifies that he, or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount less than USD 10,000 from the Anna Foundation (The Netherlands); an amount less than USD 10,000 from the Marco Polo Fund (The Netherlands); and an amount less than USD 10,000 from the Groningen University Fund (The Netherlands). NR 21 TC 0 Z9 0 U1 4 U2 6 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 MAY PY 2016 VL 474 IS 5 BP 1257 EP 1265 DI 10.1007/s11999-016-4706-6 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DI2UQ UT WOS:000373354800028 PM 26797912 ER PT J AU Spanyer, J Hines, J Beaumont, CM Yerasimides, J AF Spanyer, Jonathon Hines, Jennifer Beaumont, Christopher Maxwell Yerasimides, Jonathan TI Catastrophic Femoral Neck Failure after THA with the Accolade((R)) I Stem in Three Patients SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID MODULAR HIP PROSTHESES; ARTHROPLASTY; FRACTURE; COMPONENT; CORROSION; TAPER AB Case Description We report a series of three femoral stem failures, each occurring at the head-neck junction, with all patients experiencing limited and painful ambulation, leading to subsequent revision arthroplasty. All patients were male with high-offset femoral stems and increased head lengths, and each had undergone primary THA at a minimum of 7 years before presentation (average, 94 months). There were no associated deep infections or cases of aseptic loosening in the cohort. Literature Review There is a paucity of similar reports in the literature regarding femoral stem failure at the head-neck junction. When failures of titanium stems have been reported, failure has been attributed to material design and geometry, laser etching, overload, implant alignment, and patient characteristics. Purpose and Clinical Relevance Catastrophic failures of femoral stems at the head-neck junction are a rare cause for revision after THA. Component material and design, surgical technique, and patient factors may contribute. C1 [Spanyer, Jonathon] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Hines, Jennifer] St Joseph Mercy Hlth Syst, Dept Internal Med, 5301 E Huron River Dr, Ypsilanti, MI 48197 USA. [Beaumont, Christopher Maxwell] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Yerasimides, Jonathan] Univ Louisville, Dept Orthopaed Surg, Louisville, KY 40292 USA. [Yerasimides, Jonathan] Norton Healthcare, Louisville, KY USA. RP Hines, J (reprint author), St Joseph Mercy Hlth Syst, Dept Internal Med, 5301 E Huron River Dr, Ypsilanti, MI 48197 USA. EM jennifer.e.hines@gmail.com NR 19 TC 0 Z9 0 U1 1 U2 1 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 MAY PY 2016 VL 474 IS 5 BP 1333 EP 1338 DI 10.1007/s11999-015-4438-z PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DI2UQ UT WOS:000373354800040 PM 26152781 ER PT J AU Crippa, S Capurso, G Camma, C Delle Fave, G Fernandez-del Castillo, C Falconi, M AF Crippa, Stefano Capurso, Gabriele Camma, Calogero Delle Fave, Gianfranco Fernandez-del Castillo, Carlos Falconi, Massimo TI Risk of pancreatic malignancy and mortality in branch-duct IPMNs undergoing surveillance: A systematic review and meta-analysis SO DIGESTIVE AND LIVER DISEASE LA English DT Review DE Follow-up; Non-operative management; Pancreatectomy; Pancreatic cancer ID PAPILLARY-MUCINOUS NEOPLASMS; TERM-FOLLOW-UP; INTERNATIONAL-CONSENSUS-GUIDELINES; NATURAL-HISTORY; CYSTIC NEOPLASMS; MANAGEMENT STRATEGY; TUMOR; RESECTION; ADENOCARCINOMAS; ULTRASONOGRAPHY AB Background: Safety of non-operative management for low-risk branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) is debated. Aim: To perform a systematic review/meta-analysis to determine their risk of developing pancreatic malignancy and of pancreatic malignancy-related deaths. Methods: A MEDLINE search was performed and methodology was based on PRISMA statement. Incidence rates of overall pancreatic malignancy, malignant BD-IPMN, IPMN-distinct PDAC, and of pancreatic malignancy-related death rates were calculated by dividing the total number of events by the total number of person-years (pyrs) of follow-up. Heterogeneity was determined by I-2 statistic. Results: 20 studies including 2177 patients were included. Mean follow-up ranged from 29.3 to 76.7 months. Overall, 82 patients (3.7%) developed a pancreatic malignancy with a pooled estimate rate of 0.007/pyrs (I-2 = 32.8%). The pooled estimate rate of malignant IPMN was 0.004/ pyrs (I-2 = 40.8%), and the pooled estimate rate of distinct PDAC 0.002/pyrs (I-2 = 0%). The rate of death due to pancreatic malignancy during follow-up was 0.9%, with an overall pooled estimate rate of death of 0.002/pyrs (I-2 = 0%). Conclusion: Non-operative management of low-risk BD-IPMN is safe, with a very low risk of malignant transformation of IPMN and of distinct PDAC. The rate of pancreatic malignancy-related mortality is low, particularly when compared with the mortality of pancreatic surgery. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 [Crippa, Stefano; Falconi, Massimo] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Div Pancreat Surg, Via Olgettina 60, I-20132 Milan, Italy. [Capurso, Gabriele; Delle Fave, Gianfranco] Univ Roma La Sapienza, Fac Med & Psychol, S Andrea Hosp, Digest & Liver Dis Unit, Rome, Italy. [Camma, Calogero] Univ Palermo, Dept Internal Med, Gastroenterol Unit, Palermo, Italy. [Fernandez-del Castillo, Carlos] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Falconi, M (reprint author), Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Div Pancreat Surg, Via Olgettina 60, I-20132 Milan, Italy. EM falconi.massimo@hsr.it OI Falconi, Massimo/0000-0001-9654-7243 NR 62 TC 3 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD MAY PY 2016 VL 48 IS 5 BP 473 EP 479 DI 10.1016/j.dld.2016.02.003 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DI7ZT UT WOS:000373721200003 PM 26965783 ER PT J AU Wortman, JR Tirumani, SH Tirumani, H Shinagare, AB Jagannathan, JP Hornick, JL Ramaiya, NH AF Wortman, Jeremy R. Tirumani, Sree Harsha Tirumani, Harika Shinagare, Atul B. Jagannathan, Jyothi P. Hornick, Jason L. Ramaiya, Nikhil H. TI Neoadjuvant radiation in primary extremity liposarcoma: correlation of MRI features with histopathology SO EUROPEAN RADIOLOGY LA English DT Article DE Soft tissue sarcoma; Myxoid liposarcoma; Pleomorphic liposarcoma; Radiotherapy; MRI ID SOFT-TISSUE SARCOMAS; INDUCED PATHOLOGICAL NECROSIS; TUMOR RESPONSE ASSESSMENT; EXCELLENT LOCAL-CONTROL; MYXOID LIPOSARCOMA; POSTOPERATIVE RADIOTHERAPY; CHOI CRITERIA; CHEMOTHERAPY; THERAPY AB Objective To evaluate MRI features of response of primary extremity liposarcoma (LPS) to neoadjuvant radiation therapy (RT) with histopathologic correlation. Methods In this IRB-approved study including 125 patients with extremity LPS treated with neoadjuvant RT from 2000 to 2013, MRI of the primary tumour in 18 patients (5 pleomorphic LPS, 13 myxoid LPS) before and after RT were reviewed by two radiologists by consensus. Histopathology of the surgical specimens was reviewed by a pathologist with expertise in sarcomas. Results In the pleomorphic LPS cohort, 3/5 tumours increased in size; 3/5 decreased in enhancing component; and 3/5 increased in peritumoral oedema, intratumoral haemorrhage, and necrosis. In the myxoid LPS cohort, 12/13 tumours decreased in size, 8/13 decreased in enhancing component, and 5/13 increased in internal fat following RT. Histopathology showed a parts per thousand yen50 % residual tumour in 1/5 pleomorphic LPS and 2/13 myxoid LPS. Hyalinization/necrosis of a parts per thousand yen75 % was noted in 4/5 pleomorphic LPS and 11/13 myxoid LPS. Cytodifferentiation was noted in 1/5 pleomorphic and 9/13 myxoid LPS. Conclusion While pleomorphic LPS showed an increase in size, peritumoral oedema, intratumoral haemorrhage, and necrosis on MRI following neoadjuvant RT, myxoid LPS showed a decrease in size and enhancement with an increase in internal fat. C1 [Wortman, Jeremy R.; Tirumani, Sree Harsha; Shinagare, Atul B.; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Tirumani, Sree Harsha; Tirumani, Harika; Shinagare, Atul B.; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. [Tirumani, Harika] Univ Arkansas Med Sci, Dept Radiol, Little Rock, AR 72205 USA. [Hornick, Jason L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Wortman, JR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM jwortman@partners.org; sreeharsha_tirumani@dfci.harvard.edu; harika_tirumani@dfci.harvard.edu; ashinagare@partners.org; jjagannathan@partners.org; jhornick@partners.org; nramaiya@partners.org NR 21 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD MAY PY 2016 VL 26 IS 5 BP 1226 EP 1234 DI 10.1007/s00330-015-3953-3 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI6XA UT WOS:000373642300003 PM 26314480 ER PT J AU Kim, DW Kim, HJ Kim, KW Byun, JH Kim, SY Song, KB Ramaiya, NH Tirumani, SH Hong, SM AF Kim, Dong Wook Kim, Hyoung Jung Kim, Kyung Won Byun, Jae Ho Kim, So Yeon Song, Ki Byung Ramaiya, Nikhil H. Tirumani, Sree Harsha Hong, Seung-Mo TI Prognostic value of CT findings to predict survival outcomes in patients with pancreatic neuroendocrine neoplasms: a single institutional study of 161 patients SO EUROPEAN RADIOLOGY LA English DT Article DE Pancreas; Neuroendocrine neoplasm; Overall survival; Recurrence free survival; CT ID ENDOCRINE TUMORS; MICROVASCULAR DENSITY; HELICAL CT; ADENOCARCINOMA; CLASSIFICATION; EXPRESSION; FEATURES; SYSTEM; CANCER; MDCT AB Objectives To evaluate the prognostic value of CT to predict recurrence-free and overall survival in patients with pancreatic neuroendocrine neoplasms (PanNENs). Methods Between January 2004 and December 2012, 161 consecutive patients who underwent preoperative triphasic CT and surgical resection with curative intent for PanNENs were identified. The tumour consistency, margin, presence of calcification, pancreatic duct dilatation, bile duct dilatation, vascular invasion, and hepatic metastases were evaluated. The tumour size, arterial enhancement ratio, and portal enhancement ratio were measured. The Cox proportional hazard model was used to determine the association between CT features and recurrence-free survival and overall survival. Results By multivariate analysis, tumour size (> 3 cm) (hazard ratio, 3.314; p = 0.006), portal enhancement ratio (a parts per thousand currency sign1.1) (hazard ratio, 2.718; p = 0.006), and hepatic metastases (hazard ratio, 4.374; p = 0.003) were independent significant variables for worse recurrence-free survival. Portal enhancement ratio (a parts per thousand currency sign1.1) (hazard ratio, 5.951; p = 0.001) and hepatic metastases (hazard ratio, 4.122; p = 0.021) were independent significant variables for worse overall survival. Conclusions Portal enhancement ratio (a parts per thousand currency sign1.1) and hepatic metastases assessed on CT were common independent prognostic factors for worse recurrence-free survival and overall survival in patients with PanNENs. C1 [Kim, Dong Wook; Kim, Hyoung Jung; Kim, Kyung Won; Byun, Jae Ho; Kim, So Yeon] Univ Ulsan, Coll Med, Dept Radiol, 86 Asanbyeongwon Gil, Seoul 138736, South Korea. [Kim, Dong Wook; Kim, Hyoung Jung; Kim, Kyung Won; Byun, Jae Ho; Kim, So Yeon] Univ Ulsan, Coll Med, Res Inst Radiol, Asan Med Ctr, 86 Asanbyeongwon Gil, Seoul 138736, South Korea. [Song, Ki Byung] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Surg, Seoul 138736, South Korea. [Ramaiya, Nikhil H.; Tirumani, Sree Harsha] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging,Brigham & Womens Hosp, 44 Binney St, Boston, MA 02115 USA. [Hong, Seung-Mo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. RP Kim, HJ (reprint author), Univ Ulsan, Coll Med, Dept Radiol, 86 Asanbyeongwon Gil, Seoul 138736, South Korea.; Kim, HJ (reprint author), Univ Ulsan, Coll Med, Res Inst Radiol, Asan Med Ctr, 86 Asanbyeongwon Gil, Seoul 138736, South Korea. EM hjk@amc.seoul.kr FU Ministry of Education, Science and Technology, South Korea [2012R1A1A1012731] FX The scientific guarantor of this publication is Hyoung Jung Kim. The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. This study has received funding by the Ministry of Education, Science and Technology, South Korea (grant 2012R1A1A1012731). Min-Ju Kim (Department of Clinical Epidemiology and Biostatistics, Asan Medical Center) kindly provided statistical advice for this manuscript. One of the authors (KW Kim) has significant statistical expertise. Institutional Review Board approval was obtained. Written informed consent was waived by the Institutional Review Board. NR 24 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD MAY PY 2016 VL 26 IS 5 BP 1320 EP 1329 DI 10.1007/s00330-015-3943-5 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI6XA UT WOS:000373642300013 PM 26253259 ER PT J AU Guerrero-Berroa, E Ravona-Springer, R Heymann, A Schmeidler, J Hoffman, H Preiss, R Koifmann, K Greenbaum, L Levy, A Silverman, JM Leroith, D Sano, M Schnaider-Beeri, M AF Guerrero-Berroa, Elizabeth Ravona-Springer, Ramit Heymann, Anthony Schmeidler, James Hoffman, Hadas Preiss, Rachel Koifmann, Keren Greenbaum, Lior Levy, Andrew Silverman, Jeremy M. Leroith, Derek Sano, Mary Schnaider-Beeri, Michal TI Ethnicity/culture modulates the relationships of the haptoglobin (Hp) 1-1 phenotype with cognitive function in older individuals with type 2 diabetes SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE cognitive function; cognitive domains; diabetes; haptoglobin; ethnicity/culture; older adults ID SMALL VESSEL DISEASE; NEUROPSYCHOLOGICAL BATTERY; ALZHEIMERS-DISEASE; CARDIOVASCULAR-DISEASE; DEMENTIA; RISK; SUSCEPTIBILITY; CERAD; POLYMORPHISM; EDUCATION AB Objective: The haptoglobin (Hp) genotype has been associated with cognitive function in type 2 diabetes. Because ethnicity/culture has been associated with both cognitive function and Hp genotype frequencies, we examined whether it modulates the association of Hp with cognitive function. Methods: This cross-sectional study evaluated 787 cognitively normal older individuals (> 65 years of age) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline study. Interactions in two-way analyses of covariance compared Group (Non-Ashkenazi versus Ashkenazi Jews) on the associations of Hp phenotype (Hp 1-1 versus non-Hp 1-1) with five cognitive outcome measures. The primary control variables were age, gender, and education. Results: Compared with Ashkenazi Jews, non-Ashkenazi Jews with the Hp 1-1 phenotype had significantly poorer cognitive function than non-Hp 1-1 in the domains of Attention/Working Memory (p= 0.035) and Executive Function (p= 0.023), but not in Language/Semantic Categorization (p= 0.432), Episodic Memory (p= 0.268), or Overall Cognition (p= 0.082). After controlling for additional covariates (type 2 diabetes-related characteristics, cardiovascular risk factors, Mini-mental State Examination, and extent of depressive symptoms), Attention/Working Memory (p= 0.038) and Executive Function (p= 0.013) remained significant. Conclusions: Older individuals from specific ethnic/cultural backgrounds with the Hp 1-1 phenotype may benefit more from treatment targeted at decreasing or halting the detrimental effects of Hp 1-1 on the brain. Future studies should examine differential associations of Hp 1-1 and cognitive impairment, especially for groups with high prevalence of both, such as African-Americans and Hispanics. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Guerrero-Berroa, Elizabeth; Schmeidler, James; Silverman, Jeremy M.; Sano, Mary; Schnaider-Beeri, Michal] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Guerrero-Berroa, Elizabeth; Silverman, Jeremy M.; Sano, Mary] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Ravona-Springer, Ramit; Koifmann, Keren; Greenbaum, Lior; Schnaider-Beeri, Michal] Chaim Sheba Med Ctr, Joseph Sagol Neurosci Ctr, Ramat Gan, Israel. [Ravona-Springer, Ramit; Heymann, Anthony] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Heymann, Anthony; Hoffman, Hadas; Preiss, Rachel] Maccabi Healthcare Serv, Tel Aviv, Israel. [Levy, Andrew] Technion Israel Inst Technol, Technion Fac Med, Haifa, Israel. [Leroith, Derek] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Guerrero-Berroa, E (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Guerrero-Berroa, E (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. EM elizabeth.guerrero-berroa@mssm.edu FU NIA [R01 AG034087, P50 AG05138]; Helen Bader Foundation; Leroy Schecter Foundation; Irma T. Hirschl Scholar award; Alzheimer's Association [MNIRGD-14-321113] FX This study was supported by NIA grants R01 AG034087 to Dr. Beeri and P50 AG05138 to Dr. Sano; the Helen Bader Foundation, the Leroy Schecter Foundation, and the Irma T. Hirschl Scholar award to Dr. Beeri; and the Alzheimer's Association grant MNIRGD-14-321113 to Dr. Guerrero-Berroa. NR 45 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD MAY PY 2016 VL 31 IS 5 BP 494 EP 501 DI 10.1002/gps.4354 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DI8RA UT WOS:000373767400006 PM 26388309 ER PT J AU Randall, ET Travers, LV Shapiro, JB Bohnert, AM AF Randall, Edin T. Travers, Lea V. Shapiro, Jenna B. Bohnert, Amy M. TI Reasons for the "after-school pressure cooker" in Affluent Communities: It's Not How Much Time, but Why SO JOURNAL OF CHILD AND FAMILY STUDIES LA English DT Article DE Affluence; Adolescence; Over-scheduling; Organized activity involvement; Adjustment ID ORGANIZED ACTIVITY INVOLVEMENT; OVER-SCHEDULING HYPOTHESIS; YOUTH ACTIVITY INVOLVEMENT; SELF-DETERMINATION THEORY; EXTRACURRICULAR PARTICIPATION; LONGITUDINAL EXAMINATION; SOCIOECONOMIC-STATUS; ACADEMIC OUTCOMES; EARLY ADOLESCENTS; MOTIVATION AB This study extends the over-scheduling hypothesis literature by focusing on affluent adolescents and exploring relations between psychosocial adjustment and reasons for organized activity (OA) involvement rather than focusing solely on time spent in OAs. Variable-and person-centered analyses were used to evaluate associations between intensity of OA participation and reasons for involvement, perceived parental pressure, and adjustment (depressive symptoms, anxiety symptoms, life satisfaction) in a sample of 10th graders (N = 122) from affluent communities. When adolescents' perceptions of parental pressure were controlled for in analyses, more intensely involved youth reported lower levels of depressive symptoms. "For Fun" was the most highly rated reason for involvement and was linked to lower levels of perceived parental pressure, but was unrelated to all indicators of adjustment. Conversely, involvement in OAs "for Parents" was linked to more perceived parental pressure and lower levels of life satisfaction. Two OA participant profiles emerged in person-centered analyses: (1) primarily intrinsic reasons (high Fun, moderate Future, low Parents) and (2) intrinsic and extrinsic reasons (high Fun, high Future, high Parents) for involvement. OA participation simultaneously motivated by extrinsic and intrinsic reasons was linked to fewer psychosocial benefits than intrinsically motivated OA involvement. C1 [Randall, Edin T.] Boston Childrens Hosp Waltham, Mayo Family Pediat Pain Rehabil Ctr, 9 Hope Ave, Waltham, MA 02453 USA. [Travers, Lea V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shapiro, Jenna B.; Bohnert, Amy M.] Loyola Univ, Chicago, IL 60660 USA. RP Randall, ET (reprint author), Boston Childrens Hosp Waltham, Mayo Family Pediat Pain Rehabil Ctr, 9 Hope Ave, Waltham, MA 02453 USA. EM edin.randall@childrens.harvard.edu NR 58 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1062-1024 EI 1573-2843 J9 J CHILD FAM STUD JI J. Child Fam. Stud. PD MAY PY 2016 VL 25 IS 5 BP 1559 EP 1569 DI 10.1007/s10826-015-0330-4 PG 11 WC Family Studies; Psychology, Developmental; Psychiatry SC Family Studies; Psychology; Psychiatry GA DI5ZM UT WOS:000373579000018 ER PT J AU Hwang, JW Xin, SC Ou, YM Zhang, WY Liang, YL Chen, J Yang, XQ Chen, XY Guo, TW Yang, XJ Ma, WH Li, J Zhao, BC Tu, Y Kong, J AF Hwang, J. W. Xin, S. C. Ou, Y. M. Zhang, W. Y. Liang, Y. L. Chen, J. Yang, X. Q. Chen, X. Y. Guo, T. W. Yang, X. J. Ma, W. H. Li, J. Zhao, B. C. Tu, Y. Kong, J. TI Enhanced default mode network connectivity with ventral striatum in subthreshold depression individuals SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Subthreshold depression; Resting-state functional connectivity; Default mode network; Independent component analysis; fMRI; Ventral striatum ID STATE FUNCTIONAL CONNECTIVITY; ANTERIOR CINGULATE CORTEX; MAJOR DEPRESSION; REWARD; DISORDER; ADOLESCENTS; DYSFUNCTION; SYMPTOMS; DISEASE; NEUROSCIENCE AB Subthreshold depression (StD) is a highly prevalent condition associated with increased service utilization and social morbidity. Nevertheless, due to limitations in current diagnostic systems that set the boundary for major depressive disorder (MDD), very few brain imaging studies on the neurobiology of StD have been carried out, and its underlying neurobiological mechanism remains unclear. In recent years, accumulating evidence suggests that the disruption of the default mode network (DMN), a network involved in self-referential processing, affective cognition, and emotion regulation, is involved in major depressive disorder. Using independent component analysis, we investigated resting-state default mode network (DMN) functional connectivity (FC) changes in two cohorts of StD patients with different age ranges (young and middle-aged, n = 57) as well as matched controls (n = 79). We found significant FC increase between the DMN and ventral striatum (key region in the reward network), in both cohorts of StD patients in comparison with controls. In addition, we also found the FC between the DMN and ventral striatum was positively and significantly associated with scores on the Center for Epidemiologic Studies Depression Scale (CES-D), a measurement of depressive symptomatology. We speculate that this enhanced FC between the DMN and the ventral striatum may reflect a self compensation to ameliorate the lowered reward function. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Hwang, J. W.; Xin, S. C.; Zhang, W. Y.; Liang, Y. L.; Yang, X. Q.; Guo, T. W.; Yang, X. J.; Ma, W. H.; Li, J.; Zhao, B. C.; Tu, Y.] Beijing Univ Chinese Med, Sch Acupuncture Moxibust & Tuina, Beijing 100029, Peoples R China. [Hwang, J. W.; Chen, X. Y.; Kong, J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02129 USA. [Ou, Y. M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02129 USA. [Liang, Y. L.] Wellesley Coll, Neurosci Program, Wellesley, MA 02181 USA. [Chen, J.] Beijing Univ Chinese Med, Sch Management, Beijing, Peoples R China. [Zhang, W. Y.] Capital Med Univ, Beijing Rehabil Hosp, Beijing, Peoples R China. [Yang, X. Q.] Beijing Univ Chinese Med, Inst Hlth Preserving Chinese Med, Beijing 100029, Peoples R China. [Guo, T. W.] Beijing Univ Chinese Med, Dongzhimen Hosp, Dept Hematol & Oncol, Beijing, Peoples R China. RP Tu, Y (reprint author), Beijing Univ Chinese Med, Sch Acupuncture Moxibust & Tuina, Beijing 100029, Peoples R China.; Kong, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02129 USA. EM tuyab@263.net; kongj@nmr.mgh.harvard.edu FU International Collaboration Research Program at Science and Technology of China [2007DFA30780]; NIH (NCCIH) [R01AT005280, PO1-AT002048, R01AT008563] FX This scientific work was supported by an International Collaboration Research Program at Science and Technology of China (2007DFA30780) Grant to Tuya Bao. Jian Kong is supported by R01AT005280, PO1-AT002048 and R01AT008563 from NIH (NCCIH). NR 64 TC 4 Z9 4 U1 4 U2 11 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 MAY PY 2016 VL 76 BP 111 EP 120 DI 10.1016/j.jpsychires.2016.02.005 PG 10 WC Psychiatry SC Psychiatry GA DI3QB UT WOS:000373412400014 PM 26922247 ER PT J AU Narayanan, KL Chopra, V Rosas, HD Malarick, K Hersch, S AF Narayanan, K. Lakshmi Chopra, Vanita Rosas, H. Diana Malarick, Keith Hersch, Steven TI Rho Kinase Pathway Alterations in the Brain and Leukocytes in Huntington's Disease SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Huntington's disease; Rho kinase pathway; mRNA expression; Biomarker ID POLYGLUTAMINE AGGREGATION; MUTANT HUNTINGTIN; GENE-EXPRESSION; ROCK-I; PHOSPHORYLATION; ACTIVATION; DEGRADATION; INHIBITION; TOXICITY; BLOOD AB Huntington's disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the huntingtin gene. Therapeutic approaches targeting mutant huntingtin (mtHtt) or its downstream toxic consequences are under development, including Rho kinase pathway inhibition. We investigated the messenger RNA (mRNA) expression of Rho kinase pathway genes, including RhoA (Ras homolog family member A), ROCK1 (Rho-associated kinase1), PRK2 (protein kinase C-related protein kinase 2), Profilin1, cofilin1, MYPT1 (myosin phosphatase target subunit 1), and LIMK1 (LIM domain kinase 1) in HD human blood leukocytes, postmortem brain, and in R6/2 HD mouse brain tissue using qPCR. RhoA, ROCK1, PRK2, Profilin1, cofilin1, and MYPT1 were significantly increased in HD blood compared to controls. In frontal cortex of HD postmortem brain tissue, the expression of RhoA, ROCK1, PRK2, Profilin1, and MYPT1 were also significantly increased. In the brain from 4-week-old R6/2 mice, the expression of Rock1, Prk2, Cofilin1, and MYPT1 was significantly increased while RhoA, Rock1, Profilin1, Cofilin1, and Mypt1 were increased and Limk1 mRNA decreased in 13-week-old R6/2 mice. Western blot analysis using human postmortem tissues for ROCK1 and Profilin1 demonstrated significantly increased protein levels, which correlated with the mRNA increases. Collectively, we have shown the panel of Rho kinase pathway genes to be highly altered in human HD blood, postmortem brain tissue, and in R6/2 mice. These studies confirm that HD upregulates the Rho kinase pathway and identifies mRNAs that could serve as peripheral markers in HD patients and translational markers in HD mouse models. C1 [Narayanan, K. Lakshmi; Chopra, Vanita; Rosas, H. Diana; Malarick, Keith; Hersch, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,MassGen Inst Neurodegenerat Dis, East,Bldg 114,Room 2005, Charlestown, MA 02129 USA. [Rosas, H. Diana; Malarick, Keith] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Rosas, H. Diana; Malarick, Keith] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Hersch, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,MassGen Inst Neurodegenerat Dis, East,Bldg 114,Room 2005, Charlestown, MA 02129 USA. EM hersch@helix.mgh.harvard.edu FU National Institute of Health Grant [P01NS058793]; Huntington's Disease Society of America (HDSA) Coalition for the Cure FX This study was funded by the National Institute of Health Grant (P01NS058793) and the Huntington's Disease Society of America (HDSA) Coalition for the Cure. We thank the patients who have provided the valuable biological samples for this study. We are grateful to the Tissue Resource Centre of the Alzheimer Disease Research Center (ADRC) at Massachusetts General Hospital and Neurological Foundation of New Zealand Human Brain Bank, Auckland, for providing the human postmortem brain. NR 20 TC 1 Z9 1 U1 1 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD MAY PY 2016 VL 53 IS 4 BP 2132 EP 2140 DI 10.1007/s12035-015-9147-9 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DI6WS UT WOS:000373641500006 PM 25941073 ER PT J AU Carlson, LC Hatcher, KW Tomberg, L Kabetu, C Ayala, R Vander Burg, R AF Carlson, Lucas C. Hatcher, Kristin W. Tomberg, Lindsay Kabetu, Charles Ayala, Ruben Vander Burg, Richard TI Inequitable Access to Timely Cleft Palate Surgery in Low- and Middle-Income Countries SO WORLD JOURNAL OF SURGERY LA English DT Article ID ORAL CLEFTS; GLOBAL HEALTH; LIP; EXPERIENCE; MORTALITY; EQUITY; BIRTH; CARE AB Delayed cleft palate repair has significant implications for physical, mental, and social well-being and has been suggested to lead to an increased risk of infant and under-five mortality in low- and middle-income countries (LMICs). Using medical records from Operation Smile international programs taking place in eleven different LMICs between March and May 2014, we performed a logistic regression assessing the relationship between delayed surgery access, defined as primary palatoplasty presentation after 24 months of age, and GDP per capita across 11 countries. Median age of presentation ranged from 13 to 24 months in upper-middle-income countries, 17 to 35 months in lower-middle-income countries, and 14 to 66 months in low-income countries. Our analysis demonstrated a 14 % increase in the odds of late surgery [OR = 0.88 (P < 0.001)] for every 1000 USD decrease of GDP per capita. In low- and lower-middle-income countries, this relationship was even stronger, with an OR of 0.59 (P < 0.001), indicating a 70 % increase in the odds of late surgery for every 1000 USD decrease in GDP per capita. There is a strong negative correlation between national income status and delayed access to primary cleft palate surgery, indicating a high degree of inequity in access to surgery, particularly in low- and lower-middle-income countries. As the importance of surgery in global health is increasingly recognized, an equity perspective must be included in the global dialog to ensure that the world's poor have fair and equitable access to essential surgical care. C1 [Carlson, Lucas C.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St,NH-2, Boston, MA 02115 USA. [Carlson, Lucas C.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Hatcher, Kristin W.; Tomberg, Lindsay; Ayala, Ruben; Vander Burg, Richard] Operat Smile Inc, Virginia Beach, VA USA. [Kabetu, Charles] Kenyatta Natl Hosp, Dept Anesthesiol, Nairobi, Kenya. RP Carlson, LC (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St,NH-2, Boston, MA 02115 USA.; Carlson, LC (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM lccarlson@partners.org NR 36 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD MAY PY 2016 VL 40 IS 5 BP 1047 EP 1052 DI 10.1007/s00268-015-3374-0 PG 6 WC Surgery SC Surgery GA DI6YK UT WOS:000373645900004 PM 26669785 ER PT J AU Barnett, MD Williams, BR Tucker, RO AF Barnett, Michael D. Williams, Beverly R. Tucker, Rodney O. TI Sudden Advanced Illness: An Emerging Concept Among Palliative Care and Surgical Critical Care Physicians SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE critical care; surgery; palliative care; prognostication; decision making; caregiver issues ID OF-LIFE CARE; INTENSIVE-CARE; UNIT; END; TRAUMA; SERVICES; ICU; PROJECT; MODELS AB Background: End-of-life discussions in critically-ill patients with acute surgical conditions may be rushed and occur earlier during hospitalization. This study explores the concept of sudden advanced illness (SAI) and its relevance to patients requiring Palliative and Surgical Critical Care. Methods: Semi-structured interviews were completed with 16 physicians, querying each about (1) definitional components, (2) illustrative cases, and (3) comfort with SAI. Analysis was done by grounded theory. Results: SAI was characterized as unforeseen, emerging abruptly and producing devastating injury, often in healthy, younger patients. There is (1) prognostic uncertainty, (2) loss of capacity, and (3) unprepared surrogate decision-making. Cases are emotionally-charged and often personal. Conclusion: The emerging concept of SAI is important for understanding how Palliative Care can enhance care for this subset of patients. C1 [Barnett, Michael D.; Williams, Beverly R.; Tucker, Rodney O.] Univ Alabama Birmingham, Ctr Palliat & Support Care, 1720 2nd Ave S,CH19 219, Birmingham, AL 35294 USA. [Barnett, Michael D.; Williams, Beverly R.; Tucker, Rodney O.] Univ Alabama Birmingham, Div Geriatr Gerontol & Palliat Care, Birmingham, AL USA. [Barnett, Michael D.] Univ Alabama Birmingham, Div Gen Pediat & Adolescent Med, Birmingham, AL USA. [Williams, Beverly R.] Birmingham VA Med Ctr, Birmingham Atlanta VA Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. RP Barnett, MD (reprint author), Univ Alabama Birmingham, Ctr Palliat & Support Care, 1720 2nd Ave S,CH19 219, Birmingham, AL 35294 USA. EM mbarnett@peds.uab.edu NR 23 TC 0 Z9 0 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD MAY PY 2016 VL 33 IS 4 BP 321 EP 326 DI 10.1177/1049909114565108 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DH6CX UT WOS:000372879700002 PM 25548391 ER PT J AU Hutt, E Whitfield, E Min, SJ Jones, J Weber, M Albright, K Levy, C O'Toole, T AF Hutt, Evelyn Whitfield, Emily Min, Sung-Joon Jones, Jacqueline Weber, Mary Albright, Karen Levy, Cari O'Toole, Thomas TI Challenges of Providing End-of-Life Care for Homeless Veterans SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE veteran; palliative care; homelessness ID DEATH; ADULTS; BOSTON AB Objective: To describe challenges of caring for homeless veterans at end of life (EOL) as perceived by Veterans Affairs Medical Center (VAMC) homeless and EOL care staff. Design: E-mail survey. Setting/participants: Homelessness and EOL programs at VAMCs. Measurements: Programs and their ratings of personal, structural, and clinical care challenges were described statistically. Homelessness and EOL program responses were compared in unadjusted analyses and using multivariable models. Results: Of 152 VAMCs, 50 (33%) completed the survey. The VAMCs treated an average of 6.5 homeless veterans at EOL annually. Lack of appropriate housing was the most critical challenge. The EOL programs expressed somewhat more concern about lack of appropriate care site and care coordination than did homelessness programs. Conclusions: Personal, clinical, and structural challenges face care providers for veterans who are homeless at EOL. Deeper understanding of these challenges will require qualitative study of homeless veterans and care providers. C1 [Hutt, Evelyn; Whitfield, Emily; Levy, Cari] Denver Vet Affairs Med Ctr VAMC, Denver, CO USA. [Hutt, Evelyn; Whitfield, Emily; Min, Sung-Joon; Albright, Karen; Levy, Cari] Univ Colorado, Sch Med, Dept Med, Denver, CO USA. [Jones, Jacqueline; Weber, Mary] Univ Colorado, Coll Nursing, Denver, CO USA. [O'Toole, Thomas] Providence Vet Affairs Med Ctr, Providence, RI USA. [O'Toole, Thomas] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02912 USA. RP Hutt, E (reprint author), Denver VA Med Ctr, Res, 1055 Clermont St,Mail Code A151, Denver, CO 80220 USA. EM evelyn.hutt@ucdenver.edu FU Department of Veterans Affairs [10-322] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The funding for this study was provided by Merit Award 10-322 from the Department of Veterans Affairs. The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. NR 12 TC 0 Z9 0 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD MAY PY 2016 VL 33 IS 4 BP 381 EP 389 DI 10.1177/1049909115572992 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DH6CX UT WOS:000372879700011 PM 25701660 ER PT J AU Liu, JF Matulonis, UA AF Liu, Joyce F. Matulonis, Ursula A. TI What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment? SO CURRENT ONCOLOGY REPORTS LA English DT Review DE Ovarian cancer; PARP inhibitors; Olaparib; Veliparib; Rucaparib; Niraparib ID NEGATIVE BREAST-CANCER; RECURRENT EPITHELIAL OVARIAN; OLAPARIB MAINTENANCE THERAPY; RANDOMIZED PHASE-2 TRIAL; RECOMBINATION DNA-REPAIR; BRCA MUTATION CARRIERS; HOMOLOGOUS RECOMBINATION; POLY(ADP-RIBOSE) POLYMERASE; FALLOPIAN-TUBE; DOWN-REGULATION AB Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anticancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA-mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer. C1 [Liu, Joyce F.; Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Liu, JF (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM joyce_liu@dfci.harvard.edu NR 47 TC 4 Z9 4 U1 6 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD MAY PY 2016 VL 18 IS 5 AR 29 DI 10.1007/s11912-016-0515-z PG 9 WC Oncology SC Oncology GA DH1HQ UT WOS:000372535400002 PM 26984416 ER PT J AU DeLisi, LE Fleischhacker, WW AF DeLisi, Lynn E. Fleischhacker, W. Wolfgang TI How precise is precision medicine for schizophrenia? SO CURRENT OPINION IN PSYCHIATRY LA English DT Editorial Material ID POLYGENIC RISK SCORE; MOOD DISORDERS; BRAIN; PSYCHOSIS; PRODROME; PEOPLE C1 [DeLisi, Lynn E.] VA Boston Healthcare Syst, Dept Psychiat, 940 Belmont Ave, Brockton, MA 02301 USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. [Fleischhacker, W. Wolfgang] Med Univ Innsbruck, Dept Psychiat Psychotherapy & Psychosomat, Div Psychiat 1, A-6020 Innsbruck, Austria. RP DeLisi, LE (reprint author), VA Boston Healthcare Syst, Dept Psychiat, 940 Belmont Ave, Brockton, MA 02301 USA. EM Lynn.DeLisi@VA.gov NR 28 TC 0 Z9 0 U1 10 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7367 EI 1473-6578 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAY PY 2016 VL 29 IS 3 BP 187 EP 189 DI 10.1097/YCO.0000000000000245 PG 3 WC Psychiatry SC Psychiatry GA DI0YX UT WOS:000373224300001 PM 26998940 ER PT J AU McNally, JM McCarley, RW AF McNally, James M. McCarley, Robert W. TI Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE parvalbumin; interneurons; gamma band oscillations; N-methyl-D-aspartate receptor; schizophrenia ID MAGNETIC-RESONANCE-SPECTROSCOPY; ANTERIOR CINGULATE CORTEX; PREFRONTAL CORTEX; IN-VIVO; PARVALBUMIN NEURONS; VISUAL-CORTEX; FREQUENCY OSCILLATIONS; NETWORK OSCILLATIONS; GABA CONCENTRATION; AMINOBUTYRIC-ACID AB Purpose of review We review our current understanding of abnormal gamma band oscillations in schizophrenia, their association with symptoms and the underlying cortical circuit abnormality, with a particular focus on the role of fast-spiking parvalbumin gamma-aminobutyric acid (GABA) neurons in the disease state. Recent findings Clinical electrophysiological studies of schizophrenia patients and pharmacological models of the disorder show an increase in spontaneous gamma band activity (not stimulus-evoked) measures. These findings provide a crucial link between preclinical and clinical work examining the role of gamma band activity in schizophrenia. MRI-based experiments measuring cortical GABA provides evidence supporting impaired GABAergic neurotransmission in schizophrenia patients, which is correlated with gamma band activity level. Several studies suggest that stimulation of the cortical circuitry, directly or via subcortical structures, has the potential to modulate cortical gamma activity, and improve cognitive function. Abnormal gamma band activity is observed in patients with schizophrenia and disease models in animals, and is suggested to underlie the psychosis and cognitive/perceptual deficits. Convergent evidence from both clinical and preclinical studies suggest the central factor in gamma band abnormalities is impaired GABAergic neurotransmission, particularly in a subclass of neurons which express parvalbumin. Rescue of gamma band abnormalities presents an intriguing option for therapeutic intervention. C1 Harvard Univ, Sch Med, VA Boston Healthcare Syst, Neurosci Lab, Brockton, MA 02301 USA. Harvard Univ, Sch Med, Dept Psychiat, Brockton, MA 02301 USA. RP McCarley, RW (reprint author), Harvard Univ, Sch Med, VABHS, Dept Psychiat, 940 Belmont St, Brockton, MA 02301 USA. EM robert_mccarley@hms.harvard.ed FU Department of Veterans Affairs (VA); National Institute of Health [R01 MH039683] FX The review was supported by the Department of Veterans Affairs (VA Merit Award to R.W.M., and VA Career Development Award to J.M.M.) and National Institute of Health R01 MH039683 to R.W.M. NR 92 TC 2 Z9 2 U1 8 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7367 EI 1473-6578 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAY PY 2016 VL 29 IS 3 BP 202 EP 210 DI 10.1097/YCO.0000000000000244 PG 9 WC Psychiatry SC Psychiatry GA DI0YX UT WOS:000373224300004 PM 26900672 ER PT J AU Crawford, MB DeLisi, LE AF Crawford, Mitchell B. DeLisi, Lynn E. TI Issues related to sex differences in antipsychotic treatment SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE women; menopause; antipsychotic; antipsychotic; gender; sex; pregnancy ID ATYPICAL ANTIPSYCHOTICS; GENDER-DIFFERENCES; BIRTH-WEIGHT; PREGNANCY; SCHIZOPHRENIA; EXPOSURE; WOMEN; DRUGS; OUTCOMES; MEDICATIONS AB Purpose of review The effectiveness, side-effect profiles, and numerous other characteristics of antipsychotic medications have been extensively studied. However, the majority of publications do not address the many potential sex differences in efficacy and doses of medications, as well as other sex-specific considerations. Recent findings Of studies that exist, some suggest that female patients respond to lower doses of antipsychotic medications than males and that side-effect profiles vary between the sexes. However, the majority of preclinical trials use only male laboratory animals, and human clinical trials consist of too few women to analyze their response as a separate group. Although changes in hormone production occurring at multiple stages throughout a women's life (such as during pregnancy, breast feeding, menopause, and postmenopausal) are presented as too complex to deal with in clinical trials, they could instead be embraced as clinical dilemmas that require additional study and consideration. We suggest that a focus should be made to reanalyze data from existing major treatment trials of antipsychotics to determine what medications specifically provide the most efficacy for female patients and at what dose range. In addition, new prospective studies are needed to specifically address appropriate adjustments in psychopharmacologic treatment for female patients during pregnancy, and when postmenopausal. More studies of the effects of antipsychotics on male and female fetuses in utero and during breast feeding are also needed to better manage women with schizophrenia and their offspring on a long-term basis in the community. There is currently too little known about sex differences in neuropharmacology. With the new USA National Institutes of Health policy to include sex in all new proposals, the time has come to close this gap in knowledge. C1 [Crawford, Mitchell B.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Harvard South Shore Residency Training Program, Brockton, MA 02401 USA. [DeLisi, Lynn E.] VA Boston Healthcare Syst, Brockton, MA USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. RP DeLisi, LE (reprint author), 940 Belmont Ave, Brockton, MA 02301 USA. EM Lynn.DeLisi@VA.gov NR 49 TC 3 Z9 4 U1 4 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7367 EI 1473-6578 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAY PY 2016 VL 29 IS 3 BP 211 EP 217 DI 10.1097/YCO.0000000000000243 PG 7 WC Psychiatry SC Psychiatry GA DI0YX UT WOS:000373224300005 PM 26906336 ER PT J AU Goodwin, RA Jamal, R Booth, CM Goss, PE Eisenhauer, EA Tu, DS Shepherd, LE AF Goodwin, Rachel A. Jamal, Rahima Booth, Christopher M. Goss, Paul E. Eisenhauer, Elizabeth A. Tu, Dongsheng Shepherd, Lois E. TI Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA. 17 SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Adjuvant letrozole; Diabetes; Hypertension; Coronary artery disease; Prognostic; Predictive ID STAGE BREAST-CANCER; RANDOMIZED-TRIAL; INSULIN; TAMOXIFEN; METFORMIN; THERAPY AB Background: Women with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA. 17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA. 17. Patients and methods: Disease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. Results: DM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15-0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45-1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98-2.3], p = 0.06) and OS (HR = 1.61 [0.95-2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26-3.51], p = 0.004) than those free of CM. Conclusions: DM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Goodwin, Rachel A.] Univ Ottawa, Ottawa Hosp Res Inst, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada. [Jamal, Rahima] CHUM, Notre Dame Hosp, Montreal, PQ, Canada. [Booth, Christopher M.; Eisenhauer, Elizabeth A.; Tu, Dongsheng; Shepherd, Lois E.] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. [Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Goodwin, RA (reprint author), Univ Ottawa, Ottawa Hosp Res Inst, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada. EM rgoodwin@ottawahospital.on.ca NR 19 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD MAY PY 2016 VL 58 BP 97 EP 103 DI 10.1016/j.ejca.2016.01.014 PG 7 WC Oncology SC Oncology GA DI0TR UT WOS:000373210700012 PM 26986765 ER PT J AU Sahm, F Jakobiec, FA Meyer, J Schrimpf, D Eberhart, CG Hovestadt, V Capper, D Lambo, S Ryzhova, M Schuller, U Zheludkova, O Kumirova, E Lichter, P von Deimling, A Jones, DTW Pfister, SM Kool, M Korshunov, A AF Sahm, Felix Jakobiec, Frederick A. Meyer, Jochen Schrimpf, Daniel Eberhart, Charles G. Hovestadt, Volker Capper, David Lambo, Sander Ryzhova, Marina Schueller, Ulrich Zheludkova, Olga Kumirova, Ella Lichter, Peter von Deimling, Andreas Jones, David T. W. Pfister, Stefan M. Kool, Marcel Korshunov, Andrey TI Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas SO GENES CHROMOSOMES & CANCER LA English DT Article ID PLEUROPULMONARY BLASTOMA; MULTILAYERED ROSETTES; EMBRYONAL TUMORS; CANCER; C19MC; GENE AB Intraocular medulloepithelioma (IO-MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. Little is known about the cytogenetics, molecular biology, and pathogenesis of this tumor. In the present study we investigated the mutational landscape of 19 IO-MEPL using targeted next-generation sequencing. Routinely prepared paraffin-embedded samples were assessed with high-coverage genome sequencing on the Illumina NextSeq 500 platform using a customized gene panel set covering the coding region of 130 genes. This revealed several notable genomic alterations, including mutations of DICER1 (6 tumors) and KMT2D (also known as MLL2; 5 tumors)which are frequently recurrent and mutually exclusive molecular events for IO-MEPL. Non-recurrent mutations in the cancer-associated genes BRCA2, BRCA1, NOTCH2, CDH1, and GSE1 were also identified. IO-MEPL samples harboring a DICER1 mutation disclosed few chromosomal alterations and formed a separate DNA methylation cluster, indicating potential differences in genetic and epigenetic events arising perhaps from the presence of this aberration in the tumor genome. The high proportion of recurrent somatic DICER1 and KMT2D mutations in this series of sporadic IO-MEPL points to their likely important roles in the molecular pathogenesis of these rare embryonal tumors, and perhaps suggests the existence of distinct molecular variants of IO-MEPL. Although the precise role of these recurrent mutations in the development of IO-MEPL, and their relationship to pro-oncogenic molecular mechanisms, have yet to be determined, unraveling their roles could eventually be exploited for nonsurgical therapies of these neoplasms. (c) 2016 Wiley Periodicals, Inc. C1 [Sahm, Felix; Meyer, Jochen; Schrimpf, Daniel; Capper, David; von Deimling, Andreas; Korshunov, Andrey] Univ Hosp, Clin Cooperat Unit Neuropathol, German Canc Res Ctr DKFZ, Heidelberg, Germany. [Sahm, Felix; Meyer, Jochen; Schrimpf, Daniel; Capper, David; von Deimling, Andreas; Korshunov, Andrey] Univ Hosp, Dept Neuropathol, Heidelberg, Germany. [Sahm, Felix; Meyer, Jochen; Schrimpf, Daniel; Capper, David; Lambo, Sander; Lichter, Peter; von Deimling, Andreas; Jones, David T. W.; Pfister, Stefan M.; Kool, Marcel; Korshunov, Andrey] German Canc Consortium DKTK, Core Ctr, D-69120 Heidelberg, Germany. [Jakobiec, Frederick A.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirmary, David G Cogan Ophthalm Pathol Lab, Boston, MA USA. [Eberhart, Charles G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hovestadt, Volker; Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Lambo, Sander; Jones, David T. W.; Pfister, Stefan M.; Kool, Marcel] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Ryzhova, Marina] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow, Russia. [Schueller, Ulrich] Univ Munich, Ctr Neuropathol, Munich, Germany. [Zheludkova, Olga] Russian Sci Ctr Radiol, Dept Neurooncol, Moscow, Russia. [Kumirova, Ella] Fed Res Clin Ctr Pediat Hematol Oncol Immunol, Dept Neurooncol, Moscow, Russia. [Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany. RP Korshunov, A (reprint author), German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM Andrey.korshunov@med.uni-heidelberg.de RI von Deimling, Andreas/F-7774-2013; Capper, David/I-8500-2014; OI von Deimling, Andreas/0000-0002-5863-540X; Hovestadt, Volker/0000-0002-3480-6649 FU German Cancer Research Center (DKFZ)-Heidelberg Center for Personalized Oncology (HIPO) Personalized Oncology Programm (POP) FX Supported by: the German Cancer Research Center (DKFZ)-Heidelberg Center for Personalized Oncology (HIPO) Personalized Oncology Programm (POP). NR 26 TC 3 Z9 3 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 2016 VL 55 IS 5 BP 418 EP 427 DI 10.1002/gcc.22344 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DH6PR UT WOS:000372913800002 PM 26841698 ER PT J AU Adams, DC Wang, Y Hariri, LP Suter, MJ AF Adams, David C. Wang, Yan Hariri, Lida P. Suter, Melissa J. TI Advances in Endoscopic Optical Coherence Tomography Catheter Designs SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Biomedical optics; catheters; diagnostic imaging; endoscopy; optical coherence tomography (OCT); optical imaging; scanning catheter microscopy ID MEMS SCANNING CATHETER; AMERICAN-HEART-ASSOCIATION; CORONARY-ARTERY-DISEASE; IN-VIVO; BARRETTS-ESOPHAGUS; INTRAVASCULAR ULTRASOUND; ULTRAHIGH-RESOLUTION; RADIOFREQUENCY ABLATION; IMAGING CATHETER; ATHEROSCLEROTIC PLAQUES AB The use of endoscopic Optical Coherence Tomography (OCT) in the clinical setting has gained momentum in recent years. This is largely due to the advances in OCT catheter designs that are tailored to specific clinical applications. In this review, we summarize many of the designs currently used in patient studies, and additionally discuss a number of novel designs that are yet to be implemented and tested in the clinical setting. With advances in endoscopic OCT catheter designs, we are now beginning to uncover the true clinical potential of this technology particularly in screening, surveillance, biopsy guidance, diagnosis, and therapy-monitoring applications. C1 [Adams, David C.; Wang, Yan; Suter, Melissa J.] Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Hariri, Lida P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hariri, Lida P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Adams, DC; Wang, Y; Suter, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA USA.; Hariri, LP (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Hariri, LP (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM dadams5@mgh.harvard.edu; ywang57@mgh.harvard.edu; lhariri@mgh.harvard.edu; msuter@mgh.harvard.edu NR 115 TC 0 Z9 0 U1 11 U2 17 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD MAY-JUN PY 2016 VL 22 IS 3 AR 6802012 DI 10.1109/JSTQE.2015.2510295 PG 12 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA DH8RZ UT WOS:000373065200001 ER PT J AU Abolmaali, SS Tamaddon, AM Mohammadi, S Amoozgar, Z Dinarvand, R AF Abolmaali, Samira Sadat Tamaddon, Ali Mohammad Mohammadi, Samaneh Amoozgar, Zohreh Dinarvand, Rasoul TI Chemically crosslinked nanogels of PEGylated poly ethyleneimine (L-histidine substituted) synthesized via metal ion coordinated self-assembly for delivery of methotrexate: Cytocompatibility, cellular delivery and antitumor activity in resistant cells SO MATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS LA English DT Article DE Self-assembled nanogel; PEGylated poly ethyleneimine; L-Histidine substitution; Cellular delivery; Cytocompatibility; Antitumor activity; Methotrexate; In-vitro ID BLOCK-COPOLYMER MICELLES; RHEUMATOID-ARTHRITIS; POLYMERIC MICELLES; GENE DELIVERY; IN-VITRO; NANOPARTICLES; RELEASE; CANCER; OPTIMIZATION; MECHANISMS AB Self-assembled nanogels were engineered by forming Zn2+-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-L-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by H-1-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77-83 nm and a relatively high drug loading (54 +/- 4% w/w), showed a low polydispersity and neutral surface charges. The MIX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo. (C) 2016 Elsevier B.V. All rights reserved. C1 [Abolmaali, Samira Sadat] Shiraz Univ Med Sci, Pharmaceut Nanotechnol Dept, Shiraz 71345, Iran. [Tamaddon, Ali Mohammad; Mohammadi, Samaneh] Shiraz Univ Med Sci, Ctr Nanotechnol Drug Delivery, Shiraz 71345, Iran. [Amoozgar, Zohreh] Dana Farber Canc Inst, Dept Canc Immunol & Aids, Boston, MA 02115 USA. [Amoozgar, Zohreh] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Dinarvand, Rasoul] Univ Tehran Med Sci, Fac Pharm, Tehran 14174, Iran. RP Tamaddon, AM (reprint author), Shiraz Univ Med Sci, Dept Pharmaceut Nanotechnol, Ctr Nanotechnol Drug Delivery, Shiraz 71345, Iran. EM s.abolmaali@gmail.com; amtamadon@gmail.com; samaneh.mohammadi1986@gmail.com; zohreh_amoozgar@dfci.harvard.edu; dinarvand@tums.ac.ir FU SUMS; Nanotechnology Research Center, Tehran University of Medical Sciences (TUMS); Harvard Medical School [9294] FX The authors gratefully acknowledge use of the facilities of the Center for Nanotechnology in Drug Delivery at Shiraz University of Medical Sciences (SUMS). This study was funded by SUMS grant in partnership with and Nanotechnology Research Center, Tehran University of Medical Sciences (TUMS) and Zohreh Amoozgar from Department of Cancer Immunology and Aids, Dana-Farber Cancer Institute and Harvard Medical School (Grant #9294). NR 45 TC 2 Z9 2 U1 12 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-4931 EI 1873-0191 J9 MAT SCI ENG C-MATER JI Mater. Sci. Eng. C-Mater. Biol. Appl. PD MAY 1 PY 2016 VL 62 BP 897 EP 907 DI 10.1016/j.msec.2016.02.045 PG 11 WC Materials Science, Biomaterials SC Materials Science GA DH4MC UT WOS:000372759100107 PM 26952497 ER PT J AU Stulac, S Munyaneza, RBM Chai, J Bigirimana, JB Nyishime, M Tapela, N Chaffee, S Lehmann, L Shulman, LN AF Stulac, Sara Munyaneza, Richard B. Mark Chai, Jeanne Bigirimana, Jean Bosco Nyishime, Merab Tapela, Neo Chaffee, Sara Lehmann, Leslie Shulman, Lawrence N. TI Initiating Childhood Cancer Treatment in Rural Rwanda: A Partnership-Based Approach SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Africa; partnership; pediatric oncology; resource-poor ID MORTALITY AB Background. More than 85% of pediatric cancer cases and 95% of deaths occur in resource-poor countries that use less than 5% of the world's health resources. In the developed world, approximately 81% of children with cancer can be cured. Models applicable in the most resource-poor settings are needed to address global inequities in pediatric cancer treatment. Procedure. Between 2006 and 2011, a cohort of children received cancer therapy using a new approach in rural Rwanda. Children were managed by a team of a Rwandan generalist doctor, Rwandan nurse case manager, Rwanda-based US-trained pediatrician, and US-based pediatric oncologist. Biopsies and staging studies were obtained in-country. Pathologic diagnoses were made at US or European laboratories. Rwanda-based clinicians and the pediatric oncologist jointly generated treatment plans by telephone and email. Results. Treatment was provided to 24 patients. Diagnoses included lymphomas (n = 10), sarcomas (n = 9), leukemias (n = 2), and other malignancies (n = 3). Standard chemotherapy regimens included CHOP, ABVD, VA, COP/COMP, and actino-VAC. Thirteen patients were in remission at the completion of data collection. Two succumbed to treatment complications and nine had progressive disease. There were no patients who abandoned treatment. The mean overall survival was 31 months and mean disease-free survival was 18 months. Conclusions. These data suggest that chemotherapy can be administered with curative intent to a subset of cancer patients in this setting.This approach provides a platform for pediatric cancer care models, relying on local physicians collaborating with remote specialist consultants to deliver subspecialty care in resource-poor settings. C1 [Stulac, Sara; Chai, Jeanne; Shulman, Lawrence N.] Partners Hlth, 888 Commonwealth Ave, Boston, MA 02215 USA. [Stulac, Sara; Tapela, Neo; Shulman, Lawrence N.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Stulac, Sara; Shulman, Lawrence N.] Harvard Univ, Sch Med, Boston, MA USA. [Stulac, Sara; Lehmann, Leslie] Boston Childrens Hosp, Boston, MA USA. [Munyaneza, Richard B. Mark; Nyishime, Merab; Tapela, Neo] Minist Hlth, Kigali, Rwanda. [Bigirimana, Jean Bosco; Tapela, Neo] Inshuti Mu Buzima, Kigali, Rwanda. [Chaffee, Sara] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Lehmann, Leslie; Shulman, Lawrence N.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Stulac, S (reprint author), Partners Hlth, 888 Commonwealth Ave, Boston, MA 02215 USA. EM sstulac@pih.org NR 12 TC 0 Z9 0 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAY PY 2016 VL 63 IS 5 BP 813 EP 817 DI 10.1002/pbc.25903 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DH7CD UT WOS:000372947900008 PM 26785111 ER PT J AU Sanford, E Wolbrink, T Mack, J Rowe, R AF Sanford, Ethan Wolbrink, Traci Mack, Jennifer Grant Rowe, R. TI Severe Tumor Lysis Syndrome and Acute Pulmonary Edema Requiring Extracorporeal Membrane Oxygenation Following Initiation of Chemotherapy for Metastatic Alveolar Rhabdomyosarcoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE alveolar rhabdomyosarcoma; ECMO; pediatric cancer; tumor lysis syndrome ID LIFE-SUPPORT; RESPIRATORY-FAILURE; CHILDREN; MALIGNANCY; EXPERIENCE AB We present an 8-year-old male with metastatic alveolar rhabdomyosarcoma (ARMS) who developed precipitous cardiopulmonary collapse with severe tumor lysis syndrome (TLS) 48 hr after initiation of chemotherapy. Despite no detectable pulmonary metastases, acute hypoxemic respiratory failure developed, requiring extracorporeal membrane oxygenation (ECMO). Although TLS has been reported in disseminated ARMS, this singular case of life-threatening respiratory deterioration developing after initiation of chemotherapy presented unique therapeutic dilemmas. We review the clinical aspects of this case, including possible mechanisms of respiratory failure, and discuss the role of ECMO utilization in pediatric oncology. C1 [Sanford, Ethan] Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Sanford, Ethan] Brigham & Womens Hosp, Dept Anesthesiol, 75 Francis St, Boston, MA 02115 USA. [Wolbrink, Traci] Boston Childrens Hosp, Dept Anesthesia & Crit Care Med, Boston, MA USA. [Mack, Jennifer; Grant Rowe, R.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. RP Rowe, R (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM robert_rowe@dfci.harvard.edu FU NHLBI NIH HHS [T32 HL007574] NR 16 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 MAY PY 2016 VL 63 IS 5 BP 928 EP 930 DI 10.1002/pbc.25879 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DH7CD UT WOS:000372947900028 PM 26713672 ER PT J AU Huang, AJ AF Huang, Ambrose J. TI Fluoroscopically guided lumbar facet joint injection using an interlaminar approach and loss of resistance technique SO SKELETAL RADIOLOGY LA English DT Article DE Spine; Facet joint; Fluoroscopy; Injection ID LOW-BACK; SPREAD; PAIN AB To describe a new technique for performing fluoroscopically guided lumbar facet joint injections using an interlaminar approach and loss-of-resistance technique and to report the initial success rate of this technique in a small series of patients. The institutional radiology database was retrospectively reviewed to identify patients who underwent fluoroscopically guided lumbar facet joint injections. Between 1 May 2014 and 31 October 2015, one radiologist attempted fluoroscopically guided lumbar facet joint injections using an interlaminar approach and loss-of-resistance technique in ten severely osteoarthritic facet joints (4 patients). Patient demographics, facet joint side and level, and whether or not an intra-articular facet joint injection was achieved were recorded. Intra-articular injection was achieved using the interlaminar approach and loss-of-resistance technique in five facet joints. Fluoroscopically guided lumbar facet joint injection using an interlaminar approach and loss-of-resistance technique is an alternative approach to a direct posterior facet joint injection and may be particularly useful for severely osteoarthritic facet joints, where bulky osteophytes and/or extreme curvature of the joints in the transverse plane threaten to preclude direct posterior access to the joints. C1 [Huang, Ambrose J.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. RP Huang, AJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM ajhuang@mgh.harvard.edu NR 9 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD MAY PY 2016 VL 45 IS 5 BP 671 EP 676 DI 10.1007/s00256-016-2341-7 PG 6 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DH6MG UT WOS:000372904200012 PM 26825995 ER PT J AU Mukherjee, J Bajwa, AK Wooten, DW Hillmer, AT Pan, ML Pandey, SK Saigal, N Christian, BT AF Mukherjee, Jogeshwar Bajwa, Alisha K. Wooten, Dustin W. Hillmer, Ansel T. Pan, Min-Liang Pandey, Suresh K. Saigal, Neil Christian, Bradley T. TI Comparative assessment of F-18-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE raphe nucleus; hippocampus; translational research; receptor selectivity; P-glycoprotein ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; HUMAN BRAIN; ALZHEIMERS-DISEASE; MESSENGER-RNA; 1A RECEPTORS; BLOOD-FLOW; BINDING; RADIOLIGAND; WAY-100635 AB We have developed F-18-trans-Mefway (F-18-Mefway) for positron emission tomography (PET) imaging studies of serotonin 5-HT1A receptors which are implicated in various brain functions. Translation of imaging the 5-HT1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of F-18-Mefway in normal mice, rats, monkeys, and healthy human volunteers. Mefway was found to be very selective, with subnanomolar affinity for the 5-HT1A receptor. Affinities of >55nM were found for all other human-cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30M) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P-glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of F-18-Mefway binding. Consistent binding of F-18-Mefway in cortical regions, hippocampus, and raphe was observed across all species. F-18-Mefway in the human brain regions correlated with the known postmortem distribution of 5-HT1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in rodents, whereas monkeys and humans showed a raphe to cerebellum ratio of approximately 3. F-18-Mefway appears to be an effective 5-HT1A receptor imaging agent in all models, including humans. F-18-Mefway therefore may be used to quantify 5-HT1A receptor distribution in brain regions for the study of various CNS disorders. (c) 2015 Wiley Periodicals, Inc. C1 [Mukherjee, Jogeshwar; Bajwa, Alisha K.; Pan, Min-Liang; Pandey, Suresh K.; Saigal, Neil] Univ Calif Irvine, Dept Radiol Sci, Preclin Imaging, Irvine, CA 92697 USA. [Wooten, Dustin W.; Hillmer, Ansel T.; Christian, Bradley T.] Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA. [Wooten, Dustin W.; Hillmer, Ansel T.; Christian, Bradley T.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Bajwa, Alisha K.] Midwestern Univ, Glendale, AZ USA. [Wooten, Dustin W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hillmer, Ansel T.] Yale Univ, New Haven, CT USA. [Pandey, Suresh K.] IBA Mol, Somerset, NJ USA. RP Mukherjee, J (reprint author), Univ Calif Irvine, Dept Radiol Sci, B138 Med Sci, Irvine, CA 92697 USA. EM j.mukherjee@uci.edu RI Mukherjee, Jogeshwar/O-1320-2013 OI Mukherjee, Jogeshwar/0000-0003-1009-877X FU National Institute of Aging [R21/R33 AG030524] FX Grant sponsor: National Institute of Aging; Grant number: R21/R33 AG030524 (to J.M.). NR 68 TC 2 Z9 2 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD MAY 1 PY 2016 VL 524 IS 7 BP 1457 EP 1471 DI 10.1002/cne.23919 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA DG2RK UT WOS:000371915200008 PM 26509362 ER PT J AU Nechuta, S Chen, WY Cai, H Poole, EM Kwan, ML Flatt, SW Patterson, RE Pierce, JP Caan, BJ Shu, XO AF Nechuta, Sarah Chen, Wendy Y. Cai, Hui Poole, Elizabeth M. Kwan, Marilyn L. Flatt, Shirley W. Patterson, Ruth E. Pierce, John P. Caan, Bette J. Shu, Xiao Ou TI A pooled analysis of post-diagnosis lifestyle factors in association with late estrogen-receptor-positive breast cancer prognosis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lifestyle factors; recurrence; mortality; breast cancer; prospective; cohort ID PHYSICAL-ACTIVITY QUESTIONNAIRE; BODY-MASS INDEX; POOLING PROJECT; RANDOMIZED-TRIAL; ADJUVANT THERAPY; WEIGHT CHANGE; LIVING WHEL; SURVIVAL; RECURRENCE; WOMEN AB Lifestyle factors have been well studied in relation to breast cancer prognosis overall; however, associations of lifestyle and late outcomes (>5 years after diagnosis) have been much less studied, and no studies have focused on estrogen receptor-positive (ER+) breast cancer survivors, who may have high risk of late recurrence and mortality. We utilized a large prospective pooling study to evaluate the associations of lifestyle factors with late recurrence and all-cause mortality among 6,295 5-year ER+ Stage I-III breast cancer survivors. Pooled and harmonized data were available on clinical factors and lifestyle factors (pre- to post-diagnosis weight change, body mass index (BMI) (kg/m(2)), recreational physical activity, alcohol intake and smoking history), measured on average 2.1 years after diagnosis. Updated information for weight only was available. Study heterogeneity was evaluated by the Q-statistic. Multivariable Cox regression models were stratified by study. Adjusting for clinical factors and potential confounders, 10% weight gain and obesity (BMI, 30-34.99 and 35) were associated with increased risk of late recurrence (hazard ratios (95% confidence intervals): 1.24 (1.00-1.53), 1.40 (1.05-1.86) and 1.41 (1.02-1.93), respectively). Daily alcohol intake was associated with late recurrence, 1.28 (1.01-1.62). Physical activity was inversely associated with late all-cause mortality (0.81 (0.71-0.93) and 0.71 (0.61-0.82) for 4.9 to <17.4 and 17.4 metabolic equivalent-hr/week). A U-shaped association was observed for late all-cause mortality and BMI using updated weight (1.42 (1.15-1.74) and 1.40 (1.09-1.81), <21.5 and 35, respectively). Smoking was associated with increased risk of late outcomes. In this large prospective pooling project, modifiable lifestyle factors were associated with late outcomes among long-term ER+ breast cancer survivors. What's new? Late recurrence is a major concern for women with ER+ breast cancer, which accounts for close to two-thirds of diagnosed breast cancers. The factors that predispose survivors to late recurrence, however, are not fully understood. This report describes a role for certain lifestyle factors. Using pooled data from prospective cohorts, the authors' show that post-diagnosis lifestyle factors, including alcohol intake, exercise, obesity and smoking, are associated with late breast cancer outcomes in estrogen receptor-positive breast cancer survivors. The modifiable nature of these factors could have implications for long-term survivorship care guidelines. C1 [Nechuta, Sarah; Cai, Hui; Shu, Xiao Ou] Vanderbilt Univ Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol, Dept Med, Nashville, TN USA. [Nechuta, Sarah; Cai, Hui; Shu, Xiao Ou] Vanderbilt Univ Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Chen, Wendy Y.; Poole, Elizabeth M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kwan, Marilyn L.; Caan, Bette J.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Flatt, Shirley W.; Patterson, Ruth E.; Pierce, John P.] Univ Calif San Diego, Moores UCSD Canc Ctr, Canc Prevent Program, San Diego, CA 92103 USA. RP Nechuta, S (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, 2525 West End Ave,3rd Floor, Nashville, TN 37203 USA. EM sarah.nechuta@vanderbilt.edu FU National Cancer Institute at the National Institutes of Health (NIH) [R03CA171013-01]; Susan G. Komen Foundation [KG100988]; NIH [R01 CA129059, P01 CA87969, 3R01 CA118229-03S1] FX Grant sponsor: National Cancer Institute at the National Institutes of Health (NIH); Grant number: R03CA171013-01; Grant sponsor: Susan G. Komen Foundation; Grant number: #KG100988; Grant sponsor: NIH; Grant numbers: R01 CA129059, P01 CA87969, 3R01 CA118229-03S1 NR 48 TC 14 Z9 14 U1 3 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2016 VL 138 IS 9 BP 2088 EP 2097 DI 10.1002/ijc.29940 PG 10 WC Oncology SC Oncology GA DF2GY UT WOS:000371161800004 PM 26606746 ER PT J AU Keum, N Cao, Y Oh, H Smith-Warner, SA Orav, J Wu, K Fuchs, CS Cho, E Giovannucci, EL AF Keum, NaNa Cao, Yin Oh, Hannah Smith-Warner, Stephanie A. Orav, John Wu, Kana Fuchs, Charles S. Cho, Eunyoung Giovannucci, Edward L. TI Sedentary behaviors and light-intensity activities in relation to colorectal cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE TV watching; sedentary behaviors; sitting; light-intensity activities; colorectal cancer; epidemiology ID PHYSICAL-ACTIVITY QUESTIONNAIRE; DOSE-RESPONSE METAANALYSIS; TYPE-2 DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; ENERGY-EXPENDITURE; CALCIUM INTAKE; LIFE-STYLE; OBESITY; HEALTH; TIME AB A recent meta-analysis found that sedentary behaviors are associated with an increased colorectal cancer (CRC) risk. Yet, the finding on TV viewing time, the most widely used surrogate of sedentary behaviors, was based on only two studies. Furthermore, light-intensity activities (e.g., standing and slow walking), non-sedentary by posture but close to sedentary behaviors by Metabolic Equivalent Task values, have not been investigated in relation to CRC risk. Thus, we prospectively analyzed the relationships based on 69,715 women from Nurses' Health Study (1992-2010) and 36,806 men from Health Professionals Follow-Up Study (1988-2010). Throughout follow-up, time spent on sedentary behaviors including sitting watching TV and on light-intensity activities were assessed repeatedly; incidence of CRC was ascertained. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models from each cohort. A total of 1,119 and 913 incident cases were documented from women and men, respectively. The multivariable HR comparing21 versus<7 hr/week of sitting watching TV was 1.21 (95% CI=1.02 to 1.43, p(trend)=.01) in women and 1.06 (95% CI=0.84 to 1.34, p(trend)=.93) in men. In women, those highly sedentary and physically less active had an approximately 41% elevated risk of CRC (95% CI=1.03 to 1.92) compared with those less sedentary and physically more active. The other sedentary behaviors and light-intensity activities were not related to CRC risk in women or men. In conclusion, we found that prolonged sitting time watching TV was associated with an increased CRC risk in women but not in men. What's new? While sedentary behaviors have been generally found to be associated with an increased colorectal cancer (CRC) risk, their role in the etiology of CRC remains to be better understood. This cohort study prospectively examined diverse sedentary behaviors and light-intensity activities such as standing and slow walking in relation to CRC risk in men and women. By demonstrating that sitting time watching TV is an independent risk factor of CRC in women, this study may provide evidence supporting the need to encourage public health recommendations emphasizing the importance of reducing sedentary time, especially prolonged TV watching, on top of increasing physical activity. C1 [Keum, NaNa; Cao, Yin; Oh, Hannah; Smith-Warner, Stephanie A.; Wu, Kana; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Bldg 2,3rd Floor,665 Huntington Ave, Boston, MA 02115 USA. [Keum, NaNa; Cao, Yin; Oh, Hannah; Smith-Warner, Stephanie A.; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Bldg 2,3rd Floor,665 Huntington Ave, Boston, MA 02115 USA. [Orav, John] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Orav, John; Giovannucci, Edward L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Cho, Eunyoung; Giovannucci, Edward L.] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Keum, N (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Bldg 2,3rd Floor,665 Huntington Ave, Boston, MA 02115 USA.; Keum, N (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Bldg 2,3rd Floor,665 Huntington Ave, Boston, MA 02115 USA. EM nak212@mail.harvard.edu OI Oh, Hannah/0000-0002-8368-3032 FU Entertainment Industry Foundation's National Colorectal Cancer Research Alliance; [P01 CA87969]; [UM1 CA167552]; [P01 CA 55075]; [UM1 CA186107] FX NaNa Keum had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We would like to thank the participants and staff of the HPFS and NHS for their valuable contributions as well as the 36 state cancer registries for their help. The authors assume full responsibility for analyses and interpretation of these data. This research was funded by the following federal grants: P01 CA87969, UM1 CA167552, P01 CA 55075, and UM1 CA186107. In addition, funding came from the Entertainment Industry Foundation's National Colorectal Cancer Research Alliance. The funders had no role in: design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. NR 33 TC 1 Z9 1 U1 4 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2016 VL 138 IS 9 BP 2109 EP 2117 DI 10.1002/ijc.29953 PG 9 WC Oncology SC Oncology GA DF2GY UT WOS:000371161800006 PM 26649988 ER PT J AU Egede, LE Bishu, KG Walker, RJ Dismuke, CE AF Egede, Leonard E. Bishu, Kinfe G. Walker, Rebekah J. Dismuke, Clara E. TI Impact of diagnosed depression on healthcare costs in adults with and without diabetes: United States, 2004-2011 SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Diabetes; Depression; Cost; Comorbidities; Expenditures ID COMORBID DEPRESSION; MEDICAL COSTS; PREVALENCE; COMPLICATIONS; EXPENDITURES; BURDEN; MODELS AB Objective: This study used the Medical Expenditures Panel Survey (MEPS) to estimate the cost of diabetes, depression, and comorbid diabetes and depression over 8 years. Methods: An 8-year pooled dataset was created using the household and medical provider components of MEPS. Medical expenditures were adjusted to a common 2014 dollar value. Analyses used responses of 147,095 individuals > 18 years of age for the years 2004-2011. The dependent variable in this study was total healthcare expenditure and the primary independent variables were diabetes and depression status. A two-part (probit/GLM) model was used to estimate the annual medical spending and marginal effects were calculated for incremental cost. Results: In the pooled sample, after adjusting for socio-demographic factors, comorbidities and time trend covariates, the incremental cost of depression only was $2654 (95% CI 2343-2966), diabetes was $2692 (95% CI 2338-3046), and both was $6037 (CI 95% 5243-6830) when compared to patients with none. Based on the unadjusted mean, annual average aggregate cost of depression only was estimated at $238.3 billion, diabetes only $150.1 billion and depression and diabetes together was $77.6 billion. Conclusion: Costs at both the individual and aggregate level are significant, with comorbid diagnoses resulting in higher incremental costs than the sum of the costs for each diagnosis alone. In addition, while the cost of depression increased over time, the cost of diabetes decreased over time, much due to decreased inpatient costs. This study highlights the tremendous cost savings possible through more aggressive screening, diagnosis, and treatment of depression. (C) 2016 Elsevier B.V. All rights reserved. C1 [Egede, Leonard E.; Bishu, Kinfe G.; Walker, Rebekah J.; Dismuke, Clara E.] Med Univ S Carolina, Dept Med, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Egede, Leonard E.; Bishu, Kinfe G.; Walker, Rebekah J.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Dept Med, Charleston, SC 29425 USA. [Egede, Leonard E.; Walker, Rebekah J.; Dismuke, Clara E.] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280G, Charleston, SC 29425 USA. EM egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Disease [K24DK093699-01] FX This study was supported by Grant K24DK093699-01 from The National Institute of Diabetes and Digestive and Kidney Disease (PI: Leonard Egede). NR 40 TC 1 Z9 1 U1 5 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAY PY 2016 VL 195 BP 119 EP 126 DI 10.1016/j.jad.2016.02.011 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DF3PP UT WOS:000371257400014 PM 26890289 ER PT J AU Forrest, LN Bodell, LP Witte, TK Goodwin, N Bartlett, ML Siegfried, N Eddy, KT Thomas, JJ Franko, DL Smith, AR AF Forrest, Lauren N. Bodell, Lindsay P. Witte, Tracy K. Goodwin, Natalie Bartlett, Mary L. Siegfried, Nicole Eddy, Kamryn T. Thomas, Jennifer J. Franko, Debra L. Smith, April R. TI Associations between eating disorder symptoms and suicidal ideation through thwarted belongingness and perceived burdensomeness among eating disorder patients SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Eating disorders; Suicidal ideation; Burdensomeness; Fasting; Body dissatisfaction ID INTERPERSONAL-PSYCHOLOGICAL THEORY; ACQUIRED CAPABILITY; ANOREXIA-NERVOSA; BULIMIA-NERVOSA; LAXATIVE ABUSE; OVER-EXERCISE; MENTAL-HEALTH; RISK-FACTORS; ADOLESCENTS; BEHAVIOR AB Background: Suicidal ideation is relatively common among people with eating disorders (EDs). The Interpersonal-Psychological Theory of Suicide holds that suicidal ideation has two proximal causes: thwarted belongingness and perceived burdensomeness. It is unknown which ED symptoms are positively associated with suicidal ideation, and whether thwarted belongingness and perceived burdensomeness explain those associations. Method: We tested two parallel mediation models to determine whether current and lifetime ED symptoms were positively related to suicidal ideation through thwarted belongingness and perceived burdensomeness among ED patients (n=98), controlling for current depression. In each model, ED symptoms and depression were predictors, thwarted belongingness and perceived burdensomeness were mediators, and suicidal ideation was the outcome. Results: The first model included current symptoms; current body dissatisfaction (ab=0.04, 95% CI [0.01, 0.061) and fasting (ab=0.12, 95% CI [0.01, 0.221) were indirectly related to increased suicidal ideation through higher burdensomeness, controlling for depression. The second model included lifetime symptoms; lifetime fasting (ab=0.18, 95% CI [0.07, 0.291) was indirectly related to increased suicidal ideation through higher burdensomeness, controlling for depression. Limitations: The sample size prevented the use of latent variables for thwarted belongingness and perceived burdensomeness, and the cross-sectional data prevented testing for bidirectional relations among ED symptoms, thwarted belongingness, perceived burdensomeness, and suicidal ideation. Conclusions: Results underscore the importance of exploring transdiagnostic ED symptoms, including body dissatisfaction and fasting in particular, that may intensify burdensomeness and thereby contribute to suicidal ideation over and above depressive symptoms in this high-risk population. (C) 2016 Elsevier B.V. All rights reserved. C1 [Forrest, Lauren N.; Smith, April R.] Miami Univ, Dept Psychol, 90 N Patterson Dr, Oxford, OH 45056 USA. [Bodell, Lindsay P.] Univ Pittsburgh, Sch Med, M240 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. [Witte, Tracy K.] Auburn Univ, Dept Psychol, 226 Thach Hall, Auburn, AL 36849 USA. [Goodwin, Natalie] Eating Recovery Ctr Washington, 1231 116th Ave NE, Bellevue, WA 98004 USA. [Bartlett, Mary L.; Siegfried, Nicole] Castlewood Treatment Ctr, 2807 Greystone Commercial Blvd 36, Birmingham, AL 35242 USA. [Eddy, Kamryn T.; Thomas, Jennifer J.; Franko, Debra L.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, 2 Longfellow Pl,Suite 200, Boston, MA 02114 USA. [Eddy, Kamryn T.; Thomas, Jennifer J.] Harvard Univ, Sch Med, Dept Psychiat, 25 Shattuck St, Boston, MA 02115 USA. [Franko, Debra L.] Northeastern Univ, Behrakis Hlth Sci Ctr 123, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Franko, Debra L.] Northeastern Univ, Behrakis Hlth Sci Ctr 123, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. RP Smith, AR (reprint author), Miami Univ, Dept Psychol, 90 N Patterson Dr, Oxford, OH 45056 USA. EM aprilsmith@miamioh.edu NR 56 TC 3 Z9 3 U1 5 U2 32 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAY PY 2016 VL 195 BP 127 EP 135 DI 10.1016/j.jad.2016.02.017 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DF3PP UT WOS:000371257400015 PM 26895090 ER PT J AU Rong, PJ Liu, J Wang, LP Liu, RP Fang, JL Zhao, JJ Zhao, YF Wang, HH Vangel, M Sun, SR Ben, H Park, J Li, SY Meng, H Zhu, B Kong, J AF Rong, Peijing Liu, Jun Wang, Liping Liu, Rupeng Fang, Jiliang Zhao, Jingjun Zhao, Yufeng Wang, Honghong Vangel, Mark Sun, Sharon Ben, Hui Park, Joel Li, Shaoyuan Meng, Hong Zhu, Bing Kong, Jian TI Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Transcutaneous auricular vagus nerve stimulation; Transcutaneous vagus nerve stimulation; Major depressive disorder; Depression; Hamilton depression rating scale ID TREATMENT-RESISTANT DEPRESSION; ASTERISK-D REPORT; SUBTHRESHOLD DEPRESSION; TRIAL; THERAPY; VNS; EPILEPSY; NETWORK AB Background: Depression presents a significant burden to both patients and society. One treatment that has emerged is vagus nerve stimulation (VNS), an FDA-approved physical treatment for depressive disorders. However, the application of this intervention has been limited by the involvement of surgery and potential side effects. The aim of this study is to explore the effectiveness of stimulating the superficial branches of the vagus nerve as a solo treatment for MDD. Methods: This is a nonrandomized, controlled study. The first cohort of patients (n=91) only received transcutaneous auricular VNS (taVNS) for 12 weeks. In the second cohort (n=69), patients first received 4 weeks of sham taVNS followed by 8 weeks of taVNS. All treatments were self-administered by the patients at home after they received training from the hospitals. The primary outcome measurement was the 24-item Hamilton Depression Rating Scale measured at weeks 0, 4, 8, and 12. Data analysis included a timelag analysis comparing (1) real and sham taVNS groups at week 4; (2) the real taVNS group at week 4 vs the sham taVNS group at week 8 (fourth week of real taVNS following 4 weeks of sham); and (3) the real taVNS group at week 8 vs the sham taVNS group at week 12 (eighth week of real taVNS following sham). Results: After four weeks of treatment, MDD patients in the taVNS group showed greater improvement than patients in the sham taVNS group as indicated by Hamilton score changes as well as response and remission rates at week four. In addition, we also found that the clinical improvements continued until week 12 during taVNS. Limitations: Patients were not randomized in this study. Conclusions: Our results suggest that taVNS is a promising, safe, and cost-effective therapeutic method for mild and moderate MDD. (C) 2016 Elsevier B.V. All rights reserved. C1 [Rong, Peijing; Liu, Rupeng; Fang, Jiliang; Zhao, Jingjun; Ben, Hui; Li, Shaoyuan; Meng, Hong; Zhu, Bing] China Acad Chinese Med Sci, Inst Acu Mox, Beijing 100700, Peoples R China. [Liu, Jun; Fang, Jiliang; Wang, Honghong] China Acad Chinese Med Sci, Guanganmen Hosp, Beijing 100053, Peoples R China. [Wang, Liping] Beijing Univ TCM, Huguosi TCM Hosp, Beijing 100035, Peoples R China. [Zhao, Yufeng] China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing 100700, Peoples R China. [Vangel, Mark] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Sun, Sharon; Park, Joel; Kong, Jian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Rong, PJ (reprint author), China Acad Chinese Med Sci, Inst Acu Mox, Beijing 100700, Peoples R China.; Kong, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. EM rongpj@hotmail.com; kongj@nmr.mgh.harvard.edu FU Special Program of Chinese Medicine of the National Basic Research Program of China [2012CB518503]; "Twelfth Five-year Plan" National Science and Technology Support Program of China [2012BAF14B10]; Beijing Natural Science Foundation of China [7111007]; Acupuncture Hospital affiliated with the China Academy of Chinese Medical Sciences; NCCIH/NIH [R01AT006364, R01AT008563, R21AT008707, P01 AT006663] FX The work is supported by the Special Program of Chinese Medicine of the National Basic Research Program of China (973 Program 2012CB518503), the "Twelfth Five-year Plan" National Science and Technology Support Program of China (2012BAF14B10) and the Beijing Natural Science Foundation of China (7111007), the Acupuncture Hospital affiliated with the China Academy of Chinese Medical Sciences, and the Institutional Ethics Committee of the China Academy of Chinese Medical Sciences for their invaluable contributions to the study. Jian Kong is supported by R01AT006364 (NCCIH/NIH), R01AT008563, (NCCIH/NIH), R21AT008707 (NCCIH/NIH), and P01 AT006663 (NCCIH/NIH). NR 41 TC 5 Z9 5 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAY PY 2016 VL 195 BP 172 EP 179 DI 10.1016/j.jad.2016.02.031 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DF3PP UT WOS:000371257400021 PM 26896810 ER PT J AU Levy, SD Alladina, JW Hibbert, KA Harris, RS Bajwa, EK Hess, DR AF Levy, Sean D. Alladina, Jehan W. Hibbert, Kathryn A. Harris, R. Scott Bajwa, Ednan K. Hess, Dean R. TI High-flow oxygen therapy and other inhaled therapies in intensive care units SO LANCET LA English DT Article ID ACUTE RESPIRATORY-DISTRESS; ACUTE LUNG INJURY; VENTILATOR-ASSOCIATED PNEUMONIA; RANDOMIZED CONTROLLED-TRIAL; NASAL CANNULA OXYGEN; CRITICALLY-ILL PATIENTS; OBSTRUCTIVE PULMONARY-DISEASE; CONTROLLED CLINICAL-TRIAL; NITRIC-OXIDE; NONINVASIVE VENTILATION AB In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method. C1 [Levy, Sean D.; Alladina, Jehan W.; Hibbert, Kathryn A.; Harris, R. Scott; Bajwa, Ednan K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pulm Crit Care & Sleep Med, Boston, MA USA. [Hess, Dean R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Resp Care, Boston, MA USA. RP Hess, DR (reprint author), Massachusetts Gen Hosp, Resp Care, Boston, MA 02114 USA. EM dhess@mgh.harvard.edu FU Merck; Philips Respironics; Medtronic Covidien; Bayer; McGraw-Hill; UpToDate; American Board of Internal Medicine FX RSH receives consulting fees from Merck for service on a clinical adjudication committee for pneumonia events in a clinical trial. DRH reports personal fees from Philips Respironics, Medtronic Covidien, Bayer, McGraw-Hill, Jones and Bartlett, UpToDate, and the American Board of Internal Medicine. SDL, JWA, KAH, and EKB declare no competing interests. NR 103 TC 0 Z9 1 U1 7 U2 14 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 APR 30 PY 2016 VL 387 IS 10030 BP 1867 EP 1878 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DK6SS UT WOS:000375056100035 PM 27203510 ER PT J AU Yu, DH Sun, CL Zheng, ZZ Wang, XL Chen, DY Wu, H Wang, XQ Shi, FX AF Yu, Dehong Sun, Changling Zheng, Zhaozhu Wang, Xueling Chen, Dongye Wu, Hao Wang, Xiaoqin Shi, Fuxin TI Inner ear delivery of dexamethasone using injectable silk-polyethylene glycol (PEG) hydrogel SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Silk fibroin; Hydrogel; Dexamethasone; Inner ear; Drug delivery ID LOCAL-DRUG DELIVERY; TRIAMCINOLONE ACETONIDE; SUSTAINED-RELEASE; HEARING-LOSS; BIOMATERIALS; STEROIDS; PROTEIN; SYSTEM AB Minimally invasive delivery and sustained release of therapeutics to the inner ear are of importance to the medical treatment of inner ear disease. In this study, the injectable silk fibroin-polyethylene glycol (Silk-PEG) hydrogel was investigated as a drug delivery carrier to deliver poorly soluble micronized dexamethasone (mDEX) to the inner ear of guinea pigs. Encapsulation of mDEX with a loading up to 5% (w/v) did not significantly change the silk gelation time, and mDEX were evenly distributed in the PEG-Silk hydrogel as visualized by SEM. The loading of mDEX in Silk-PEG hydrogel largely influenced in vitro drug release kinetics. The optimized Silk-PEG-mDEX hydrogel (2.5% w/v loading, in situ-forming, 10 mu l) was administered directly onto the round window membrane of guinea pigs. The DEX concentration in perilymph maintained above 100 ng/ml for at least 10 days for the Silk-PEG formulation while less than 12 h for the control sample of free mDEX. Minimal systemic exposure was achieved with low DEX concentrations (< 0.2 mu g/ml) in cerebrospinal fluid (CSF) and plasma in the first 2 h after the local application of the Silk-PEG-mDEX hydrogel. A transient hearing threshold shift was found but then resolved after 14 days as revealed by auditory brainstem response (ABR), showing minimal inflammatory responses on the round window membrane and scala taympani. The Silk-PEG hydrogel completely degraded in 21 days. Thus, the injectable PEG-Silk hydrogel is an effective and safe vehicle for inner ear delivery and sustained release of glucocorticoid. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yu, Dehong; Sun, Changling; Wang, Xueling; Chen, Dongye; Wu, Hao] Shanghai Jiao Tong Univ, Xinhua Hosp, Dept Otolaryngol Head & Neck Surg,Ear Inst,Sch Me, Shanghai Key Lab Translat Med Ear & Nose Dis, Shanghai 200092, Peoples R China. [Zheng, Zhaozhu; Wang, Xiaoqin] Soochow Univ, Natl Engn Lab Modern Silk, Suzhou 215123, Peoples R China. [Sun, Changling] Jiangnan Univ, Peoples Hosp Wuxi City 4, Affiliated Hosp, Dept Otolaryngol Head & Neck Surg, Wuxi 214062, Peoples R China. [Shi, Fuxin] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol,Eaton Peabody Lab, Boston, MA 02115 USA. RP Wang, XQ (reprint author), 199 Renai Rd,Suzhou Ind Pk, Suzhou 215123, Jiangsu, Peoples R China.; Wu, H (reprint author), Room 915,Sci & Educ Bldg,Kong Jiang Rd 1665, Shanghai 200092, Peoples R China. EM wuhao622@sh163.net; wangxiaoqin@suda.edu.cn FU National Natural Science Foundation of China [81170924, 81302709, 51273138, 81330023]; Shanghai Committee of Science and Technology [14DZ2260300]; Shanghai municipal health bureau [2012Y343]; Xinhua hospital foundation [13YJ19]; Start-up Fund of Soochow University [14317432] FX This work was supported by the Major Program of the National Natural Science Foundation of China (No. 81330023), National Natural Science Foundation of China (Nos. 81170924 and 81302709, 51273138), Shanghai Committee of Science and Technology (14DZ2260300), Shanghai municipal health bureau (No. 2012Y343) and Xinhua hospital foundation (No. 13YJ19), and the Start-up Fund of Soochow University (Project no. 14317432). We also thank Simatech Inc., in Soochow, China to provide lyophilized sterile silk power and technical guidance on making Silk-PEG hydrogel. NR 22 TC 3 Z9 3 U1 15 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD APR 30 PY 2016 VL 503 IS 1-2 BP 229 EP 237 DI 10.1016/j.ijpharm.2016.02.048 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH5GX UT WOS:000372815600023 PM 26972377 ER PT J AU Yucesoy, B Barabasi, AL AF Yucesoy, Burcu Barabasi, Albert-Laszlo TI Untangling performance from success SO EPJ DATA SCIENCE LA English DT Article DE success; performance; popularity ID FAME; SCIENTISTS; SPORTS; MODELS; SOCCER AB Fame, popularity and celebrity status, frequently used tokens of success, are often loosely related to, or even divorced from professional performance. This dichotomy is partly rooted in the difficulty to distinguish performance, an individual measure that captures the actions of a performer, from success, a collective measure that captures a community's reactions to these actions. Yet, finding the relationship between the two measures is essential for all areas that aim to objectively reward excellence, from science to business. Here we quantify the relationship between performance and success by focusing on tennis, an individual sport where the two quantities can be independently measured. We show that a predictive model, relying only on a tennis player's performance in tournaments, can accurately predict an athlete's popularity, both during a player's active years and after retirement. Hence the model establishes a direct link between performance and momentary popularity. The agreement between the performance-driven and observed popularity suggests that in most areas of human achievement exceptional visibility may be rooted in detectable performance measures. C1 [Yucesoy, Burcu; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Yucesoy, Burcu; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, Budapest, Hungary. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Cent European Univ, Ctr Network Sci, Budapest, Hungary. EM barabasi@gmail.com FU Air Force Office of Scientific Research (AFOSR) [FA9550-15-1-0077, FA9550-15-1-0364] FX We wish to thank Tamas Hamori for his guidance toward a deeper understanding of the tennis world, Kim Albrect for helpful visualizations and other colleagues at the CCNR, especially those in the success group, for valuable discussions and comments. This research was supported by Air Force Office of Scientific Research (AFOSR) under agreements FA9550-15-1-0077 and FA9550-15-1-0364. NR 42 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2193-1127 J9 EPJ DATA SCI JI EPJ Data Sci. PD APR 29 PY 2016 VL 5 AR 17 DI 10.1140/epjds/s13688-016-0079-z PG 10 WC Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Mathematics; Mathematical Methods In Social Sciences GA EA9MS UT WOS:000386968900001 ER PT J AU Li, YC Cooper, A Odibo, IN Ahmed, A Murphy, P Koonce, R Dajani, NK Lowery, CL Roberts, DJ Maroteaux, L Kilic, F AF Li, Yicong Cooper, Anthonya Odibo, Imelda N. Ahmed, Asli Murphy, Pamela Koonce, Ruston Dajani, Nafisa K. Lowery, Curtis L. Roberts, Drucilla J. Maroteaux, Luc Kilic, Fusun TI Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BIOGENIC-AMINE NEUROTRANSMITTERS; HUMAN SEROTONIN TRANSPORTER; VILLOUS TROPHOBLAST CELLS; HUMAN TERM PLACENTAE; FUNCTIONAL CONSEQUENCES; HETERO-OLIGOMERIZATION; DOPAMINE TRANSPORTER; HOMO-OLIGOMERIZATION; SURFACE EXPRESSION; GRANULE SECRETION AB Earlier findings have identified the requirement of insulin signaling on maturation and the translocation of serotonin (5-HT) transporter, SERT to the plasma membrane of the trophoblast in placenta. Because of the defect on insulin receptor (IR) in the trophoblast of the gestational diabetes mellitus (GDM)-associated placenta, SERT is found entrapped in the cytoplasm of the GDM-trophoblast. SERT is encoded by the same gene expressed in trophoblast and platelets. Additionally, alteration in plasma 5-HT levels and the 5-HT uptake rates are associated with the aggregation rates of platelets. Therefore, here, we investigated a novel hypothesis that GDM-associated defects in platelet IR should change their 5-HT uptake rates, and this should be a leading factor for thrombosis in GDM maternal blood. The maternal blood and the placentas were obtained at the time of cesarean section from the GDM and non-diabetic subjects (n = 6 for each group), and the platelets and trophoblasts were isolated to determine the IR activity, surface level of SERT, and their 5-HT uptake rates. Interestingly, no significant differences were evident in IR tyrosine phosphorylation or the downstream elements, AKT and S6K in platelets and their aggregation rates in both groups. Furthermore, insulin stimulation up-regulated 5-HT uptake rates of GDM-platelets as it does in the control group. However, the phosphorylation of IR and the downstream elements were significantly lower in GDM-trophoblast and showed no response to the insulin stimulation while they showed 4-fold increase to insulin stimulation in control group. Similarly, the 5-HT uptake rates of GDM-trophoblast and the SERT expression on their surface were severalfold lower compared with control subjects. IR is expressed in all tissues, but it is not known if diabetes affects IR in all tissues equally. Here, for the first time, our findings with clinical samples show that in GDM-associated defect on IR is tissue type-dependent. While IR is impaired in GDM-placenta, it is unaffected in GDM-platelet. C1 [Li, Yicong; Cooper, Anthonya; Ahmed, Asli; Koonce, Ruston; Kilic, Fusun] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Coll Med, Little Rock, AR 72205 USA. [Odibo, Imelda N.; Murphy, Pamela; Dajani, Nafisa K.; Lowery, Curtis L.] Univ Arkansas Med Sci, Dept Obstet & Gynecol, Coll Med, Little Rock, AR 72205 USA. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Maroteaux, Luc] Univ Paris 06, INSERM, UMR S839, Inst Fer Moulin, F-75005 Paris, France. RP Kilic, F (reprint author), Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Coll Med, Little Rock, AR 72205 USA. EM kilicfusun@uams.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [HL091196]; Eunice Kennedy Shriver NICHHD [058697, 053477]; American Heart Association [13GRNT17240014]; Minnie Merrill Sturgis Diabetes Research Fund; Sturgis Charitable Trust; Centre National de la Recherche Scientifique; Institut National de la Sante et de la Recherche Medicale; Universite Pierre et Marie Curie; Fondation pour la Recherche Medicale; French Ministry of Research (Agence Nationale pour la Recherche) FX This work was supported by National Heart, Lung, and Blood Institute, National Institutes of Health HL091196; Eunice Kennedy Shriver NICHHD 058697 and 053477; American Heart Association (13GRNT17240014); and the Minnie Merrill Sturgis Diabetes Research Fund; and the Sturgis Charitable Trust (to F. K.) This work was also supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Sante et de la Recherche Medicale, the Universite Pierre et Marie Curie, and by grants from the Fondation pour la Recherche Medicale, the French Ministry of Research (Agence Nationale pour la Recherche) (to L. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 61 TC 0 Z9 0 U1 3 U2 5 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 APR 29 PY 2016 VL 291 IS 18 BP 9657 EP 9665 DI 10.1074/jbc.M116.713693 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL4JY UT WOS:000375602300024 PM 26921319 ER PT J AU Morris, JN Howard, EP Steel, K Berg, K Tchalla, A Munankarmi, A David, D AF Morris, John N. Howard, Elizabeth P. Steel, Knight Berg, Katherine Tchalla, Achille Munankarmi, Amy David, Daniel TI Strategies to reduce the risk of falling: Cohort study analysis with 1-year follow-up in community dwelling older adults SO BMC GERIATRICS LA English DT Article DE Strategies to reduce risk of falls; Community-dwelling older adults; interRAI assessment ID RANDOMIZED CONTROLLED-TRIAL; PHYSICAL FUNCTION; ELDERLY-PEOPLE; VISUAL-ACUITY; REHABILITATION; HEALTH; ASSOCIATIONS; PREVENTION; POPULATION; PREDICTORS AB Background: According to the CDC, falls rank among the leading causes of accidental death in the United States, resulting in significant health care costs annually. In this paper we present information about everyday lifestyle decisions of the older adult that may help reduce the risk of falling. We pursued two lines of inquiry: first, we identify and then test known mutable fall risk factors and ask how the resolution of such problems correlates with changes in fall rates. Second, we identify a series of everyday lifestyle options that persons may follow and then ask, does such engagement (e.g., engagement in exercise programs) lessen the older adult's risk of falling and if it does, will the relationship hold as the count of risk factors increases? Methods: Using a secondary analysis of lifestyle choices and risk changes that may explain fall rates over one year, we drew on a data set of 13,623 community residing elders in independent housing sites from 24 US states. All older adults were assessed at baseline, and a subset assessed one year later (n = 4,563) using two interRAI tools: the interRAI Community Health Assessment and interRAI Wellness Assessment. Results: For the vast majority of risk measures, problem resolution is followed by lower rate of falls. This is true for physical measures such as doing housework, meal preparation, unsteady gait, transferring, and dressing the lower body. Similarly, this pattern is observed for clinical measures such as depression, memory, vision, dizziness, and fatigue. Among the older adults who had a falls risk at the baseline assessment, about 20 % improve, that is, they had a decreased falls rate when the problem risk improved. This outcome suggests that improvement of physical or clinical states potentially may result in a decreased falls rate. Additionally, physical exercise and cognitive activities are associated with a lower rate of falls. Conclusions: The resolution of risk problems and physical and cognitive lifestyle choices are related to lower fall rates in elders in the community. The results presented here point to specific areas, that when targeted, may reduce the risk of falls. In addition, when there is problem resolution for specific clinical conditions, a decreased risk for falls also may occur. C1 [Morris, John N.] Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. [Howard, Elizabeth P.] Northeastern Univ, Sch Nursing, 360 Huntington Ave, Boston, MA 02115 USA. [Steel, Knight] Hackensack Univ, Med Ctr, 30 Prospect Ave, Hackensack, NJ 07601 USA. [Berg, Katherine] Univ Toronto, Dept Phys Therapy, 160-500 Univ Ave, Toronto, ON M5G 1V7, Canada. [Berg, Katherine] Univ Toronto, Rehabil Sci Inst, 160-500 Univ Ave, Toronto, ON M5G 1V7, Canada. [Tchalla, Achille] Univ Limoges, Dept Geriatr Med, IFR Geist 145, F-87025 Limoges, France. [Tchalla, Achille] CHU Limoges, EA HAVAE 6310, F-87025 Limoges, France. [Munankarmi, Amy] Northeastern Univ, 360 Huntington Ave, Boston, MA 02115 USA. [David, Daniel] San Francisco VA Med Ctr, VA Qual Scholar Geriatr Palliat & Extended Care S, San Francisco, CA 94121 USA. RP Howard, EP (reprint author), Northeastern Univ, Sch Nursing, 360 Huntington Ave, Boston, MA 02115 USA. EM e.howard@neu.edu FU COLLAGE FX Financial support was provided partially by COLLAGE with the remainder being self-supported. NR 51 TC 0 Z9 0 U1 7 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2318 J9 BMC GERIATR JI BMC Geriatr. PD APR 29 PY 2016 VL 16 AR 92 DI 10.1186/s12877-016-0267-5 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK7IT UT WOS:000375099100001 PM 27129303 ER PT J AU English, L Miller, JS Mbusa, R Matte, M Kenney, J Bwambale, S Ntaro, M Patel, P Mulogo, E Stone, GS AF English, Lacey Miller, James S. Mbusa, Rapheal Matte, Michael Kenney, Jessica Bwambale, Shem Ntaro, Moses Patel, Palka Mulogo, Edgar Stone, Geren S. TI Monitoring iCCM referral systems: Bugoye Integrated Community Case Management Initiative (BIMI) in Uganda SO MALARIA JOURNAL LA English DT Article DE Africa; Child mortality; Case management; Referral; Paediatric malaria ID SOUTH-AFRICA; ARTESUNATE; ADVICE AB Background: In Uganda, over half of under-five child mortality is attributed to three infectious diseases: malaria, pneumonia and diarrhoea. Integrated community case management (iCCM) trains village health workers (VHWs) to provide in-home diagnosis and treatment of these common childhood illnesses. For severely ill children, iCCM relies on a functioning referral system to ensure timely treatment at a health facility. However, referral completion rates vary widely among iCCM programmes and are difficult to monitor. The Bugoye Integrated Community Case Management Initiative (BIMI) is an iCCM programme operating in Bugoye sub-county, Uganda. This case study describes BIMI's experience with monitoring referral completion at Bugoye Health Centre III (BHC), and outlines improvements to be made within iCCM referral systems. Methods: This study triangulated multiple data sources to evaluate the strengths and gaps in the BIMI referral system. Three quantitative data sources were reviewed: (1) VHW report of referred patients, (2) referral forms found at BHC, and (3) BHC patient records. These data sources were collated and triangulated from January-December 2014. The goal was to determine if patients were completing their referrals and if referrals were adequately documented using routine data sources. Results: From January-December 2014, there were 268 patients referred to BHC, as documented by VHWs. However, only 52 of these patients had referral forms stored at BHC. Of the 52 referral forms found, 22 of these patients were also found in BHC register books recorded by clinic staff. Thus, the study found a mismatch between VHW reports of patient referrals and the referral visits documented at BHC. This discrepancy may indicate several gaps: (1) referred patients may not be completing their referral, (2) referral forms may be getting lost at BHC, and, (3) referred patients may be going to other health facilities or drug shops, rather than BHC, for their referral. Conclusions: This study demonstrates the challenges of effectively monitoring iCCM referral completion, given identified limitations such as discordant data sources, incomplete record keeping and lack of unique identifiers. There is a need to innovate and improve the ways by which referral compliance is monitored using routine data, in order to improve the percentage of referrals completed. Through research and field experience, this study proposes programmatic and technological solutions to rectify these gaps within iCCM programmes facing similar challenges. With improved monitoring, VHWs will be empowered to increase referral completion, allowing critically ill children to access needed health services. C1 [English, Lacey] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Miller, James S.] Harvard Univ, Sch Med, Boston, MA USA. [Mbusa, Rapheal; Bwambale, Shem] Bugoye Hlth Ctr III, Bugoye, Uganda. [Matte, Michael; Ntaro, Moses; Mulogo, Edgar] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Kenney, Jessica; Patel, Palka; Stone, Geren S.] Massachusetts Gen Hosp, Global Primary Care Program, Boston, MA 02114 USA. RP English, L (reprint author), Univ N Carolina, Sch Med, Chapel Hill, NC USA. EM Lacey_English@med.unc.edu NR 24 TC 2 Z9 2 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD APR 29 PY 2016 VL 15 AR 247 DI 10.1186/s12936-016-1300-z PG 7 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DK7HU UT WOS:000375096600001 PM 27129920 ER PT J AU Zhernakova, A Kurilshikov, A Bonder, MJ Tigchelaar, EF Schirmer, M Vatanen, T Mujagic, Z Vila, AV Falony, G Vieira-Silva, S Wang, J Imhann, F Brandsma, E Jankipersadsing, SA Joossens, M Cenit, MC Deelen, P Swertz, MA Weersma, RK Feskens, EJM Netea, MG Gevers, D Jonkers, D Franke, L Aulchenko, YS Huttenhower, C Raes, J Hofker, MH Xavier, RJ Wijmenga, C Fu, JY AF Zhernakova, Alexandra Kurilshikov, Alexander Bonder, Marc Jan Tigchelaar, Ettje F. Schirmer, Melanie Vatanen, Tommi Mujagic, Zlatan Vila, Arnau Vich Falony, Gwen Vieira-Silva, Sara Wang, Jun Imhann, Floris Brandsma, Eelke Jankipersadsing, Soesma A. Joossens, Marie Cenit, Maria Carmen Deelen, Patrick Swertz, Morris A. Weersma, Rinse K. Feskens, Edith J. M. Netea, Mihai G. Gevers, Dirk Jonkers, Daisy Franke, Lude Aulchenko, Yurii S. Huttenhower, Curtis Raes, Jeroen Hofker, Marten H. Xavier, Ramnik J. Wijmenga, Cisca Fu, Jingyuan CA LifeLines Cohort Study TI Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity SO SCIENCE LA English DT Article ID CHROMOGRANIN-A; ENTEROTYPES; POLYPHENOLS; METABOLISM; CHILDREN AB Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These factors collectively explain 18.7% of the variation seen in the interindividual distance of microbial composition. We could associate 110 factors to 125 species and observed that fecal chromogranin A (CgA), a protein secreted by enteroendocrine cells, was exclusively associated with 61 microbial species whose abundance collectively accounted for 53% of microbial composition. Low CgA concentrations were seen in individuals with a more diverse microbiome. These results are an important step toward a better understanding of environment-diet-microbe-host interactions. C1 [Zhernakova, Alexandra; Bonder, Marc Jan; Tigchelaar, Ettje F.; Jankipersadsing, Soesma A.; Cenit, Maria Carmen; Deelen, Patrick; Swertz, Morris A.; Franke, Lude; Wijmenga, Cisca; Fu, Jingyuan] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Zhernakova, Alexandra; Tigchelaar, Ettje F.; Mujagic, Zlatan; Feskens, Edith J. M.] Top Inst Food & Nutr, Wageningen, Netherlands. [Kurilshikov, Alexander] Inst Chem Biol & Fundamental Med SB RAS, Novosibirsk, Russia. [Kurilshikov, Alexander; Aulchenko, Yurii S.] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Schirmer, Melanie; Vatanen, Tommi; Gevers, Dirk; Huttenhower, Curtis; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Schirmer, Melanie; Huttenhower, Curtis] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Vatanen, Tommi] Aalto Univ, Sch Sci, Dept Comp Sci, Espoo, Finland. [Mujagic, Zlatan; Jonkers, Daisy] Maastricht Univ, Med Ctr, NUTRIM Sch Nutr & Translat Res Metab, Div Gastroenterol Hepatol,Dept Internal Med, NL-6200 MD Maastricht, Netherlands. [Vila, Arnau Vich; Imhann, Floris; Weersma, Rinse K.] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands. [Falony, Gwen; Vieira-Silva, Sara; Wang, Jun; Joossens, Marie; Raes, Jeroen] KU Leuven Univ Leuven, Dept Microbiol & Immunol, Rega Inst Med Res, Lab Mol Bacteriol, Leuven, Belgium. [Falony, Gwen; Vieira-Silva, Sara; Wang, Jun; Joossens, Marie; Raes, Jeroen] VIB, Ctr Biol Dis, Leuven, Belgium. [Brandsma, Eelke; Hofker, Marten H.; Fu, Jingyuan] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands. [Joossens, Marie; Raes, Jeroen] Vrije Univ Brussel, Fac Sci & Bioengn Sci, Microbiol Unit, Brussels, Belgium. [Cenit, Maria Carmen] Natl Res Council IATA CSIC, Inst Agrochem & Food Technol, Microbial Ecol Nutr & Hlth Res Grp, Valencia, Spain. [Cenit, Maria Carmen] Dr Peset Univ Hosp, Dept Pediat, Valencia, Spain. [Deelen, Patrick; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands. [Feskens, Edith J. M.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands. [Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 ED Nijmegen, Netherlands. [Aulchenko, Yurii S.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. [Aulchenko, Yurii S.] PolyOmica, Groningen, Netherlands. [Aulchenko, Yurii S.] Inst Cytol & Genet SB RAS, Novosibirsk, Russia. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Xavier, Ramnik J.] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Zhernakova, A; Wijmenga, C; Fu, JY (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.; Zhernakova, A (reprint author), Top Inst Food & Nutr, Wageningen, Netherlands.; Fu, JY (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands. EM a.zhernakova@umcg.nl; wijmenga@umcg.nl; j.fu@umcg.nl RI Franke, Lude/P-7036-2016; Wijmenga, Cisca/D-2173-2009; OI Franke, Lude/0000-0002-5159-8802; Kurilshikov, Alexander/0000-0003-2541-5627; Vieira-Silva, Sara/0000-0002-4616-7602; Bonder, Marc Jan/0000-0002-8431-3180 FU Top Institute Food and Nutrition, Wageningen [TiFN GH001]; Netherlands Organization for Scientific Research [NWO-VIDI 864.13.013, ZonMW-VIDI 917.14.374, ZonMW-VIDI 016.136308]; CardioVasculair Onderzoek Nederland [CVON 2012-03]; University of Groningen; Fundacion Alfonso Martin Escudero; European Research Council (ERC) under the European Union [2012-322698]; ERC [310312, 637640]; VIB; FWO; IWT (Agency for Innovation by Science and Technology); Rega institute for Medical Research; KU Leuven; NIH; JDRF; CCFA; EU [305564, 305479]; [259867]; [FP7 METACARDIS HEALTH-F4-2012-305312] FX We thank the LifeLines-DEEP participants and the Groningen LifeLines staff for their collaboration. We thank J. Dekens, (A. Platteel, and A. Maatman for management and technical support. We thank J. Senior and K. McIntyre for editing the manuscript. This project was funded by grants from the Top Institute Food and Nutrition, Wageningen, to C.W. (TiFN GH001); the Netherlands Organization for Scientific Research to J.F. (NWO-VIDI 864.13.013), L.F. (ZonMW-VIDI 917.14.374), and R.K.W. (ZonMW-VIDI 016.136308) and CardioVasculair Onderzoek Nederland to M.H.H. and A.Z. (CVON 2012-03). A.Z. holds a Rosalind Franklin Fellowship (University of Groningen), and M.C.C. holds a postdoctoral fellowship from the Fundacion Alfonso Martin Escudero. This research received funding from the European Research Council (ERC) under the European Union's Seventh Framework Program: C.W. is supported by FP7/2007-2013)/ERC advanced Grant Agreement no. 2012-322698. M.G.N. is supported by an ERC Consolidator Grant (no. 310312). L.F. is supported by FP7/2007-2013, grant agreement 259867, and by an ERC Starting Grant, grant agreement 637640 (ImmRisk). J.R. and G.F. are supported by FP7 METACARDIS HEALTH-F4-2012-305312, VIB, FWO, IWT (Agency for Innovation by Science and Technology), the Rega institute for Medical Research, and KU Leuven. S.V.-S. and M.J. are supported by postdoctoral fellowships from FWO. T.V. M.S. and R.J.X. are supported by NIH, JDRF, and CCFA. A.Z. C.W. and J.F. designed the study. A.Z., E.F.T., L.F. and C.W. initiated the cohort and collected cohort data. A.Z., E.F.T., Z.M., S.A.J., M.C.C., and D.G. generated data. A.Z., A.K., M.J.B., E.F.T., M.S., T.V., A.V.V., G.F., S.V.-S., J.W., F.I., P.D., M.A.S., C.H., R.J.X., and J.F. analyzed data. G.F, S.V.-S., J.W., E.B., M.J. R.K.W., E.J.M.F. M.G.N., D.G., D.J., L.F., Y.S.A., C.H., J.R., R.J.X. and M.H.H. participated in integral discussions. A.Z., A.K., M.J.B., R.J.X., C.W., and J.F. wrote the manuscript. The authors have no conflicts of interest to report. The raw sequence data for both MGS and 163 rRNA gene sequencing data sets, and age and gender integration per sample are available from the European genome-phenome archive (https://www.ebi.ac.uk/ega/) at aocession, number EGAS00001001704. Other phenotypic data can be requested from the LifeLines cohort study (https://lifelines.nl/lifelines-research/access-to-lifelines) following the standard protocol for data access. The study was approved by the institutional review board of UMCG, ref.M12. 113965. D.J. has additional funding from EU FP7/ no. 305564 and EU FP/ no. 305479. C.H. is on the Scientific Advisory Board for Seres Therapeutics. Y.S.A. is a director and co-owner of PolyOmica, which provides services in statistical (gen)omics. NR 29 TC 52 Z9 52 U1 55 U2 81 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 APR 29 PY 2016 VL 352 IS 6285 BP 565 EP 569 DI 10.1126/science.aad3369 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5ZA UT WOS:000374998600040 PM 27126040 ER PT J AU Shen, JK Cote, GM Gao, Y Choy, E Mankin, HJ Hornicek, FJ Duan, ZF AF Shen, Jacson K. Cote, Gregory M. Gao, Yan Choy, Edwin Mankin, Henry J. Hornicek, Francis J. Duan, Zhenfeng TI Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro SO SCIENTIFIC REPORTS LA English DT Article ID AGGRESSIVE BREAST-CANCER; MESENCHYMAL STEM-CELLS; SOFT-TISSUE SARCOMAS; HISTONE METHYLTRANSFERASE; SELECTIVE-INHIBITION; SWI/SNF COMPLEXES; RHABDOID TUMORS; ZESTE HOMOLOG-2; EZH2; POLYCOMB AB Synovial sarcoma is an aggressive soft tissue sarcoma genetically defined by the fusion oncogene SS18-SSX. It is hypothesized that either SS18-SSX disrupts SWI/SNF complex inhibition of the polycomb complex 2 (PRC2) methyltransferase Enhancer of Zeste Homologue 2 (EZH2), or that SS18-SSX is able to directly recruit PRC2 to aberrantly silence target genes. This is of potential therapeutic value as several EZH2 small molecule inhibitors are entering early phase clinical trials. In this study, we first confirmed EZH2 expression in the 76% of human synovial sarcoma samples. We subsequently investigated EZH2 as a therapeutic target in synovial sarcoma in vitro. Knockdown of EZH2 by shRNA or siRNA resulted in inhibition of cell growth and migration across a series of synovial sarcoma cell lines. The EZH2 selective small-molecule inhibitor EPZ005687 similarly suppressed cell proliferation and migration. These data support the hypothesis that targeting EZH2 may be a promising therapeutic strategy in the treatment of synovial sarcoma; clinical trials are initiating enrollment currently. C1 [Shen, Jacson K.; Gao, Yan; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Cote, Gregory M.; Choy, Edwin] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Gattegno and Wechsler funds; Kenneth Stanton Fund; Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH) [UO1, CA 151452-01]; Sarcoma SPORE/NIH; Academic Enrichment Fund of MGH Orthopaedics FX This work was supported in part by grants from the Gattegno and Wechsler funds and the Kenneth Stanton Fund. Z.D. is supported in part through a grant from Sarcoma Foundation of America (SFA), a grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA 151452-01, a pilot grant from Sarcoma SPORE/NIH, and a grant from an Academic Enrichment Fund of MGH Orthopaedics. NR 60 TC 4 Z9 4 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 29 PY 2016 VL 6 AR 25239 DI 10.1038/srep25239 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8NK UT WOS:000375183400001 PM 27125524 ER PT J AU Saper, RB Lemaster, CM Elwy, AR Paris, R Herman, PM Plumb, DN Sherman, KJ Groessl, EJ Lynch, S Wang, SW Weinberg, J AF Saper, Robert B. Lemaster, Chelsey M. Elwy, A. Rani Paris, Ruth Herman, Patricia M. Plumb, Dorothy N. Sherman, Karen J. Groessl, Erik J. Lynch, Susan Wang, Shihwe Weinberg, Janice TI Yoga versus education for Veterans with chronic low back pain: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Veterans; Low back pain; Military families; Randomized controlled trial; Yoga; Cost-effectiveness ID POSTTRAUMATIC-STRESS-DISORDER; QUALITY-OF-LIFE; TRAUMATIC BRAIN-INJURY; SELF-CARE BOOK; ANXIETY DISORDERS; OUTCOME MEASURES; HATHA YOGA; NATIONAL-SURVEY; COMPARING YOGA; CLINICAL-TRIAL AB Background: Chronic low back pain is the most frequent pain condition in Veterans and causes substantial suffering, decreased functional capacity, and lower quality of life. Symptoms of post-traumatic stress, depression, and mild traumatic brain injury are highly prevalent in Veterans with back pain. Yoga for low back pain has been demonstrated to be effective for civilians in randomized controlled trials. However, it is unknown if results from previously published trials generalize to military populations. Methods/design: This study is a parallel randomized controlled trial comparing yoga to education for 120 Veterans with chronic low back pain. Participants are Veterans >= 18 years old with low back pain present on at least half the days in the past six months and a self-reported average pain intensity in the previous week of >= 4 on a 0-10 scale. The 24-week study has an initial 12-week intervention period, where participants are randomized equally into (1) a standardized weekly group yoga class with home practice or (2) education delivered with a self-care book. Primary outcome measures are change at 12 weeks in low back pain intensity measured by the Defense and Veterans Pain Rating Scale (0-10) and back-related function using the 23-point Roland Morris Disability Questionnaire. In the subsequent 12-week follow-up period, yoga participants are encouraged to continue home yoga practice and education participants continue following recommendations from the book. Qualitative interviews with Veterans in the yoga group and their partners explore the impact of chronic low back pain and yoga on family relationships. We also assess cost-effectiveness from three perspectives: the Veteran, the Veterans Health Administration, and society using electronic medical records, self-reported cost data, and study records. Discussion: This study will help determine if yoga can become an effective treatment for Veterans with chronic low back pain and psychological comorbidities. C1 [Saper, Robert B.; Lemaster, Chelsey M.] Boston Univ, Sch Med, Dept Family Med, Boston, MA 02118 USA. [Saper, Robert B.; Lemaster, Chelsey M.] Boston Med Ctr, Boston, MA USA. [Elwy, A. Rani] VA Boston Healthcare Syst, Ctr Informat Disseminat & Educ Resources, Boston, MA USA. [Elwy, A. Rani] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Paris, Ruth] Boston Univ, Sch Social Work, Boston, MA 02215 USA. [Herman, Patricia M.] RAND Corp, Santa Monica, CA USA. [Plumb, Dorothy N.; Wang, Shihwe] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Sherman, Karen J.] Grp Hlth Res Inst, Seattle, WA USA. [Sherman, Karen J.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Groessl, Erik J.] VA San Diego Healthcare Syst, San Diego, CA USA. [Groessl, Erik J.] Univ Calif San Diego, Sch Med, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Lynch, Susan] There & Back Again Inc, Wakefield, MA USA. [Weinberg, Janice] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Saper, RB (reprint author), Boston Univ, Sch Med, Dept Family Med, Boston, MA 02118 USA. EM robert.saper@bmc.org FU National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health [3R01AT005956-05S1] FX This publication was made possible by grant number 3R01AT005956-05S1 from the National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCCIH. NR 106 TC 0 Z9 0 U1 9 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD APR 29 PY 2016 VL 17 AR 224 DI 10.1186/s13063-016-1321-5 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DK7HF UT WOS:000375095100001 PM 27129472 ER PT J AU Flynn, R Paz, K Du, J Reichenbach, DK Taylor, PA Panoskaltsis-Mortari, A Vulic, A Luznik, L MacDonald, KKP Hill, GR Nyuydzefe, MS Weiss, JM Chen, W Trzeciak, A Serody, JS Aguilar, EG Murphy, WJ Maillard, I Munn, D Koreth, J Cutler, CS Antin, JH Ritz, J Waksal, SD Zanin-Zhorov, A Blazar, BR AF Flynn, Ryan Paz, Katelyn Du, Jing Reichenbach, Dawn K. Taylor, Patricia A. Panoskaltsis-Mortari, Angela Vulic, Ante Luznik, Leo MacDonald, Kelli K. P. Hill, Geoffrey R. Nyuydzefe, Melanie S. Weiss, Jonathan M. Chen, Wei Trzeciak, Alissa Serody, Jon S. Aguilar, Ethan G. Murphy, William J. Maillard, Ivan Munn, David Koreth, John Cutler, Corey S. Antin, Joseph H. Ritz, Jerome Waksal, Samuel D. Zanin-Zhorov, Alexandra Blazar, Bruce R. TI Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; HELPER T-CELLS; B-CELLS; BRONCHIOLITIS OBLITERANS; TGF-BETA; TRANSPLANTATION; HOMEOSTASIS; IL-21; IL-17; DIFFERENTIATION AB Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic bone marrow transplantation (BMT). The discovery of novel therapeutics is dependent on assessment in preclinical murine models of cGVHD. Rho-associated kinase 2 (ROCK2) recently was shown to be implicated in regulation of interleukin-21 (IL-21) and IL-17 secretion in mice and humans. Here, we report that the selective ROCK2 inhibitor KD025 effectively ameliorates cGVHD in multiple models: a full major histocompatibility complex (MHC) mismatch model of multiorgan system cGVHD with bronchiolitis obliterans syndrome and a minor MHC mismatch model of sclerodermatous GVHD. Treatment with KD025 resulted in normalization of pathogenic pulmonary function, which correlates with a marked reduction of antibody and collagen deposition in the lungs of treated mice to levels comparable to non-cGVHD controls. Spleens of mice treated with KD025 had decreased frequency of T follicular helper cells and increased frequency of T follicular regulatory cells, accompanied by a reduction in signal transducer and activator of transcription 3 (STAT3) and concurrent increase in STAT5 phosphorylation. The critical role of STAT3 in this cGVHD model was confirmed by data showing that mice transplanted with inducible STAT3-deficient T cells had pulmonary function comparable to the healthy negative controls. The therapeutic potential of targeted ROCK2 inhibition in the clinic was solidified further by human data demonstrating the KD025 inhibits the secretion of IL-21, IL-17, and interferon gamma along with decreasing phosphorylated STAT3 and reduced protein expression of interferon regulatory factor 4 and B-cell lymphoma 6 (BCL6) in human peripheral blood mononuclear cells purified from active cGVHD patients. Together these data highlight the potential of targeted ROCK2 inhibition for clinical cGVHD therapy. C1 [Flynn, Ryan; Paz, Katelyn; Du, Jing; Reichenbach, Dawn K.; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Univ Minnesota, Masonic Canc Ctr, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Flynn, Ryan; Paz, Katelyn; Du, Jing; Reichenbach, Dawn K.; Taylor, Patricia A.; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Vulic, Ante; Luznik, Leo] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Vulic, Ante; Luznik, Leo] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [MacDonald, Kelli K. P.; Hill, Geoffrey R.] Queensland Inst Med Res, Dept Immunol, Brisbane, Qld 4006, Australia. [Nyuydzefe, Melanie S.; Weiss, Jonathan M.; Chen, Wei; Trzeciak, Alissa; Waksal, Samuel D.; Zanin-Zhorov, Alexandra] Kadmon Res Inst, 450 East 29th St, New York, NY 10016 USA. [Serody, Jon S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Microbiol & Immunol, Div Hematol Oncol, Chapel Hill, NC 27599 USA. [Aguilar, Ethan G.; Murphy, William J.] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Maillard, Ivan] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Maillard, Ivan] Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Munn, David] Georgia Hlth Sci Univ, Dept Pediat, Augusta, GA USA. [Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Zanin-Zhorov, A (reprint author), Kadmon Res Inst, 450 East 29th St, New York, NY 10016 USA.; Blazar, BR (reprint author), Univ Minnesota, MMC 109,420 Delaware St SE, Minneapolis, MN 55455 USA. EM alexandra.zanin-zhorov@kadmon.com; blaza001@umn.edu RI Hill, Geoffrey/O-2630-2016; MacDonald, Kelli/O-2722-2016 OI Hill, Geoffrey/0000-0003-2994-0429; MacDonald, Kelli/0000-0003-3451-4221 FU National Institutes of Health, National Cancer Institute [P01 CA142106-06A1, 5P01-CA047741-20, R01-CA122779]; National Institute of Allergy and Infectious Diseases [P01AI 056299, T32 AI 007313, K08HL107756]; Leukemia and Lymphoma Society [6458-15, 6462-15]; Kadmon Corporation FX This study was funded by the National Institutes of Health, National Cancer Institute grants P01 CA142106-06A1 and 5P01-CA047741-20 (B.R.B.) and R01-CA122779 (L.L.); National Institute of Allergy and Infectious Diseases grants P01AI 056299, T32 AI 007313, and K08HL107756; Leukemia and Lymphoma Society Translational Research grants 6458-15 and 6462-15; and the Kadmon Corporation. NR 42 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD APR 28 PY 2016 VL 127 IS 17 BP 2144 EP 2154 DI 10.1182/blood-2015-10-678706 PG 11 WC Hematology SC Hematology GA DK7AB UT WOS:000375076100015 PM 26983850 ER PT J AU Hua, G Lv, X He, C Remmenga, SW Rodabough, KJ Dong, J Yang, L Lele, SM Yang, P Zhou, J Karst, A Drapkin, RI Davis, JS Wang, C AF Hua, G. Lv, X. He, C. Remmenga, S. W. Rodabough, K. J. Dong, J. Yang, L. Lele, S. M. Yang, P. Zhou, J. Karst, A. Drapkin, R. I. Davis, J. S. Wang, C. TI YAP induces high-grade serous carcinoma in fallopian tube secretory epithelial cells SO ONCOGENE LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; OVARIAN-CANCER CELLS; HIPPO SIGNALING PATHWAY; TRANSCRIPTIONAL COACTIVATOR; UNITED-STATES; MOUSE MODEL; EXPRESSION; TRANSFORMATION; PROLIFERATION; DROSOPHILA AB Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from fallopian tube secretory epithelial cells (FTSECs). However, the molecular mechanisms underlying the initiation and progression of HGSC derived from FTSECs remains unclear. In this study, we found that the Hippo/Yes-associated protein (YAP) signaling pathway has a critical role in the initiation and progression of fallopian tube and ovarian HGSC. Importantly, YAP was overexpressed in inflammatory and cancerous fallopian tube tissues. Further, overexpression of wild-type YAP, or constitutively active YAP in immortalized FTSECs, induced cell proliferation, migration, colony formation and tumorigenesis. Moreover, the Hippo/YAP and the fibroblast growth factor (FGF) signaling pathways formed an autocrine/paracrine-positive feedback loop to drive the progression of the FTSEC-derived HGSC. Evidence in this study strongly suggests that combined therapy with inhibitors of YAP (such as verteporfin) and FGF receptors (such as BGJ398) can provide a novel therapeutic strategy to treat fallopian tube and ovarian HGSC. C1 [Hua, G.; Lv, X.; He, C.; Remmenga, S. W.; Rodabough, K. J.; Davis, J. S.; Wang, C.] Univ Nebraska Med Ctr, Dept Obstet Gynecol, Olson Ctr Womens Hlth, Omaha, NE USA. [Hua, G.; He, C.; Yang, L.] Huazhong Agr Univ, Coll Anim Sci & Technol, Key Lab Agr Anim Genet Breeding & Reprod, Minist Educ, Wuhan, Peoples R China. [Dong, J.; Davis, J. S.; Wang, C.] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Lele, S. M.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Yang, P.] Univ Maryland, Sch Med, Dept Obstet Gynecol & Reprod Sci, Baltimore, MD 21201 USA. [Zhou, J.] Urumuqi Gen Hosp Lanzhou Mil Reg, Dept Obstet & Gynecol, Urumqi, Peoples R China. [Karst, A.; Drapkin, R. I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Davis, J. S.] Omaha Vet Affairs Med Ctr, Omaha, NE USA. RP Wang, C (reprint author), Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Dept Obstet Gynecol, Olson Ctr Womens Hlth, 985860 Nebraska Med Ctr, Omaha, NE 68198 USA. EM chengwang@unmc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [5R00HD059985, 5P01AG029531]; Olson Center for Women's Health; Fred and Pamela Buffett Cancer Center [LB595]; Colleen's Dream Foundation; Omaha Veterans Administration Medical Center [5I01BX000512]; National Institute of Food and Agriculture [2011-67015-20076] FX We thank Dr Adam Karpf (The Pamela and Fred Cancer Center, University of Nebraska Medical Center) for providing ovarian HGSC cell lines. We acknowledge the cBioPortal for Cancer Genomics (http://cbioportal.org) for providing data sets and online analyzing tools. We also acknowledge the TCGA research Network (http://cancergenome.nih.gov) for providing data sets. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R00HD059985, 5P01AG029531); the Olson Center for Women's Health (no number); the Fred and Pamela Buffett Cancer Center (LB595), the Colleen's Dream Foundation (no number), the Omaha Veterans Administration Medical Center (5I01BX000512) and the National Institute of Food and Agriculture (2011-67015-20076). We thank Melody Montgomery at the University of Nebraska Medical Center (UNMC) Research Editorial Office for the professional editing of the manuscript. NR 75 TC 5 Z9 5 U1 2 U2 3 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 APR 28 PY 2016 VL 35 IS 17 BP 2247 EP 2265 DI 10.1038/onc.2015.288 PG 19 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DK5UK UT WOS:000374986000010 PM 26364602 ER PT J AU Nguyen, AT Tsai, CL Hwang, LY Lai, DJ Markham, C Patel, B AF Anh Tuan Nguyen Tsai, Chu-lin Hwang, Lu-yu Lai, Dejian Markham, Christine Patel, Bela TI Obesity and Mortality, Length of Stay and Hospital Cost among Patients with Sepsis: A Nationwide Inpatient Retrospective Cohort Study SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; INTENSIVE-CARE-UNIT; SEPTIC SHOCK; LOGISTIC-REGRESSION; POOLED ANALYSIS; ALL-CAUSE; PARADOX; ASSOCIATION; OUTCOMES; DISEASE AB Objectives The objective of this study was to examine the association between obesity and all-cause mortality, length of stay and hospital cost among patients with sepsis 20 years of age or older. Materials and Methods It was a retrospective cohort study. The dataset was the Nationwide Inpatient Sample 2011, the largest publicly available all-payer inpatient care database in the United States. Hospitalizations of sepsis patients 20 years of age or older were included. All 25 primary and secondary diagnosis fields were screened to identify patients with sepsis using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Obesity was the exposure of interest. It was one of the 29 standardized Elixhauser comorbidity measures and readily available in the dataset as a dichotomized variable. The outcome measures were all-cause in-hospital death, length of stay and hospital cost. Results After weighting, our sample projected to a population size of 1,763,000, providing an approximation for the number of hospital discharges of all sepsis patients 20 years of age or older in the US in 2011. The overall all-cause mortality rate was 14.8%, the median hospital length of stay was 7 days and the median hospital cost was $15,917. After adjustment, the all-cause mortality was lower (adjusted OR = 0.84; 95% CI = 0.81 to 0.88); the average hospital length of stay was longer (adjusted difference = 0.65 day; 95% CI = 0.44 to 0.86) and the hospital cost per stay was higher (adjusted difference = $2,927; 95% CI = $1,606 to $4,247) for obese sepsis patients as compared to non-obese ones. Conclusion With this large and nationally representative sample of over 1,000 hospitals in the US, we found that obesity was significantly associated with a 16% decrease in the odds of dying among hospitalized sepsis patients; however it was also associated with greater duration and cost of hospitalization. C1 [Anh Tuan Nguyen] Vinmec Int Hosp, Dept Gen Planning, Hanoi, Vietnam. [Tsai, Chu-lin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Hwang, Lu-yu] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Houston, TX 77030 USA. [Lai, Dejian] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Biostat, Houston, TX 77030 USA. [Markham, Christine] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Hlth Promot & Behav Sci, Houston, TX 77030 USA. [Patel, Bela] Univ Texas Hlth Sci Ctr Houston, Sch Med, Div Crit Care Med, Houston, TX 77030 USA. RP Nguyen, AT (reprint author), Vinmec Int Hosp, Dept Gen Planning, Hanoi, Vietnam. EM nguyentuananh.fsh@gmail.com OI Nguyen, Anh/0000-0003-2608-0152 NR 43 TC 0 Z9 0 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 28 PY 2016 VL 11 IS 4 AR e0154599 DI 10.1371/journal.pone.0154599 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8XE UT WOS:000375211700111 PM 27124716 ER PT J AU Vergidis, P Clancy, CJ Shields, RK Park, SY Wildfeuer, BN Simmons, RL Nguyen, MH AF Vergidis, Pascalis Clancy, Cornelius J. Shields, Ryan K. Park, Seo Young Wildfeuer, Brett N. Simmons, Richard L. Nguyen, M. Hong TI Intra-Abdominal Candidiasis: The Importance of Early Source Control and Antifungal Treatment SO PLOS ONE LA English DT Article ID INTENSIVE-CARE-UNIT; INVASIVE CANDIDIASIS; ABDOMINAL CANDIDIASIS; SURGICAL-PATIENTS; NONCULTURE DIAGNOSTICS; RISK-FACTORS; PERITONITIS; INFECTIONS; MANAGEMENT; MORTALITY AB Intra-abdominal candidiasis (IAC) is poorly understood compared to candidemia. We described the clinical characteristics, microbiology, treatment and outcomes of IAC, and identified risk factors for mortality. We performed a retrospective study of adults diagnosed with IAC at our center in 2012-2013. Risk factors for mortality were evaluated using multivariable logistic regression. We identified 163 patients with IAC, compared to 161 with candidemia. Types of IAC were intra-abdominal abscesses (55%), secondary peritonitis (33%), primary peritonitis (5%), infected pancreatic necrosis (5%), and cholecystitis/cholangitis (3%). Eighty-three percent and 66% of secondary peritonitis and abscesses, respectively, stemmed from gastrointestinal (GI) tract sources. C. albicans (56%) and C. glabrata (24%) were the most common species. Bacterial co-infections and candidemia occurred in 67% and 6% of patients, respectively. Seventy-two percent of patients underwent an early source control intervention (within 5 days) and 72% received early antifungal treatment. 100-day mortality was 28%, and highest with primary (88%) or secondary (40%) peritonitis. Younger age, abscesses and early source control were independent predictors of survival. Younger age, abscesses and early antifungal treatment were independently associated with survival for IAC stemming from GI tract sources. Infectious diseases (ID) consultations were obtained in only 48% of patients. Consulted patients were significantly more likely to receive antifungal treatment. IAC is a common disease associated with heterogeneous manifestations, which result in poor outcomes. All patients should undergo source control interventions and receive antifungal treatment promptly. It is important for the ID community to become more engaged in treating IAC. C1 [Vergidis, Pascalis; Clancy, Cornelius J.; Shields, Ryan K.; Wildfeuer, Brett N.; Nguyen, M. Hong] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Park, Seo Young] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Simmons, Richard L.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. RP Vergidis, P (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. EM vergidisp@upmc.edu FU National Institutes of Health (NIH) [R21AI107290]; National Center for Advancing Translational Sciences of the NIH [KL2TR000146]; NIH [K08AI114883] FX The study was supported, in part, by award R21AI107290 (M.H.N.) from the National Institutes of Health (NIH). P.V. is supported by the National Center for Advancing Translational Sciences of the NIH under Award Number KL2TR000146. R.K.S is supported by the NIH under award number K08AI114883. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 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 APR 28 PY 2016 VL 11 IS 4 AR e0153247 DI 10.1371/journal.pone.0153247 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8XE UT WOS:000375211700013 PM 27123857 ER PT J AU Beura, LK Hamilton, SE Bi, K Schenkel, JM Odumade, OA Casey, KA Thompson, EA Fraser, KA Rosato, PC Filali-Mouhim, A Sekaly, RP Jenkins, MK Vezys, V Haining, WN Jameson, SC Masopust, D AF Beura, Lalit K. Hamilton, Sara E. Bi, Kevin Schenkel, Jason M. Odumade, Oludare A. Casey, Kerry A. Thompson, Emily A. Fraser, Kathryn A. Rosato, Pamela C. Filali-Mouhim, Ali Sekaly, Rafick P. Jenkins, Marc K. Vezys, Vaiva Haining, W. Nicholas Jameson, Stephen C. Masopust, David TI Normalizing the environment recapitulates adult human immune traits in laboratory mice SO NATURE LA English DT Article ID CD8(+) T-CELLS; BARR-VIRUS INFECTION; HETEROLOGOUS IMMUNITY; MEMORY; MOUSE; TRANSLATION; EXPRESSION; INFLAMMATION; MAINTENANCE; IMMUNOLOGY AB Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside(1-8). Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice-like newborn, but not adult, humans-lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free- living organisms, including humans. C1 [Beura, Lalit K.; Schenkel, Jason M.; Casey, Kerry A.; Thompson, Emily A.; Fraser, Kathryn A.; Rosato, Pamela C.; Jenkins, Marc K.; Vezys, Vaiva; Masopust, David] Univ Minnesota, Dept Microbiol & Immunol, Ctr Immunol, Minneapolis, MN 55414 USA. [Hamilton, Sara E.; Odumade, Oludare A.; Jameson, Stephen C.] Univ Minnesota, Dept Lab Med & Pathol, Ctr Immunol, Minneapolis, MN 55414 USA. [Bi, Kevin; Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bi, Kevin; Haining, W. Nicholas] Childrens Hosp, Pediat Hematol & Oncol, 300 Longwood Ave, Boston, MA 02115 USA. [Filali-Mouhim, Ali; Sekaly, Rafick P.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Odumade, Oludare A.] Univ Calif San Diego, Rady Childrens Hosp, Dept Pediat, San Diego, CA 92123 USA. [Casey, Kerry A.] MedImmune LLC, Dept Resp Inflammat & Autoimmun, Gaithersburg, MD 20878 USA. RP Masopust, D (reprint author), Univ Minnesota, Dept Microbiol & Immunol, Ctr Immunol, Minneapolis, MN 55414 USA.; Jameson, SC (reprint author), Univ Minnesota, Dept Lab Med & Pathol, Ctr Immunol, Minneapolis, MN 55414 USA. EM james024@umn.edu; masopust@umn.edu OI Jenkins, Marc/0000-0001-8009-7655 FU National Institutes of Health [1R01AI111671, R01AI084913, R01AI116678, R01AI075168]; University of Minnesota FX This study was supported by National Institutes of Health grants 1R01AI111671, R01AI084913 (to D.M.), R01AI116678, R01AI075168 (to S.C.J.) and a BSL-3 suite rental waiver grant from the University of Minnesota. We thank R. Ahmed for providing reagents for pilot studies, P. Southern and D. McKenna for tissue samples or cord blood, and all members of the BSL-3 mouse team (University of Minnesota). NR 42 TC 44 Z9 44 U1 15 U2 25 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 APR 28 PY 2016 VL 532 IS 7600 BP 512 EP + DI 10.1038/nature17655 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK3KQ UT WOS:000374815900050 PM 27096360 ER PT J AU Moreau, P Masszi, T Grzasko, N Bahlis, NJ Hansson, M Pour, L Sandhu, I Ganly, P Baker, BW Jackson, SR Stoppa, AM Simpson, DR Gimsing, P Palumbo, A Garderet, L Cavo, M Kumar, S Touzeau, C Buadi, FK Laubach, JP Berg, DT Lin, J Di Bacco, A Hui, AM van de Velde, H Richardson, PG AF Moreau, P. Masszi, T. Grzasko, N. Bahlis, N. J. Hansson, M. Pour, L. Sandhu, I. Ganly, P. Baker, B. W. Jackson, S. R. Stoppa, A. -M. Simpson, D. R. Gimsing, P. Palumbo, A. Garderet, L. Cavo, M. Kumar, S. Touzeau, C. Buadi, F. K. Laubach, J. P. Berg, D. T. Lin, J. Di Bacco, A. Hui, A. -M. van de Velde, H. Richardson, P. G. CA TOURMALINE-MM1 Study Grp TI Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROTEASOME INHIBITOR MLN9708; QUALITY-OF-LIFE; RANDOMIZED PHASE-3; ANTITUMOR-ACTIVITY; BORTEZOMIB; THALIDOMIDE; THERAPY; TRANSPLANTATION; CARFILZOMIB; SUPERIORITY AB BACKGROUND Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. C1 [Moreau, P.; Touzeau, C.] Univ Hosp Hotel Dieu, F-44093 Nantes 01, France. [Stoppa, A. -M.] Inst J Paoli I Calmettes, Dept Hematol, F-13009 Marseille, France. [Garderet, L.] Hosp St Antoine, Dept Hematol & Cell Therapy, Paris, France. [Masszi, T.] Semmelweis Univ, Dept Internal Med 3, St Istvan & St Laszlo Hosp, Dept Haematol & Stem Cell Transplantat, H-1085 Budapest, Hungary. [Grzasko, N.] Med Univ Lublin, Dept Haematooncol & Bone Marrow Transplantat, Lublin, Poland. [Grzasko, N.] St Johns Canc Ctr, Lublin, Poland. [Bahlis, N. J.] Univ Calgary, Southern Alberta Canc Res Inst, Calgary, AB, Canada. [Sandhu, I.] Univ Alberta, Dept Med, Div Hematol, Edmonton, AB, Canada. [Hansson, M.] Lund Univ, Dept Hematol, Skane Univ Hosp, Lund, Sweden. [Pour, L.] Univ Hosp Brno, Hematol & Oncol, Brno, Czech Republic. [Ganly, P.] Christchurch Hosp, Dept Haematol, Christchurch, New Zealand. [Baker, B. W.] Palmerston North Hosp, Dept Haematol, Palmerston North, Manawatu, New Zealand. [Jackson, S. R.] Middlemore Hosp, Dept Haematol, Auckland 6, New Zealand. [Simpson, D. R.] North Shore Hosp, Dept Haematol, Auckland, New Zealand. [Gimsing, P.] Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark. [Palumbo, A.] Univ Turin, Div Hematol, Myeloma Unit, Turin, Italy. [Cavo, M.] Univ Bologna, St Orsola Malpighi Univ Hosp, Sch Med, Seragnoli Inst Haematol, Bologna, Italy. [Kumar, S.; Buadi, F. K.] Mayo Clin, Div Hematol, Rochester, MN USA. [Laubach, J. P.; Richardson, P. G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Berg, D. T.; Lin, J.; Di Bacco, A.; Hui, A. -M.; van de Velde, H.] Millennium Pharmaceut Inc, Cambridge, MA USA. RP Moreau, P (reprint author), Univ Hosp Hotel Dieu, F-44093 Nantes 01, France. EM philippe.moreau@chu-nantes.fr RI FACON, THIERRY/M-9736-2014; richard, chrystelle/K-8595-2015; Greil, Richard/C-7673-2017; OI FACON, THIERRY/0000-0001-7705-8460; Greil, Richard/0000-0002-4462-3694; nahi, hareth/0000-0003-4711-5094; Hari, Parameswaran/0000-0002-8800-297X FU Millennium Pharmaceuticals FX Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537. NR 33 TC 60 Z9 62 U1 11 U2 18 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 APR 28 PY 2016 VL 374 IS 17 BP 1621 EP 1634 DI 10.1056/NEJMoa1516282 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA DK3UR UT WOS:000374843400006 PM 27119237 ER PT J AU Schwamm, LH Jaff, MR Dyer, KS Gonzalez, RG Huck, AE AF Schwamm, Lee H. Jaff, Michael R. Dyer, K. Sophia Gonzalez, R. Gilberto Huck, Amelia E. TI Case 13-2016: A 49-Year-Old Woman with Sudden Hemiplegia and Aphasia during a Transatlantic Flight SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE ISCHEMIC-STROKE; PATENT FORAMEN OVALE; TISSUE-PLASMINOGEN ACTIVATOR; HEALTH-CARE PROFESSIONALS; RENAL-CELL CARCINOMA; MAY-THURNER SYNDROME; ADULTS RISK-FACTORS; TO-NEEDLE TIMES; CRYPTOGENIC STROKE; VENOUS THROMBOEMBOLISM C1 [Schwamm, Lee H.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Jaff, Michael R.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Huck, Amelia E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Schwamm, Lee H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Jaff, Michael R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Huck, Amelia E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Dyer, K. Sophia] Boston Med Ctr, Dept Emergency Med, Boston, MA USA. [Dyer, K. Sophia] Boston Univ, Sch Med, Dept Emergency Med, Boston, MA 02118 USA. RP Schwamm, LH (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA.; Schwamm, LH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. FU Lundbeck; Penumbra; Genentech; Cardinal Health; Volcano Corporation FX Dr. Gonzalez reports receiving payment for providing expert testimony related to neuroimaging in stroke diagnosis; Dr. Schwamm, receiving consulting fees from Lundbeck and Penumbra and grant support from Genentech; and Dr. Jaff, serving as an uncompensated advisor for Abbott Vascular, Boston Scientific, Cordis Corporation, Covidien Vascular, and Medtronic Vascular, serving as an uncompensated member of a data and safety monitoring board for EKOS Corporation and as a compensated member of a data and safety monitoring board for Novella, and receiving consulting fees from Cardinal Health and Volcano Corporation. No other potential conflict of interest relevant to this article was reported. NR 38 TC 1 Z9 1 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 28 PY 2016 VL 374 IS 17 BP 1671 EP 1680 DI 10.1056/NEJMcpc1501151 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DK3UR UT WOS:000374843400011 PM 27119240 ER PT J AU He, SN Mansour, MR Zimmerman, MW Ki, DH Layden, HM Akahane, K Gjini, E de Groh, ED Perez-Atayde, AR Zhu, SZ Epstein, JA Look, AT AF He, Shuning Mansour, Marc R. Zimmerman, Mark W. Ki, Dong Hyuk Layden, Hillary M. Akahane, Koshi Gjini, Evisa de Groh, Eric D. Perez-Atayde, Antonio R. Zhu, Shizhen Epstein, Jonathan A. Look, A. Thomas TI Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain SO ELIFE LA English DT Article ID CHILDRENS ONCOLOGY GROUP; HIGH-RISK NEUROBLASTOMA; MYELOABLATIVE THERAPY; 13-CIS-RETINOIC ACID; TUMOR INITIATION; GENE; ZEBRAFISH; MUTATIONS; AMPLIFICATION; SUPPRESSOR AB Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical "developmental tumor", NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf 1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation. C1 [He, Shuning; Mansour, Marc R.; Zimmerman, Mark W.; Ki, Dong Hyuk; Layden, Hillary M.; Akahane, Koshi; Zhu, Shizhen; Look, A. Thomas] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Mansour, Marc R.] UCL, UCL Canc Inst, Dept Hematol, London, England. [Gjini, Evisa] Harvard Med Sch, Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA USA. [de Groh, Eric D.; Epstein, Jonathan A.] Univ Penn, Dept Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA. [de Groh, Eric D.; Epstein, Jonathan A.] Univ Penn, Penn Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [de Groh, Eric D.; Epstein, Jonathan A.] Univ Penn, Inst Regenerat Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Perez-Atayde, Antonio R.] Harvard Med Sch, Childrens Hosp Boston, Dept Pathol, Boston, MA USA. [Zhu, Shizhen] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN USA. [Zhu, Shizhen] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA. RP He, SN; Look, AT (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM shuning_he@dfci.harvard.edu; thomas_look@dfci.harvard.edu FU U.S. Department of Defense [W81XWH-12-1-0125]; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Tumor Foundation; Rally Foundation; Kay Kendall Leukaemia Fund; Leukaemia and Lymphoma Research; Damon Runyon Cancer Research Foundation [DRSG-9-14]; National Institutes of Health [R01 CA180692] FX U.S. Department of Defense W81XWH-12-1-0125 Jonathan A Epstein A Thomas Look; Alex's Lemonade Stand Foundation for Childhood Cancer Shuning He A Thomas Look; Children's Tumor Foundation YIA Shuning He; Rally Foundation Shuning He; Kay Kendall Leukaemia Fund Marc R Mansour; Leukaemia and Lymphoma Research Marc R Mansour; Damon Runyon Cancer Research Foundation DRSG-9-14 Mark W Zimmerman; National Institutes of Health R01 CA180692 A Thomas Look; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 29 TC 4 Z9 4 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD APR 27 PY 2016 VL 5 AR e14713 DI 10.7554/eLife.14713 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EB5YT UT WOS:000387457600001 ER PT J AU Gaca, AO Gilmore, MS AF Gaca, Anthony O. Gilmore, Michael S. TI ANTIMICROBIALS A lysin to kill SO ELIFE LA English DT Editorial Material ID STREPTOCOCCUS-PYOGENES; DISEASES; DRUGS AB An enzyme produced by a bacteriophage can enter human cells and kill intracellular Streptococcus pyogenes. C1 [Gaca, Anthony O.; Gilmore, Michael S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Gaca, Anthony O.; Gilmore, Michael S.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. RP Gilmore, MS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA.; Gilmore, MS (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. EM michael_gilmore@meei.harvard.edu NR 11 TC 0 Z9 0 U1 3 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 APR 27 PY 2016 VL 5 AR e16111 DI 10.7554/eLife.16111 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DK3OX UT WOS:000374828000001 ER PT J AU Cha, J DeDora, D Nedic, S Ide, J Greenberg, T Hajcak, G Mujica-Parodi, LR AF Cha, Jiook DeDora, Daniel Nedic, Sanja Ide, Jaime Greenberg, Tsafrir Hajcak, Greg Mujica-Parodi, Lilianne Rivka TI Clinically Anxious Individuals Show Disrupted Feedback between Inferior Frontal Gyrus and Prefrontal-Limbic Control Circuit SO JOURNAL OF NEUROSCIENCE LA English DT Article DE connectivity; control systems; dynamic causal modeling; functional MRI; inferior frontal gyrus; prefrontal cortex ID GENERALIZED ANXIETY DISORDER; SPECTRUM SCALE-INVARIANCE; THREAT-RELATED STIMULI; FEAR GENERALIZATION; TRAIT ANXIETY; AVERSIVE EVENTS; BRAIN ACTIVITY; CONNECTIVITY; AMYGDALA; REACTIVITY AB Clinical anxiety is associated with generalization of conditioned fear, in which innocuous stimuli elicit alarm. Using Pavlovian fear conditioning (electric shock), we quantify generalization as the degree to which subjects' neurobiological responses track perceptual similarity gradients to a conditioned stimulus. Previous studies show that the ventromedial prefrontal cortex(vmPFC) inversely and ventral tegmental area directly track the gradient of perceptual similarity to the conditioned stimulus in healthy individuals, whereas clinically anxious individuals fail to discriminate. Here, we extend this work by identifying specific functional roles within the prefrontal-limbic circuit. We analyzed fMRI time-series acquired from 57 human subjects during a fear generalization task using entropic measures of circuit-wide regulation and feedback (power spectrum scale invariance/autocorrelation), incombination with structural (diffusion MRI-probabilistic tractography) and functional (stochastic dynamic causal modeling) measures of prefrontal-limbic connectivity within the circuit. Group comparison and correlations with anxiety severity across 57 subjects revealed dysregulatory dynamic signatures within the inferior frontal gyrus (IFG), which our prior work has linked to impaired feedback within the circuit. Bayesian model selection then identified a fully connected prefrontal-limbic model comprising the IFG, vmPFC, and amygdala. Dysregulatory IFG dynamics were associated with weaker reciprocal excitatory connectivity between the IFG and the vmPFC. The vmPFC exhibited inhibitory influence on the amygdala. Our current results, combined with our previous work across a threat-perception spectrum of 137 subjects and a meta-analysis of 366 fMRI studies, dissociate distinct roles for three prefrontal-limbic regions, wherein the IFG provides evaluation of stimulus meaning, which then informs the vmPFC in inhibiting the amygdala. C1 [Cha, Jiook] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY 10032 USA. [Cha, Jiook] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [DeDora, Daniel; Nedic, Sanja; Ide, Jaime; Mujica-Parodi, Lilianne Rivka] SUNY Stony Brook, Sch Med, Dept Biomed Engn, Stony Brook, NY 11794 USA. [DeDora, Daniel; Nedic, Sanja; Ide, Jaime; Mujica-Parodi, Lilianne Rivka] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Greenberg, Tsafrir; Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Mujica-Parodi, LR (reprint author), SUNY Stony Brook, Dept Biomed Engn, Bioengn Bldg,Room 119, Stony Brook, NY 11794 USA. EM Lilianne.Strey@stonybrook.edu RI Greenberg, Tsafrir /Q-7831-2016; OI Cha, Jiook/0000-0002-5314-7992 FU National Science Foundation [0954643] FX This research was supported by the National Science Foundation Grant 0954643 to L.R.M.-P. NR 55 TC 2 Z9 2 U1 5 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 27 PY 2016 VL 36 IS 17 BP 4708 EP 4718 DI 10.1523/JNEUROSCI.1092-15.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DK7UF UT WOS:000375130500007 PM 27122030 ER PT J AU Reddy, AT Lakshmi, SP Muchumarri, RR Reddy, RC AF Reddy, Aravind T. Lakshmi, Sowmya P. Muchumarri, Ramamohan R. Reddy, Raju C. TI Nitrated Fatty Acids Reverse Cigarette Smoke-Induced Alveolar Macrophage Activation and Inhibit Protease Activity via Electrophilic S-Alkylation SO PLOS ONE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; HUMAN CATHEPSIN-S; EPITHELIAL-CELLS; NITROLINOLEIC ACID; PPAR-GAMMA; INFLAMMATION; TRANSDUCTION; REPERFUSION; MECHANISMS; ISCHEMIA AB Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO-derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities. They are both reversible electrophiles and peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, but the physiological implications of their electrophilic activity are poorly understood. We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice. NFA (10-nitro-oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-kappa B while upregulating those of PPAR gamma. It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction. Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction. NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPAR. knockout mice, pointing to a PPAR gamma-independent mechanism of enzyme inhibition. We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S-alkylation of Cys25 when incubated with purified Cat S. These results demonstrate that NFAs' electrophilic activity, in addition to their role as PPAR. agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease. C1 [Reddy, Aravind T.; Lakshmi, Sowmya P.; Muchumarri, Ramamohan R.; Reddy, Raju C.] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Reddy, Aravind T.; Lakshmi, Sowmya P.; Muchumarri, Ramamohan R.; Reddy, Raju C.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Reddy, RC (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA.; Reddy, RC (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. EM reddyrc@upmc.edu FU U.S. Department of Veterans Affairs; National Institutes of Health [HL093196] FX This work was supported by a Merit Review award from the U.S. Department of Veterans Affairs and National Institutes of Health grant HL093196 to RCR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 27 PY 2016 VL 11 IS 4 AR e0153336 DI 10.1371/journal.pone.0153336 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5QZ UT WOS:000374976200022 PM 27119365 ER PT J AU Dinh, TKT Fendler, W Chalubinska-Fendler, J Acharya, SS O'Leary, C Deraska, PV D'Andrea, AD Chowdhury, D Kozono, D AF Dinh, Tru-Khang T. Fendler, Wojciech Chalubinska-Fendler, Justyna Acharya, Sanket S. O'Leary, Colin Deraska, Peter V. D'Andrea, Alan D. Chowdhury, Dipanjan Kozono, David TI Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer SO RADIATION ONCOLOGY LA English DT Article DE Non-small cell lung cancer; microRNAs; Radiotherapy; Thoracic ID RANDOMIZED CONTROLLED-TRIAL; PULMONARY-FIBROSIS; PCR DATA; C-MYB; RADIOTHERAPY; MICRORNAS; PNEUMONITIS; PLASMA; IDENTIFICATION; NORMALIZATION AB Background: Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities-such as radiation pneumonitis-during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors. Methods: We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines. Results: miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation. Conclusions: miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity. C1 [Dinh, Tru-Khang T.; D'Andrea, Alan D.; Chowdhury, Dipanjan; Kozono, David] Harvard Univ, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. [Dinh, Tru-Khang T.; Acharya, Sanket S.; O'Leary, Colin; Deraska, Peter V.; D'Andrea, Alan D.; Chowdhury, Dipanjan; Kozono, David] Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Fendler, Wojciech] Med Univ Lodz, Dept Biostat & Translat Med, Al Kosciuszki 4, PL-90419 Lodz, Poland. [Chalubinska-Fendler, Justyna] Med Univ Lodz, Dept Radiat Oncol, Al Kosciuszki 4, PL-90419 Lodz, Poland. [D'Andrea, Alan D.] Dana Farber Canc Inst, Ctr DNA Damage & Repair, 450 Brookline Ave, Boston, MA 02215 USA. [Kozono, David] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP D'Andrea, AD; Chowdhury, D; Kozono, D (reprint author), Harvard Univ, Sch Med, 25 Shattuck St, Boston, MA 02115 USA.; D'Andrea, AD; Chowdhury, D; Kozono, D (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA.; D'Andrea, AD (reprint author), Dana Farber Canc Inst, Ctr DNA Damage & Repair, 450 Brookline Ave, Boston, MA 02215 USA.; Kozono, D (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu; dipanjan_chowdhury@dfci.harvard.edu; dkozono@lroc.harvard.edu RI Fendler, Wojciech/S-9592-2016 OI Fendler, Wojciech/0000-0002-5083-9168 FU Howard Hughes Medical Institute; National Science Center [2012/05/N/NZ5/02621]; Foundation for Polish Science grant [127/UD/SKILLS/2015]; Department of Radiation Oncology at the Dana-Farber Cancer Institute; Brigham and Women's Hospital; LUNGevity Foundation Career Development Award [2013-02]; NIH/NCI [K08CA172354] FX TKD received a fellowship from the Howard Hughes Medical Institute. JCh-F received support from the National Science Center grant no. 2012/05/N/NZ5/02621 and Foundation for Polish Science grant no. 127/UD/SKILLS/2015. DC and DK received grant funding from the Department of Radiation Oncology at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. DK is supported by LUNGevity Foundation Career Development Award 2013-02 and NIH/NCI K08CA172354. NR 48 TC 5 Z9 5 U1 2 U2 3 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 APR 27 PY 2016 VL 11 AR 61 DI 10.1186/s13014-016-0636-4 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DK4ZP UT WOS:000374929400001 PM 27117590 ER PT J AU Aytan, N Choi, JK Carreras, I Brinkmann, V Kowall, NW Jenkins, BG Dedeoglu, A AF Aytan, Nurgul Choi, Ji-Kyung Carreras, Isabel Brinkmann, Volker Kowall, Neil W. Jenkins, Bruce G. Dedeoglu, Alpaslan TI Fingolimod modulates multiple neuroinflammatory markers in a mouse model of Alzheimer's disease SO SCIENTIFIC REPORTS LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; IMPAIR SYNAPTIC PLASTICITY; AMYLOID-BETA; SPHINGOSINE 1-PHOSPHATE; FTY720; MEMORY; BRAIN; TAURINE; PLAQUES; MICE AB Sphingosine 1-phosphate (SP1) receptors may be attractive targets for modulation of inflammatory processes in neurodegenerative diseases. Recently fingolimod, a functional S1P1 receptor antagonist, was introduced for treatment of multiple sclerosis. We postulated that anti-inflammatory mechanisms of fingolimod might also be protective in Alzheimer's disease (AD). Therefore, we treated a mouse model of AD, the 5xFAD model, with two doses of fingolimod (1 and 5 mg/kg/day) and measured the response of numerous markers of A beta pathology as well as inflammatory markers and neurochemistry using biochemical, immunohistochemistry and high resolution magic angle spinning magnetic resonance spectroscopy (MRS). In mice at 3 months of age, we found that fingolimod decreased plaque density as well as soluble plus insoluble A beta measured by ELISA. Fingolimod also decreased GFAP staining and the number of activated microglia. Taurine has been demonstrated to play a role as an endogenous anti-inflammatory molecule. Taurine levels, measured using MRS, showed a very strong inverse correlation with GFAP levels and ELISA measurements of A beta, but not with plaque density or activated microglia levels. MRS also showed an effect of fingolimod on glutamate levels. Fingolimod at 1 mg/kg/day provided better neuroprotection than 5 mg/kg/day. Together, these data suggest a potential therapeutic role for fingolimod in AD. C1 [Aytan, Nurgul; Carreras, Isabel; Kowall, Neil W.; Dedeoglu, Alpaslan] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA. [Aytan, Nurgul; Kowall, Neil W.; Dedeoglu, Alpaslan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Aytan, Nurgul; Choi, Ji-Kyung; Jenkins, Bruce G.; Dedeoglu, Alpaslan] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Aytan, Nurgul; Choi, Ji-Kyung; Jenkins, Bruce G.; Dedeoglu, Alpaslan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Carreras, Isabel] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. [Brinkmann, Volker] Novartis Pharma AG, Dev Franchise Neurosci, Novartis Campus,Fabrikstr 12, CH-4056 Basel, Switzerland. RP Dedeoglu, A (reprint author), VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA.; Dedeoglu, A (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.; Dedeoglu, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM dedeoglu@bu.edu FU Department of Veteran Affairs (Merit Award); Alzheimer Drug Discovery Foundation (ADDF) FX This research is supported by grants from the Department of Veteran Affairs (Merit Award) and Alzheimer Drug Discovery Foundation (ADDF) to A. Dedeoglu. Fingolimod was provided by Novartis. NR 43 TC 2 Z9 2 U1 3 U2 3 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 APR 27 PY 2016 VL 6 AR 24939 DI 10.1038/srep24939 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK4RC UT WOS:000374905600001 PM 27117087 ER PT J AU Jacques, C Lamoureux, F Baud'huin, M Calleja, LR Quillard, T Amiaud, J Tirode, F Redini, F Bradner, JE Heymann, D Ory, B AF Jacques, Camille Lamoureux, Francois Baud'huin, Marc Calleja, Lidia Rodriguez Quillard, Thibaut Amiaud, Jerome Tirode, Franck Redini, Francoise Bradner, James E. Heymann, Dominique Ory, Benjamin TI Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1 SO ONCOTARGET LA English DT Article DE Ewing Sarcoma; JQ1; bromodomain; epigenetic; EWS/Fli1 ID BET BROMODOMAIN INHIBITION; ENDOTHELIAL GROWTH-FACTOR; PRIMITIVE NEUROECTODERMAL TUMOR; CELL-CYCLE PROGRESSION; FUSION PROTEIN; SELECTIVE-INHIBITION; SUPER-ENHANCERS; EWS-FLI1 ONCOPROTEIN; II RECEPTOR; DNA-BINDING AB Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults. Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease. The most common case is the translocation t (11; 22) (q24; q12) which yields the EWS-Fli1 chimeric transcription factor. Finding a way to directly target EWS-Fli1 remains a central therapeutic approach to eradicate this aggressive cancer. Here we demonstrate that treating Ewing Sarcoma cells with JQ1(+), a BET bromodomain inhibitor, represses directly EWS-Fli1 transcription as well as its transcriptional program. Moreover, the Chromatin Immuno Precipitation experiments demonstrate for the first time that these results are a consequence of the depletion of BRD4, one of the BET bromodomains protein from the EWS-Fli1 promoter. In vitro, JQ1(+) treatment reduces the cell viability, impairs the cell clonogenic and the migratory abilities, and induces a G1-phase blockage as well as a time-and a dose-dependent apoptosis. Furthermore, in our in vivo model, we observed a tumor burden delay, an inhibition of the global vascularization and an increase of the mice overall survival. Taken together, our data indicate that inhibiting the BET bromodomains interferes with EWS-FLi1 transcription and could be a promising strategy in the Ewing tumors context. C1 [Jacques, Camille; Lamoureux, Francois; Baud'huin, Marc; Calleja, Lidia Rodriguez; Quillard, Thibaut; Amiaud, Jerome; Redini, Francoise; Heymann, Dominique; Ory, Benjamin] Equipe Labellisee Ligue 2012, INSERM, UMR 957, Nantes, France. [Jacques, Camille; Lamoureux, Francois; Baud'huin, Marc; Calleja, Lidia Rodriguez; Quillard, Thibaut; Amiaud, Jerome; Redini, Francoise; Heymann, Dominique; Ory, Benjamin] Nantes Atlantique Univ, Univ Nantes, Physiopathol Resorpt Osseuse & Therapie Tumeurs O, EA3822, Nantes, France. [Baud'huin, Marc; Heymann, Dominique] Nantes Univ Hosp, Nantes, France. [Tirode, Franck] INSERM, Inst Curie, U830, Paris, France. [Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Ory, B (reprint author), Equipe Labellisee Ligue 2012, INSERM, UMR 957, Nantes, France.; Ory, B (reprint author), Nantes Atlantique Univ, Univ Nantes, Physiopathol Resorpt Osseuse & Therapie Tumeurs O, EA3822, Nantes, France. EM Benjamin.ory@univ-nantes.fr RI REDINI, Francoise/K-7981-2015; OI Quillard, Thibaut/0000-0002-8096-2597 FU Seventh Framework Program ([FP7]) [264817 - BONE-NET]; INSERM; Region Pays de la Loire FX This paper was written as a part of research project which received funding from the Seventh Framework Program ([FP7/2007-2013]) under grant agreement no 264817 - BONE-NET.; Camille Jacques is funded by INSERM and Region Pays de la Loire. NR 58 TC 1 Z9 1 U1 1 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 26 PY 2016 VL 7 IS 17 BP 24125 EP 24140 DI 10.18632/oncotarget.8214 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO3UB UT WOS:000377706200087 PM 27006472 ER PT J AU Giannakis, M Mu, XJ Shukla, SA Qian, ZR Cohen, O Nishihara, R Bahl, S Cao, Y Amin-Mansour, A Yamauchi, M Sukawa, Y Stewart, C Rosenberg, M Mima, K Inamura, K Nosho, K Nowak, JA Lawrence, MS Giovannucci, EL Chan, AT Ng, K Meyerhardt, JA Van Allen, EM Getz, G Gabriel, SB Lander, ES Wu, CJ Fuchs, CS Ogino, S Garraway, LA AF Giannakis, Marios Mu, Xinmeng Jasmine Shukla, Sachet A. Qian, Zhi Rong Cohen, Ofir Nishihara, Reiko Bahl, Samira Cao, Yin Amin-Mansour, Ali Yamauchi, Mai Sukawa, Yasutaka Stewart, Chip Rosenberg, Mara Mima, Kosuke Inamura, Kentaro Nosho, Katsuhiko Nowak, Jonathan A. Lawrence, Michael S. Giovannucci, Edward L. Chan, Andrew T. Ng, Kimmie Meyerhardt, Jeffrey A. Van Allen, Eliezer M. Getz, Gad Gabriel, Stacey B. Lander, Eric S. Wu, Catherine J. Fuchs, Charles S. Ogino, Shuji Garraway, Levi A. TI Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma SO CELL REPORTS LA English DT Article ID CANCER; SURVIVAL; MUTATION; IMMUNOTHERAPY; NEOANTIGENS; MEDICINE; ANTIGENS; ASPIRIN; TARGETS; SAMPLES AB Large-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs) and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs), memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies. C1 [Giannakis, Marios; Mu, Xinmeng Jasmine; Shukla, Sachet A.; Qian, Zhi Rong; Cohen, Ofir; Nishihara, Reiko; Amin-Mansour, Ali; Yamauchi, Mai; Mima, Kosuke; Inamura, Kentaro; Ng, Kimmie; Meyerhardt, Jeffrey A.; Van Allen, Eliezer M.; Fuchs, Charles S.; Ogino, Shuji; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Giannakis, Marios; Mu, Xinmeng Jasmine; Ng, Kimmie; Meyerhardt, Jeffrey A.; Van Allen, Eliezer M.; Wu, Catherine J.; Fuchs, Charles S.; Garraway, Levi A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Giannakis, Marios; Mu, Xinmeng Jasmine; Shukla, Sachet A.; Cohen, Ofir; Bahl, Samira; Amin-Mansour, Ali; Stewart, Chip; Rosenberg, Mara; Lawrence, Michael S.; Van Allen, Eliezer M.; Getz, Gad; Gabriel, Stacey B.; Lander, Eric S.; Wu, Catherine J.; Garraway, Levi A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Nishihara, Reiko; Giovannucci, Edward L.; Ogino, Shuji] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nishihara, Reiko; Bahl, Samira; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Nishihara, Reiko] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Cao, Yin; Chan, Andrew T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Cao, Yin; Chan, Andrew T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Sukawa, Yasutaka] Keio Univ, Sch Med, Div Internal Med, Dept Gastroenterol & Hepatol, Tokyo 1088345, Japan. [Nosho, Katsuhiko] Sapporo Med Univ, Dept Gastroenterol Rheumatol & Clin Immun, Sch Med, Sapporo, Hokkaido 0608543, Japan. [Nowak, Jonathan A.; Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol,Dept Pathol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Getz, Gad] Harvard Univ, Sch Med, Ctr Canc, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lander, Eric S.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Ogino, S; Garraway, LA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Garraway, LA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA.; Garraway, LA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Ogino, S (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol,Dept Pathol, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu; levi_garraway@dfci.harvard.edu RI Mu, Xinmeng/P-2562-2016 OI Mu, Xinmeng/0000-0002-8079-0828 FU KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources); KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH) [KL2 TR001100]; Dana-Farber Cancer Institute Leadership Council; Colon Cancer Alliance-AACR Fellowship for Biomarker Research [14-40-40-GIAN]; Perry S. Levy Endowed Fellowship; BroadNext10 grant; BroadIgnite grant; Project P Fund; Blavatnik Family Foundation; Friends of the Dana-Farber Cancer Institute; NIH [U54 HG003067, K07 CA190673, K07 CA148894, K24 DK098311, R01 CA137178, R01 CA155010, P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, R01 CA151993, R35 CA197735, R01 CA118553, R01 CA168141, P50 CA127003] FX We thank N. Gupta, E. Nickerson, and S. Seepo for additional project management and the Broad Sequencing platform, as well as Xin Jin, Julian Hess, Diana Miao, Yohei Masugi, and Pavan Bachireddy for helpful discussions. We thank the participants and staff of the NHS and the HPFS for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. This work was conducted with the support of a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, Award KL2 TR001100; M.G.). This work was also supported by the Dana-Farber Cancer Institute Leadership Council (M.G.), the 2014 Colon Cancer Alliance-AACR Fellowship for Biomarker Research Grant Number 14-40-40-GIAN (M.G.), the Perry S. Levy Endowed Fellowship (M.G.), the BroadNext10 (E.M.V.A.) and BroadIgnite (E.M.V.A.) grants, the Project P Fund (C.S.F.), the Blavatnik Family Foundation (C.J.W.), and the Friends of the Dana-Farber Cancer Institute (S.O.), as well as NIH grants U54 HG003067 (E.S.L., S.B.G.), K07 CA190673 (R.N.), K07 CA148894 (Ki.N.), K24 DK098311 (A.T.C.), R01 CA137178 (A.T.C.), R01 CA155010 (C.J.W.), P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, R01 CA151993 (S.O.), R35 CA197735 (S.O.), R01 CA118553 (C.S.F.), R01 CA168141 (C.S.F.), and P50 CA127003 (M.G., L.A.G., C.S.F.). NR 31 TC 13 Z9 13 U1 3 U2 8 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 APR 26 PY 2016 VL 15 IS 4 BP 857 EP 865 DI 10.1016/j.celrep.2016.03.075 PG 9 WC Cell Biology SC Cell Biology GA DK2FS UT WOS:000374730600017 ER PT J AU Du, J Reeves, AZ Klein, JA Twedt, DJ Knodler, LA Lesser, CF AF Du, Juan Reeves, Analise Z. Klein, Jessica A. Twedt, Donna J. Knodler, Leigh A. Lesser, Cammie F. TI The type III secretion system apparatus determines the intracellular niche of bacterial pathogens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE type III secretion system; phagosomal escape; vacuole lysis; Shigella; Salmonella ID ESCHERICHIA-COLI K-12; CULTURED ANIMAL-CELLS; SHIGELLA-FLEXNERI; YERSINIA-PSEUDOTUBERCULOSIS; EPITHELIAL-CELLS; ACTIN POLYMERIZATION; PROTEIN DELIVERY; PLASMA-MEMBRANE; PORE FORMATION; HOST-CELLS AB Upon entry into host cells, intracellular bacterial pathogens establish a variety of replicative niches. Although some remodel phagosomes, others rapidly escape into the cytosol of infected cells. Little is currently known regarding how professional intracytoplasmic pathogens, including Shigella, mediate phagosomal escape. Shigella, like many other Gram-negative bacterial pathogens, uses a type III secretion system to deliver multiple proteins, referred to as effectors, into host cells. Here, using an innovative reductionist-based approach, we demonstrate that the introduction of a functional Shigella type III secretion system, but none of its effectors, into a laboratory strain of Escherichia coli is sufficient to promote the efficient vacuole lysis and escape of themodified bacteria into the cytosol of epithelial cells. This establishes for the first time, to our knowledge, a direct physiologic role for the Shigella type III secretion apparatus (T3SA) in mediating phagosomal escape. Furthermore, although protein components of the T3SA share a moderate degree of structural and functional conservation across bacterial species, we show that vacuole lysis is not a common feature of T3SA, as an effectorless strain of Yersinia remains confined to phagosomes. Additionally, by exploiting the functional interchangeability of the translocator components of the T3SA of Shigella, Salmonella, and Chromobacterium, we demonstrate that a single protein component of the T3SA translocon-Shigella IpaC, Salmonella SipC, or Chromobacterium CipC-determines the fate of intracellular pathogens within both epithelial cells and macrophages. Thus, these findings have identified a likely paradigm by which the replicative niche of many intracellular bacterial pathogens is established. C1 [Du, Juan; Reeves, Analise Z.; Lesser, Cammie F.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Cambridge, MA 02139 USA. [Du, Juan; Reeves, Analise Z.; Lesser, Cammie F.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Klein, Jessica A.; Twedt, Donna J.; Knodler, Leigh A.] Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. RP Lesser, CF (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Cambridge, MA 02139 USA.; Lesser, CF (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Knodler, LA (reprint author), Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. EM lknodler@vetmed.wsu.edu; CLESSER@mgh.harvard.edu FU NIH [AI064285, AI103882]; Paul G. Allen School for Global Animal Health; Stanley L. Adler Research Fund; Svenska Sallskapet for Medicinsk Forskning Fellowship; Poncin Scholarship FX We thank W. Spears for help with plasmid and strain construction; N. Ernst and U. Powale for critically reading the manuscript; and J. Mecsas, W. L. Picking, F. Martinez-Becerra, D. Zhou, R. W. Kaminski, J. Wilson, E. A. Miao, T. Miki, and M. B. Goldberg for sharing reagents/strains. We thank the Franceschi Microscopy and Imaging Center at Washington State University for TEM and C. Davitt, V. Lynch-Holm, D. Mullendore, and J. Benavides-Montano for their assistance with sample preparation. This work was supported by NIH Grants AI064285 and AI103882 (to C.F.L.) and startup funds from the Paul G. Allen School for Global Animal Health and the Stanley L. Adler Research Fund (to L.A.K.). J. D. was supported by a Svenska Sallskapet for Medicinsk Forskning Fellowship and J.A.K. by a Poncin Scholarship. NR 47 TC 3 Z9 3 U1 1 U2 4 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 APR 26 PY 2016 VL 113 IS 17 BP 4794 EP 4799 DI 10.1073/pnas.1520699113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK2MK UT WOS:000374748400064 PM 27078095 ER PT J AU Phillips, KA Regan, MM Ribi, K Francis, PA Puglisi, F Bellet, M Spazzapan, S Karlsson, P Budman, DR Zaman, K Abdi, EA Domchek, SM Feng, Y Price, KN Coates, AS Gelber, RD Maruff, P Boyle, F Forbes, JF Ahles, T Fleming, GF Bernhard, J AF Phillips, Kelly-Anne Regan, Meredith M. Ribi, Karin Francis, Prudence A. Puglisi, Fabio Bellet, Meritxell Spazzapan, Simon Karlsson, Per Budman, Daniel R. Zaman, Khalil Abdi, Ehtesham A. Domchek, Susan M. Feng, Yang Price, Karen N. Coates, Alan S. Gelber, Richard D. Maruff, Paul Boyle, Frances Forbes, John F. Ahles, Tim Fleming, Gini F. Bernhard, Juerg CA Co-SOFT Investigators TI Adjuvant ovarian function suppression and cognitive function in women with breast cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; ovarian function; cognitive function; quality of life; premenopausal; GnRH agonist; tamoxifen; exemestane ID ENDOCRINE THERAPY; PREMENOPAUSAL WOMEN; RANDOMIZED-TRIALS; YOUNG-WOMEN; IMPAIRMENT; CHEMOTHERAPY; EXEMESTANE; MENOPAUSE; PERFORMANCE; ALPRAZOLAM AB Background: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer. Methods: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen + OFS, exemestane + OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen + OFS and exemestane + OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test. Results: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean +/- s.d., -0.21 +/- 0.92 vs -0.04 +/- 0.49, respectively, P = 0.71, effect size = -0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics. Conclusions: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function. C1 [Phillips, Kelly-Anne; Francis, Prudence A.] Peter MacCallum Canc Ctr, Div Canc Med, St Andrews Pl, East Melbourne, Vic 3002, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Grattan St, Parkville, Vic 3010, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.; Abdi, Ehtesham A.; Coates, Alan S.; Boyle, Frances] ANZBCTG, Platt St, Waratah, NSW 2298, Australia. [Phillips, Kelly-Anne; Francis, Prudence A.; Puglisi, Fabio; Spazzapan, Simon; Karlsson, Per; Zaman, Khalil; Abdi, Ehtesham A.; Coates, Alan S.; Boyle, Frances; Forbes, John F.] Int Breast Canc Study Grp, CH-3008 Bern, Switzerland. [Regan, Meredith M.; Feng, Yang; Price, Karen N.; Gelber, Richard D.] Dana Farber Canc Inst, Ctr Stat, Dept Biostat & Computat Biol, Int Breast Canc Study Grp, 450 Brookline Ave, Boston, MA 02215 USA. [Regan, Meredith M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Ribi, Karin; Bernhard, Juerg] Int Breast Canc Study Grp Coordinating Ctr, Effingerstr 40, CH-3008 Bern, Switzerland. [Puglisi, Fabio] Univ Hosp Udine, Dept Med Oncol, Piazzale SM Misericordia 15, I-33100 Udine, Italy. [Puglisi, Fabio] Univ Udine, Sch Med Oncol, I-33100 Udine, Italy. [Bellet, Meritxell] VHIO, Barcelona 08035, Spain. [Bellet, Meritxell] Vall Hebron Univ Hosp, Barcelona 08035, Spain. [Bellet, Meritxell] SOLTI Grp, Barcelona 08008, Spain. [Spazzapan, Simon] IRCCS, Natl Canc Inst, CRO Aviano, Via F Gallini 2, I-33081 Aviano, Italy. [Karlsson, Per] Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Dept Oncol, Roda Straket 16, S-41345 Gothenburg, Sweden. [Budman, Daniel R.] Monter Canc Ctr North Shore LIJ Hlth Syst, 450 Lakeville Rd, Lake Success, NY 11042 USA. [Budman, Daniel R.] Four Penn Ctr, NRG Oncol, 1600 JFK Blvd,Suite 1020, Philadelphia, PA 19103 USA. [Zaman, Khalil] CHU Vaudois, Breast Ctr, Dept Oncol, Rue Bugnon 46, CH-1011 Lausanne, Switzerland. [Abdi, Ehtesham A.] Griffith Univ, Tweed Heads Hosp, Tweed Heads, Powell St, Tweed Heads, NSW 2485, Australia. [Domchek, Susan M.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Domchek, Susan M.] ECOG ACRIN, 1818 Market St,Suite 1100, Philadelphia, PA 19103 USA. [Price, Karen N.; Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Sydney, NSW 2006, Australia. [Coates, Alan S.] Univ Sydney, Sydney, NSW 2006, Australia. [Gelber, Richard D.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Maruff, Paul] Cogstate Ltd, 2-255 Bourke St, Melbourne, Vic 3000, Australia. [Boyle, Frances] Mater Hosp, 40 Rocklands Rd, Sydney, NSW 2060, Australia. [Forbes, John F.] Univ Newcastle, Calvary Mater Newcastle Hosp, Callaghan, NSW 2308, Australia. [Forbes, John F.] NBN Telethon Mater Inst, Australia & New Zealand Breast Canc Trials Grp, Locked Bag 7 HRMC, Newcastle, NSW 2298, Australia. [Ahles, Tim] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave Fl 7, New York, NY 10022 USA. [Ahles, Tim; Fleming, Gini F.] Alliance Clin Trials Oncol, Chicago, IL 60637 USA. [Fleming, Gini F.] Univ Chicago, Med Ctr, 5841 South Maryland Ave,MC 2115, Chicago, IL 60637 USA. [Bernhard, Juerg] Univ Hosp Bern, Inselspital, CH-3010 Bern, Switzerland. RP Phillips, KA (reprint author), Peter MacCallum Canc Ctr, Div Canc Med, St Andrews Pl, East Melbourne, Vic 3002, Australia.; Phillips, KA (reprint author), Univ Melbourne, Sir Peter MacCallum Dept Oncol, Grattan St, Parkville, Vic 3010, Australia.; Phillips, KA (reprint author), ANZBCTG, Platt St, Waratah, NSW 2298, Australia. EM Kelly.Phillips@petermac.org OI Phillips, Kelly-Anne/0000-0002-0475-1771; Puglisi, Fabio/0000-0003-0573-4938 FU Australian National Health and Medical Research Council [454507]; Breast Cancer Institute of Australia, the Fund Raising Department of the Australia and New Zealand Breast Cancer Trials Group (ANZBCTG); US NIH [SU10CA-035279-30, CA32102, U10-CA180821, CA21115, CA16116, U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974, CA077202]; Frontier Science and Technology Research Foundation; Swiss Group for Clinical Cancer Research (SAKK); US National Cancer Institute (NCI) [CA75362]; Swiss Cancer Research/Oncosuisse; NHMRC [351161, 510788]; CCSRI [015469, 021039]; Pfizer; Ipsen FX We thank the patients who participated and the staff who conducted the study at the participating centres. We also thank the ANZBCTG Trials Coordination Department staff Lauren Boyes, Ingrid Laycock, Annette Dempsey and Dianne Lindsay and the International Breast Cancer Study Group (IBCSG) Coordinating and Data Management Centres for their help with the conduct of this study. The Co-SOFT study was funded by the Australian National Health and Medical Research Council (#454507) and the Breast Cancer Institute of Australia, the Fund Raising Department of the Australia and New Zealand Breast Cancer Trials Group (ANZBCTG); US NIH SU10CA-035279-30 to DRB. KAP is an Australian National Breast Cancer Foundation Fellow. Support for the IBCSG: Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), US National Cancer Institute (NCI) (CA75362) to MMR, Swiss Cancer Research/Oncosuisse. Grant support for participating cooperative groups for the SOFT Trial: Australia and New Zealand Breast Cancer Trials Group (NHMRC 351161 and 510788); SWOG (US NIH CA32102); Alliance (US NIH U10-CA180821); ECOG-ACRIN (US NIH CA21115 and CA16116); NSABP/NRG (US NIH U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974); NCIC (US NIH CA077202 and CCSRI 015469 and 021039). The SOFT trial receives financial support for trial conduct from Pfizer, and drug supply from Pfizer and Ipsen. P.M. is a full time employee of Cogstate, Ltd. PAF has provided unpaid consultancy and an unpaid overseas presentation regarding the results of the SOFT trial for Pfizer. The IBCSG Statistical Center (MMR, YF, RDG, KNP) has received research support from Pfizer and Ipsen in support of SOFT and TEXT. NR 44 TC 3 Z9 3 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD APR 26 PY 2016 VL 114 IS 9 BP 956 EP 964 DI 10.1038/bjc.2016.71 PG 9 WC Oncology SC Oncology GA DK9QR UT WOS:000375266800002 PM 27092785 ER PT J AU Babic, A Shah, SM Song, MY Wu, K Meyerhardt, JA Ogino, S Yuan, C Giovannucci, EL Chan, AT Stampfer, MJ Fuchs, CS Ng, K AF Babic, Ana Shah, Sonali M. Song, Mingyang Wu, Kana Meyerhardt, Jeffrey A. Ogino, Shuji Yuan, Chen Giovannucci, Edward L. Chan, Andrew T. Stampfer, Meir J. Fuchs, Charles S. Ng, Kimmie TI Soluble tumour necrosis factor receptor type II and survival in colorectal cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE soluble tumour necrosis factor receptor type II; colorectal cancer; aspirin; NSAIDs ID CORONARY-HEART-DISEASE; COLON-CANCER; TNF-ALPHA; INFLAMMATORY MARKERS; CIRCULATING LEVELS; DIABETES-MELLITUS; NURSES HEALTH; ASPIRIN USE; RISK; MEN AB Background: Chronic inflammation may play a role in colorectal cancer (CRC) pathogenesis. The relationship between soluble tumour necrosis factor receptor type II (sTNF-RII) and survival among CRC patients is not well defined. Methods: We prospectively evaluated the association between pre-diagnosis plasma levels of sTNF-RII and mortality in 544 CRC patients from the Nurses' Health Study and Health Professionals Follow-Up Study diagnosed from 1990 to 2010. Primary and secondary end points were overall and CRC-specific mortality, respectively. Cox proportional hazards models were used to calculate multivariate hazard ratios for mortality. Results: Higher sTNF-RII levels were significantly associated with increased overall mortality (multivariate HR = 1.48, 95% CI 1.02-2.16, P-trend = 0.006), but not with CRC-specific mortality (HR = 1.23, 95% CI 0.72-2.08, P-trend = 0.34). In subgroup analyses, among regular aspirin users, those with higher sTNF-RII levels had an adjusted HR of 0.52 (95% CI 0.20-1.33) for overall mortality compared with those with lower sTNF-RII levels, whereas among nonregular aspirin users the adjusted HR was 2.26 (95% CI 1.23-4.01, P for interaction = 0.53). Conclusions: Among CRC patients, higher sTNF-RII levels are associated with a significant increase in overall mortality, but not CRC-specific mortality. The role of inflammation and anti-inflammatory medications in survival of CRC patients warrants further exploration. C1 [Babic, Ana; Meyerhardt, Jeffrey A.; Ogino, Shuji; Yuan, Chen; Fuchs, Charles S.; Ng, Kimmie] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shah, Sonali M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shah, Sonali M.; Ogino, Shuji; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Song, Mingyang; Wu, Kana; Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Song, Mingyang; Ogino, Shuji; Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol, Dept Pathol, Boston, MA 02215 USA. [Giovannucci, Edward L.; Chan, Andrew T.; Stampfer, Meir J.] Harvard Univ, Channing Div Network Med, Dept Med, Sch Med, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Ng, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM kimmie_ng@dfci.harvard.edu FU National Cancer Institute at the National Institutes of Health [K07 CA148894, R01 CA137178, K24 DK098311, R01 CA151993, R35 CA197735, P50 CA127003]; Damon Runyon Cancer Research Foundation; American Society of Clinical Oncology (ASCO) Career Development Award; Entertainment Industry Foundation's National Colorectal Cancer Research Alliance (NCCRA); Dana Farber Cancer Institute; NHS [UM1 CA186107, P01 CA87969, R01 CA49449]; HPFS [UM1 CA167552, P01 CA 55075] FX We thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. We assume full responsibility for analyses and interpretation of these data. This work was supported by the National Cancer Institute at the National Institutes of Health (K07 CA148894 to KN; R01 CA137178 to ATC; K24 DK098311 to ATC; R01 CA151993 and R35 CA197735 to SO; P50 CA127003 to CSF), the Damon Runyon Cancer Research Foundation (to ATC), the American Society of Clinical Oncology (ASCO) Career Development Award (to KN), the Entertainment Industry Foundation's National Colorectal Cancer Research Alliance (NCCRA), and the Dana Farber Cancer Institute Gift Funds from the Janock Fellowship and Herndon Fellowship (to SMS). Other funding sources include UM1 CA186107 (NHS cohort infrastructure grant), P01 CA87969 (NHS program project grant), R01 CA49449 (NHS blood grant), UM1 CA167552 (HPFS infrastructure grant), and P01 CA 55075 (HPFS program project grant). The sponsors did not participate in the design and conduct of the study; collection, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the article for publication. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health, ASCO, The Conquer Cancer Foundation, the Damon Runyon Cancer Research Foundation, or the NCCRA. NR 41 TC 1 Z9 1 U1 0 U2 2 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 APR 26 PY 2016 VL 114 IS 9 BP 995 EP 1002 DI 10.1038/bjc.2016.85 PG 8 WC Oncology SC Oncology GA DK9QR UT WOS:000375266800007 PM 27031855 ER PT J AU Delling, FN Rong, J Larson, MG Lehman, B Fuller, D Osypiuk, E Stantchev, P Hackman, B Manning, WJ Benjamin, EJ Levine, RA Vasan, RS AF Delling, Francesca N. Rong, Jian Larson, Martin G. Lehman, Birgitta Fuller, Deborah Osypiuk, Ewa Stantchev, Plamen Hackman, Brianne Manning, Warren J. Benjamin, Emelia J. Levine, Robert A. Vasan, Ramachandran S. TI Evolution of Mitral Valve Prolapse: Insights From the Framingham Heart Study SO CIRCULATION LA English DT Article DE echocardiography; epidemiology; mitral valve ID NATURAL-HISTORY; VENA CONTRACTA; REGURGITATION; PROGRESSION; DIAGNOSIS; COMMUNITY; SEVERITY; DETERMINANTS; ASSOCIATION; PREVALENCE AB Background Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. Methods and Results We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 5711 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P<0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height 5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P<0.05). Conclusions NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression. C1 [Delling, Francesca N.; Rong, Jian; Lehman, Birgitta; Osypiuk, Ewa; Stantchev, Plamen; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Delling, Francesca N.; Rong, Jian; Lehman, Birgitta; Osypiuk, Ewa; Stantchev, Plamen; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Delling, Francesca N.; Fuller, Deborah; Hackman, Brianne] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc,Sch Med, Boston, MA 02215 USA. [Rong, Jian] Boston Univ, Sch Med, Dept Med, Neurol Sect, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Manning, Warren J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Radiol, Sch Med, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. RP Delling, FN (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave,E-SH-458, Boston, MA 02215 USA. EM fdelling@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU Founders Affiliate American Heart Association Clinical Research Program; National Heart, Lung and Blood Institute Framingham Heart Study [N01-HC-25195, HHSN268201500001I, R01HL080124, RO1HL0107385, 2R01HL092577, 1R01HL128914, K23HL116652] FX This work was supported by the Founders Affiliate American Heart Association Clinical Research Program (to Dr Delling), and by the National Heart, Lung and Blood Institute Framingham Heart Study Contract No. N01-HC-25195 and HHSN268201500001I (both to Dr Vasan), and research grants R01HL080124, RO1HL0107385 (to Dr Vasan), 2R01HL092577, 1R01HL128914 (to Dr Benjamin), and K23HL116652 (to Dr Delling). NR 31 TC 2 Z9 3 U1 1 U2 2 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 APR 26 PY 2016 VL 133 IS 17 BP 1688 EP 1695 DI 10.1161/CIRCULATIONAHA.115.020621 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DK6QI UT WOS:000375049200012 PM 27006478 ER PT J AU Agboola, SO Bates, DW Kvedar, JC AF Agboola, Stephen O. Bates, David W. Kvedar, Joseph C. TI Digital Health and Patient Safety SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID APPS; CARE C1 [Agboola, Stephen O.; Bates, David W.; Kvedar, Joseph C.] Partners Healthcare, Boston, MA USA. [Agboola, Stephen O.; Bates, David W.; Kvedar, Joseph C.] Harvard Univ, Sch Med, Boston, MA USA. [Agboola, Stephen O.; Kvedar, Joseph C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bates, David W.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Kvedar, JC (reprint author), Partners Healthcare, Connected Hlth, 25 New Chardon St,Ste 300, Boston, MA 02114 USA. EM jkvedar@partners.org NR 10 TC 0 Z9 0 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 26 PY 2016 VL 315 IS 16 BP 1697 EP 1698 DI 10.1001/jama.2016.2402 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DK2QK UT WOS:000374759300011 PM 27115372 ER PT J AU Yeh, RW Secemsky, EA Kereiakes, DJ Normand, SLT Gershlick, AH Cohen, DJ Spertus, JA Steg, PG Cutlip, DE Rinaldi, MJ Camenzind, E Wijns, W Apruzzese, PK Song, Y Massaro, JM Mauri, L AF Yeh, Robert W. Secemsky, Eric A. Kereiakes, Dean J. Normand, Sharon-Lise T. Gershlick, Anthony H. Cohen, David J. Spertus, John A. Steg, Philippe Gabriel Cutlip, Donald E. Rinaldi, Michael J. Camenzind, Edoardo Wijns, William Apruzzese, Patricia K. Song, Yang Massaro, Joseph M. Mauri, Laura CA DAPT Study Investigators TI Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; DRUG-ELUTING STENT; RANDOMIZED CLINICAL-TRIAL; BARE-METAL; NETWORK METAANALYSIS; RISK SCORE; IMPLANTATION; THROMBOSIS; DURATION; MULTICENTER AB IMPORTANCE Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding. OBJECTIVE To develop a clinical decision tool to identify patients expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI. DESIGN, SETTING, AND PARTICIPANTS Among 11 648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014). EXPOSURES Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin. MAIN OUTCOMES AND MEASURES Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI. RESULTS Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, priormyocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; -1 point for age 65 to younger than 75 years; and -2 points for age 75 years or older. Among the high score group (score >= 2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], -3.0%[95% CI, -4.1% to -2.0%], P<.001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, -0.7%[95% CI, -1.4% to 0.09%], P=.07; interaction P<.001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4%[95% CI, -0.3% to 1.0%], P=.26) compared with the low score group (3.0% vs 1.4%; RD, 1.5%[95% CI, 0.8% to 2.3%], P<.001; interaction P=.02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding. CONCLUSION AND RELEVANCE Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts. C1 [Yeh, Robert W.] Beth Israel Deaconess Med Ctr, Smith Ctr Outcomes Res Cardiol, 185 Pilgrim Rd, Boston, MA 02215 USA. [Yeh, Robert W.; Secemsky, Eric A.; Normand, Sharon-Lise T.; Cutlip, Donald E.; Mauri, Laura] Harvard Univ, Sch Med, Boston, MA USA. [Yeh, Robert W.; Secemsky, Eric A.; Cutlip, Donald E.; Apruzzese, Patricia K.; Song, Yang; Massaro, Joseph M.; Mauri, Laura] Harvard Clin Res Inst, Boston, MA USA. [Secemsky, Eric A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kereiakes, Dean J.] Christ Hosp, Heart & Vasc Ctr, Cincinnati, OH 45219 USA. [Kereiakes, Dean J.] Lindner Ctr Res & Educ, Cincinnati, OH USA. [Normand, Sharon-Lise T.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gershlick, Anthony H.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Gershlick, Anthony H.] Univ Hosp Leicester NHS Trust, Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Cohen, David J.; Spertus, John A.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Cohen, David J.; Spertus, John A.] Univ Missouri Kansas City, Sch Med, Kansas City, MO USA. [Spertus, John A.] Washington Univ, Sch Med, St Louis, MO USA. [Steg, Philippe Gabriel] Univ Paris Diderot, Hop Bichat, INSERM, U1148, Paris, France. [Steg, Philippe Gabriel] Dept Hosp Univ Fibrosis Inflammat & Remodeling, AP HP, Paris, France. [Steg, Philippe Gabriel] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, Inst Cardiovasc Med & Sci, Natl Heart & Lung Inst, London, England. [Cutlip, Donald E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Rinaldi, Michael J.] Carolinas HealthCare Syst, Sanger Heart & Vasc Inst, Charlotte, NC USA. [Camenzind, Edoardo] Univ Hosp Nancy Brabois, Inst Loraine Coeur & Vaisseaux, Vandoeuvre Les Nancy, France. [Wijns, William] Onze Lieve Vrouwziekenhuis Hosp, Ctr Cardiovasc, Aalst, Belgium. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Mauri, Laura] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Yeh, RW (reprint author), Beth Israel Deaconess Med Ctr, Smith Ctr Outcomes Res Cardiol, 185 Pilgrim Rd, Boston, MA 02215 USA.; Mauri, L (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ryeh@bidmc.harvard.edu; lmauril@partners.org FU Harvard Clinical Research Institute; National Heart, Lung, and Blood Institute [K23 HL 118138]; US Department of Health and Human Services [1RO1FD003870-01]; Abbott Vascular; Boston Scientific; Cordis; Medtronic; Bristol-Myers Squibb; Sanofi; Eli Lilly; Daiichi Sankyo FX This article was sponsored by Harvard Clinical Research Institute, grant K23 HL 118138 from the National Heart, Lung, and Blood Institute (Dr Yeh); grant 1RO1FD003870-01 from the US Department of Health and Human Services. The 8 stent and pharmaceutical manufacturers who contributed to the funding of the DAPT study included Abbott Vascular (Xience everolimus-eluting stent), Boston Scientific (TAXUS paclitaxel-eluting and PROMUS everolimus-eluting stents), Cordis (Cypher sirolimus-eluting stent), Medtronic (Endeavor zotarolimus-eluting stent), Bristol-Myers Squibb, Sanofi, Eli Lilly, and Daiichi Sankyo. NR 32 TC 57 Z9 59 U1 4 U2 6 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 APR 26 PY 2016 VL 315 IS 16 BP 1735 EP 1749 DI 10.1001/jama.2016.3775 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DK2QK UT WOS:000374759300021 PM 27022822 ER PT J AU Rafferty, EA Durand, MA Conant, EF Copit, DS Friedewald, SM Plecha, DM Miller, DP AF Rafferty, Elizabeth A. Durand, Melissa A. Conant, Emily F. Copit, Debra Somers Friedewald, Sarah M. Plecha, Donna M. Miller, Dave P. TI Breast Cancer Screening Using Tomosynthesis and Digital Mammography in Dense and Nondense Breasts SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TUMOR CHARACTERISTICS; RISK C1 [Rafferty, Elizabeth A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Rafferty, Elizabeth A.] L&M Radiol, POB 615, West Acton, MA 01720 USA. [Durand, Melissa A.] Yale Univ, Sch Med, New Haven, CT USA. [Conant, Emily F.] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Copit, Debra Somers] Albert Einstein Healthcare Network, Philadelphia, PA USA. [Friedewald, Sarah M.] Advocate Lutheran Gen Hosp, Caldwell Breast Ctr, Park Ridge, IL USA. [Friedewald, Sarah M.] Northwestern Univ, Lynn Sage Comprehens Breast Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Plecha, Donna M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Miller, Dave P.] Genom Hlth, Redwood City, CA USA. RP Rafferty, EA (reprint author), L&M Radiol, POB 615, West Acton, MA 01720 USA. EM erafferty@lmradiology.com NR 5 TC 6 Z9 6 U1 4 U2 5 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 APR 26 PY 2016 VL 315 IS 16 BP 1784 EP 1786 DI 10.1001/jama.2016.1708 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DK2QK UT WOS:000374759300026 PM 27115381 ER PT J AU Chatterjee, NA Lewis, GD AF Chatterjee, Neal A. Lewis, Gregory D. TI Heart Rate Modulation in Heart Failure Time to Slow Down? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE chronotropic incompetence; exercise capacity; heart failure; heart rate ID CHRONOTROPIC INCOMPETENCE; EJECTION FRACTION; EXERCISE CAPACITY; TRIAL; INHIBITION; THERAPY C1 [Chatterjee, Neal A.; Lewis, Gregory D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiol Div,Dept Med, Boston, MA USA. [Lewis, Gregory D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pulm & Crit Care Unit,Dept Med, Boston, MA USA. RP Lewis, GD (reprint author), Massachusetts Gen Hosp, Heart Failure & Cardiac Transplantat Unit, Bigelow 800,Fruit St, Boston, MA 02114 USA. EM glewis@partners.org FU NHLBI NIH HHS [T-32 HL-007575, T32 HL007575, R01 HL119154] NR 14 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 26 PY 2016 VL 67 IS 16 BP 1897 EP 1900 DI 10.1016/j.jacc.2016.02.043 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK1EG UT WOS:000374654700004 PM 27102505 ER PT J AU Villar, J Schultz, MJ Kacmarek, RM AF Villar, Jesus Schultz, Marcus J. Kacmarek, Robert M. TI The LUNG SAFE: a biased presentation of the prevalence of ARDS! SO CRITICAL CARE LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; BERLIN DEFINITION; MORTALITY; INJURY; OUTCOMES AB The recent Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) challenges current data on the prevalence of acute respiratory distress syndrome (ARDS). The LUNG SAFE investigators claimed that their data demonstrated the predictive validity of the Berlin criteria. Also, the LUNG SAFE showed a disturbingly large gap between scientific evidence and medical practice. All of these statements demand that we question the interpretations of the study's findings. C1 [Villar, Jesus] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Net, Barranco Ballena S-N,4th Floor,South Wing, Las Palmas Gran Canaria, Spain. [Schultz, Marcus J.] Univ Amsterdam, Acad Med Ctr, Dept Intens Care, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesiol, Boston, MA 02115 USA. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.; Villar, J (reprint author), Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Net, Barranco Ballena S-N,4th Floor,South Wing, Las Palmas Gran Canaria, Spain. EM jesus.villar54@gmail.com FU Instituto de Salud Carlos III [CB06/06/1088, PI13/0119]; Asociacion Cientifica Pulmon y Ventilacion Mecanica FX This work was supported in part by Instituto de Salud Carlos III (CB06/06/1088, PI13/0119) and Asociacion Cientifica Pulmon y Ventilacion Mecanica. The funders had no role in the content, decision to publish, or preparation of the manuscript. NR 19 TC 2 Z9 2 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD APR 25 PY 2016 VL 20 AR 108 DI 10.1186/s13054-016-1273-x PG 3 WC Critical Care Medicine SC General & Internal Medicine GA DK3QQ UT WOS:000374832900001 PM 27109238 ER PT J AU Wong, KK Zhu, F Khatri, I Huo, Q Spaner, DE Gorczynski, RM AF Wong, Karrie K. Zhu, Fang Khatri, Ismat Huo, Qiang Spaner, David E. Gorczynski, Reginald M. TI Characterization of CD200 Ectodomain Shedding SO PLOS ONE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MEMBRANE-TYPE-1 MATRIX-METALLOPROTEINASE; L-SELECTIN CD62L; CALCIUM INFLUX; SOLUBLE CD200; CLEAVAGE; CELLS; INHIBITOR; RECEPTOR; FORM AB We have previously reported the existence of a soluble form of CD200 (sCD200) in human plasma, and found sCD200 to be elevated in the plasma of Chronic Lymphocytic Leukemia (CLL) patients. CLL cells release CD200 at a constitutive level, which could be attenuated partially by ADAM28 silencing. In this study, we further explored mechanisms of CD200 shedding beyond that of ADAM28, and performed biochemical analysis of sCD200 using materials derived from purified CLL cells and Hek293 cells stably transfected with CD200, and antibodies generated specifically against either the extracellular or cytoplasmic regions of CD200. CD200 shedding was enhanced by PMA stimulation, and the loss of cell surface CD200 could be monitored as a reduction in CD200 cell surface expression by flow cytometry, in parallel with an increase in the detection of sCD200 in the supernatant. Western blot analyses and functional studies using CD200R1 expressing Hek293 cells showed that the shed CD200 detected in CLL and Hek293-hCD200 supernatants lacked the cytoplasmic domain of CD200 but retained the functional extracellular domain required for binding to, and phosphorylation of, CD200R. These data confirms that a functionally active CD200 extracellular moiety can be cleaved from the surface of CD200 expressing cells following ectodomain shedding. C1 [Wong, Karrie K.; Zhu, Fang; Gorczynski, Reginald M.] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Zhu, Fang; Khatri, Ismat; Huo, Qiang; Gorczynski, Reginald M.] Univ Hlth Network, Transplant Res Div, Toronto, ON, Canada. [Zhu, Fang; Khatri, Ismat; Huo, Qiang; Gorczynski, Reginald M.] Univ Toronto, Toronto, ON, Canada. [Spaner, David E.] Univ Toronto, Sunnybrook Res Inst, Div Mol & Cellular Biol, Toronto, ON, Canada. [Wong, Karrie K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RP Gorczynski, RM (reprint author), Univ Toronto, Inst Med Sci, Toronto, ON, Canada.; Gorczynski, RM (reprint author), Univ Hlth Network, Transplant Res Div, Toronto, ON, Canada.; Gorczynski, RM (reprint author), Univ Toronto, Toronto, ON, Canada. EM rgorczynski@uhnres.utoronto.ca RI Zhu, Fang/L-3411-2016 FU Canadian Institutes of Health Research (CIHR) [190633]; Canadian Institutes of Health Research Regenerative Medicine Graduate Fellowship; CIHR [190633]; Leukemia and Lymphoma Society of Canada (LLSC) FX This research was supported by grants from the Canadian Institutes of Health Research (CIHR) (#190633) for RG, the Canadian Institutes of Health Research Regenerative Medicine Graduate Fellowship for KW, CIHR (#190633) and the Leukemia and Lymphoma Society of Canada (LLSC) (to DES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 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 APR 25 PY 2016 VL 11 IS 4 AR e0152073 DI 10.1371/journal.pone.0152073 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5OX UT WOS:000374970600001 PM 27111430 ER PT J AU Ziemba, AM Forman, SA AF Ziemba, Alexis M. Forman, Stuart A. TI Correction for Inhibition Leads to an Allosteric Co-Agonist Model for Pentobarbital Modulation and Activation of alpha 1 beta 3 gamma 2L GABA(A) Receptors SO PLOS ONE LA English DT Article ID TRANSMEMBRANE DOMAIN; ETOMIDATE SITES; SUBUNIT; BARBITURATE; BINDING; IDENTIFICATION; MUTATIONS; CHANNELS; BLOCK AB Background Pentobarbital, like propofol and etomidate, produces important general anesthetic effects through GABA(A) receptors. Photolabeling also indicates that pentobarbital binds to some of the same sites where propofol and etomidate act. Quantitative allosteric co-agonist models for propofol and etomidate account for modulatory and agonist effects in GABA(A) receptors and have proven valuable in establishing drug site characteristics and for functional analysis of mutants. We therefore sought to establish an allosteric co-agonist model for pentobarbital activation and modulation of alpha 1 beta 3 gamma 2L receptors, using a novel approach to first correct pentobarbital activation data for inhibitory effects in the same concentration range. Methods Using oocyte-expressed alpha 1 beta 3 gamma 2L GABA(A) receptors and two-microelectrode voltage-clamp, we quantified modulation of GABA responses by a low pentobarbital concentration and direct effects of high pentobarbital concentrations, the latter displaying mixed agonist and inhibitory effects. We then isolated and quantified pentobarbital inhibition in activated receptors using a novel single-sweep "notch" approach, and used these results to correct steady-state direct activation for inhibition. Results Combining results for GABA modulation and corrected direct activation, we estimated receptor open probability and optimized parameters for a Monod-Wyman-Changeux allosteric co-agonist model. Inhibition by pentobarbital was consistent with two sites with IC(50)s near 1 mM, while co-agonist model parameters suggest two allosteric pentobarbital agonist sites characterized by K-PB approximate to 5 mM and high efficacy. The results also indicate that pentobarbital may be a more efficacious agonist than GABA. Conclusions Our novel approach to quantifying both inhibitory and co-agonist effects of pentobarbital provides a basis for future structure-function analyses of GABA(A) receptor mutations in putative pentobarbital binding sites. C1 [Ziemba, Alexis M.; Forman, Stuart A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ziemba, Alexis M.] Rensselaer Polytech Inst, Dept Biomed Engn, Troy, NY 12180 USA. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM saforman@partners.org FU NIH [P01 GM058448] FX This research was supported by a grant to SAF from NIH (P01 GM058448). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 0 Z9 0 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 APR 25 PY 2016 VL 11 IS 4 AR e0154031 DI 10.1371/journal.pone.0154031 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5OX UT WOS:000374970600029 PM 27110714 ER PT J AU Suzuki, J Corfas, G Liberman, MC AF Suzuki, Jun Corfas, Gabriel Liberman, M. Charles TI Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure SO SCIENTIFIC REPORTS LA English DT Article ID SPIRAL GANGLION NEURONS; HAIR CELL LOSS; HIDDEN HEARING-LOSS; GUINEA-PIG COCHLEA; INNER-EAR; QUANTITATIVE-EVALUATION; DEGENERATION; EXPRESSION; SURVIVAL; INNERVATION AB In acquired sensorineural hearing loss, such as that produced by noise or aging, there can be massive loss of the synaptic connections between cochlear sensory cells and primary sensory neurons, without loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear neurons survive for months to years, there is a long therapeutic window in which to re-establish functional connections and improve hearing ability. Here we show in noise-exposed mice that local delivery of neurotrophin-3 (NT-3) to the round window niche, 24 hours after an exposure that causes an immediate loss of up to 50% loss of synapses in the cochlear basal region, can regenerate pre- and postsynaptic elements at the hair cell / cochlear nerve interface. This synaptic regeneration, as documented by confocal microscopy of immunostained cochlear sensory epithelia, was coupled with a corresponding functional recovery, as seen in the suprathreshold amplitude of auditory brainstem response Wave 1. Cochlear delivery of neurotrophins in humans is likely achievable as an office procedure via transtympanic injection, making our results highly significant in a translational context. C1 [Suzuki, Jun; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Suzuki, Jun; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Suzuki, Jun] Tohoku Univ, Grad Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Sendai, Miyagi 9808574, Japan. [Corfas, Gabriel] Univ Michigan, Kresge Hearing Res Inst, 1301 E Ann St, Ann Arbor, MI 48109 USA. [Corfas, Gabriel] Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. RP Suzuki, J (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA.; Suzuki, J (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA.; Suzuki, J (reprint author), Tohoku Univ, Grad Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Sendai, Miyagi 9808574, Japan. EM Jun_Suzuki2@meei.harvard.edu FU NIDCD [R01 DC 0188, R01 DC04820, P30 DC05209] FX Research supported by grants from the NIDCD, including R01 DC 0188 (M.C.L.), R01 DC04820 (G.C. and M.C.L.) and P30 DC05209 (M.C.L.), as well as by a gift from Decibel Therapeutics and from Tom and Helene Lauer. NR 60 TC 6 Z9 6 U1 4 U2 8 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 APR 25 PY 2016 VL 6 AR 24907 DI 10.1038/srep24907 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK1EN UT WOS:000374655400001 PM 27108594 ER PT J AU Kim, JE Scherzer, R Estrella, MM Ix, JH Shlipak, MG AF Kim, Julie E. Scherzer, Rebecca Estrella, Michelle M. Ix, Joachim H. Shlipak, Michael G. TI Tenofovir exposure alters associations of serum bicarbonate with chronic kidney disease risk in HIV-infected veterans SO AIDS LA English DT Article DE tenofovir; HIV; chronic kidney disease; bicarbonate ID ANTIRETROVIRAL THERAPY; COHORT; PROGRESSION; ACIDOSIS; OUTCOMES; HEALTH; CARE; CKD AB Objective: Among HIV-infected persons, tenofovir disoproxil fumarate (TDF) use is associated with higher risk of developing chronic kidney disease (CKD). Because lower serum bicarbonate concentrations may precede CKD onset, this study investigated the associations between TDF use and bicarbonate concentrations, and between bicarbonate with CKD risk among TDF users and nonusers. Methods: Retrospective cohort study of 16 070 HIV-infected US veterans who initiated antiretroviral therapy between 1997-2011. The association between TDF use with longitudinal bicarbonate concentrations and associations between bicarbonate with incident CKD stratified by TDF use (never, initial, and later user) were evaluated. Results: Compared with TDF users, never users had faster declines in bicarbonate concentrations: change in bicarbonate -0.11 mmol/l per year (95% confidence interval -0.16, -0.05), compared with -0.04 mmol/l per year (-0.06, 0.05) in initial users and -0.02 mmol/l per year (-0.05, 0.01) in later users. Low baseline bicarbonate (<22 mmol/l) was significantly associated with CKD risk among TDF never users (1.80; 1.21, 2.68), but not among TDF users (0.98; 0.69, 1.38). Similarly, declining bicarbonate concentrations were associated with higher CKD risk among never users (hazard ratio 1.67 per mmol/l; 1.34, 2.08), but not among TDF users (1.09; 0.98, 1.22). Interactions were highly significant for both analyses (P value = 0.001). Conclusion: Despite associations with nephrotoxicity, TDF use was associated with higher serum bicarbonate concentrations longitudinally. Additionally, TDF use obscured the strong associations of bicarbonate with CKD risk in HIV-infected persons. Therefore, the role of bicarbonate concentrations as a tool to monitor kidney health in HIV-infected persons may be limited in the setting of TDF use. C1 [Kim, Julie E.; Scherzer, Rebecca; Estrella, Michelle M.; Ix, Joachim H.; Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA. EM michael.shlipak@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [1K23DK081317]; American Heart Association [14EIA18560026]; National Institute of Aging [R01AG034853] FX R.S. received honorarium from Merck for participating in a Renal Expert Input Forum in June 2014; this honorarium was donated to NCIRE to support kidney research. M.E. was supported by grant 1K23DK081317 from the National Institute of Diabetes and Digestive and Kidney Diseases. J.I. was supported by an Established Investigator Award 14EIA18560026 from the American Heart Association. M.S. was supported by grant R01AG034853 from the National Institute of Aging. NR 25 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD APR 24 PY 2016 VL 30 IS 7 BP 1049 EP 1057 DI 10.1097/QAD.0000000000001023 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DI1AW UT WOS:000373229400001 PM 26760455 ER PT J AU Musinguzi, N Muganzi, CD Boum, Y Ronald, A Marzinke, MA Hendrix, CW Celum, C Baeten, JM Bangsberg, DR Haberer, JE AF Musinguzi, Nicholas Muganzi, Collins D. Boum, Yap, II Ronald, Allan Marzinke, Mark A. Hendrix, Craig W. Celum, Connie Baeten, Jared M. Bangsberg, David R. Haberer, Jessica E. CA Partners PrEP Ancillary Adherence TI Comparison of subjective and objective adherence measures for preexposure prophylaxis against HIV infection among serodiscordant couples in East Africa SO AIDS LA English DT Article DE tenofovir; drug levels; subjective adherence; East Africa; adherence; preexposure prophylaxis; objective adherence; serodiscordant ID SELF-REPORT MEASURES; PREP CLINICAL-TRIAL; ANTIRETROVIRAL THERAPY; MEDICATION ADHERENCE; PROTEASE INHIBITORS; PREVENTION; WOMEN; TENOFOVIR; EMTRICITABINE; CONCORDANCE AB Background: Preexposure prophylaxis (PrEP) efficacy is highly dependent on adherence. Yet, it is unclear which adherence measures perform best for PrEP. Methods: We compared three types of self-reported adherence questions (rating of ability to adhere, frequency of doses taken, percentage of doses taken) and three forms of objective adherence measurement [unannounced pill counts (UPC), electronic monitoring, plasma tenofovir levels] using data from an ancillary adherence study within a clinical trial of PrEP among East African serodiscordant couples (Partners PrEP Study). Monthly measures were assessed for the first 6 months of follow-up. Results: One thousand, one hundred and forty-seven participants contributed 6048 person-months of data to this analysis. Median adherence was high: self-reported rating (90%), self-reported frequency (93%), and self-reported percentage (97%); UPC (99%); and electronic monitoring (97%). Prevalence of steady-state daily dosing (SSDD; >= 40 ng/ml) was 74% in a random subset of tenofovir samples obtained from 365 participants. Discrimination of SSDD versus less than SSDD levels was poor for self-reported rating [area under the receiver-operating curve (AROC) 0.54], self-reported frequency (AROC 0.52), self-reported percentage (AROC 0.56) and UPC (AROC 0.58), but moderate for electronic monitoring (AROC 0.70). Correlation was moderate among self-reported measures, adherence (0.61-0.66), but low for these self-reported measures compared with UPC (0.32-0.36) and with electronic monitoring (0.22-0.28). Conclusion: Electronic monitoring was the only adherence measure with meaningful ability to discriminate between SSDD and less than SSDD plasma tenofovir levels. Correlation between subjective and objective measures was poor. Future research should explore novel approaches to adherence measurement as PrEP moves into demonstration projects and programmatic implementation. C1 [Musinguzi, Nicholas; Bangsberg, David R.] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Muganzi, Collins D.; Boum, Yap, II] Mbarara Univ Sci & Technol, EpiCtr Med Sans Frontieres, Mbarara, Uganda. [Boum, Yap, II] Mbarara Univ Sci & Technol, Dept Med Lab Sci, Mbarara, Uganda. [Ronald, Allan] Univ Manitoba, Dept Infect Dis, Winnipeg, MB, Canada. [Marzinke, Mark A.; Hendrix, Craig W.] Johns Hopkins Univ, Dept Med, Div Clin Pharmacol, Baltimore, MD USA. [Celum, Connie; Baeten, Jared M.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Baeten, Jared M.] Univ Washington, Dept Med, Seattle, WA USA. [Baeten, Jared M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bangsberg, David R.; Haberer, Jessica E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Dept Global Hlth & Populat, TH Chan Sch Publ Hlth,Ctr Global Hlth, Boston, MA USA. RP Musinguzi, N (reprint author), Mbarara Univ Sci & Technol, Global Hlth Collaborat, Plot 10-24,Lower Circular Rd, Mbarara, Uganda. EM nmusinguzi@gmail.com RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 NR 36 TC 0 Z9 0 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD APR 24 PY 2016 VL 30 IS 7 BP 1121 EP 1129 DI 10.1097/QAD.0000000000001024 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DI1BF UT WOS:000373230300001 PM 26785125 ER PT J AU Teng, MX Love, MI Davis, CA Djebali, S Dobin, A Graveley, BR Li, S Mason, CE Olson, S Pervouchine, D Sloan, CA Wei, XT Zhan, LJ Irizarry, RA AF Teng, Mingxiang Love, Michael I. Davis, Carrie A. Djebali, Sarah Dobin, Alexander Graveley, Brenton R. Li, Sheng Mason, Christopher E. Olson, Sara Pervouchine, Dmitri Sloan, Cricket A. Wei, Xintao Zhan, Lijun Irizarry, Rafael A. TI A benchmark for RNA-seq quantification pipelines SO GENOME BIOLOGY LA English DT Article ID GENECHIP EXPRESSION MEASURES; GENOME; CELL; TRANSCRIPTOMES; NORMALIZATION; ALIGNMENT; GENES AB Obtaining RNA-seq measurements involves a complex data analytical process with a large number of competing algorithms as options. There is much debate about which of these methods provides the best approach. Unfortunately, it is currently difficult to evaluate their performance due in part to a lack of sensitive assessment metrics. We present a series of statistical summaries and plots to evaluate the performance in terms of specificity and sensitivity, available as a R/Bioconductor package (http://bioconductor.org/packages/rnaseqcomp). Using two independent datasets, we assessed seven competing pipelines. Performance was generally poor, with two methods clearly underperforming and RSEM slightly outperforming the rest. C1 [Teng, Mingxiang; Love, Michael I.; Irizarry, Rafael A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Teng, Mingxiang; Love, Michael I.; Irizarry, Rafael A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. [Davis, Carrie A.; Dobin, Alexander] Cold Spring Harbor Lab, Funct Genom Grp, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. [Djebali, Sarah; Pervouchine, Dmitri] Ctr Genom Regulat CRG, Bioinformat & Genom Programme, Doctor Aiguader 88, Barcelona 08003, Spain. [Djebali, Sarah; Pervouchine, Dmitri] UPF, Doctor Aiguader 88, Barcelona 08003, Spain. [Graveley, Brenton R.; Olson, Sara; Wei, Xintao; Zhan, Lijun] UConn Hlth Ctr, Inst Syst Genom, Dept Genet & Genome Sci, Farmington, CT 06030 USA. [Li, Sheng; Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Sloan, Cricket A.] Stanford Univ, Dept Genet, 300 Pasteur Dr, Stanford, CA 94305 USA. [Teng, Mingxiang] Harbin Inst Technol, Sch Comp Sci & Technol, Harbin 150006, Peoples R China. RP Irizarry, RA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA.; Irizarry, RA (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. EM rafa@jimmy.harvard.edu OI Teng, Mingxiang/0000-0002-8536-8941; Love, Michael/0000-0001-8401-0545 FU NCI NIH HHS [T32 CA009337]; NHGRI NIH HHS [U54 HG007005] NR 40 TC 8 Z9 8 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD APR 23 PY 2016 VL 17 AR 74 DI 10.1186/s13059-016-0940-1 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DJ9JA UT WOS:000374528600001 PM 27107712 ER PT J AU Verbich, D Becker, D Vlachos, A Mundel, P Deller, T McKinney, RA AF Verbich, David Becker, Denise Vlachos, Andreas Mundel, Peter Deller, Thomas McKinney, R. Anne TI Rewiring neuronal microcircuits of the brain via spine head protrusions-a role for synaptopodin and intracellular calcium stores SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE Dendritic spines; Synaptopodin; Calcium; Structural plasticity; Ryanodine ID LONG-TERM POTENTIATION; ACTIN-ASSOCIATED PROTEIN; DENDRITIC SPINES; SYNAPTIC PLASTICITY; CORD-INJURY; HIPPOCAMPAL-NEURONS; IN-VIVO; POSTTRAUMATIC EPILEPSY; ENDOPLASMIC-RETICULUM; FUNCTIONAL RECOVERY AB Neurological diseases associated with neuronal death are also accompanied by axonal denervation of connected brain regions. In these areas, denervation leads to a decrease in afferent drive, which may in turn trigger active central nervous system (CNS) circuitry rearrangement. This rewiring process is important therapeutically, since it can partially recover functions and can be further enhanced using modern rehabilitation strategies. Nevertheless, the cellular mechanisms of brain rewiring are not fully understood. We recently reported a mechanism by which neurons remodel their local connectivity under conditions of network-perturbance: hippocampal pyramidal cells can extend spine head protrusions (SHPs), which reach out toward neighboring terminals and form new synapses. Since this form of activity-dependent rewiring is observed only on some spines, we investigated the required conditions. We speculated, that the actin-associated protein synaptopodin, which is involved in several synaptic plasticity mechanisms, could play a role in the formation and/or stabilization of SHPs. Using hippocampal slice cultures, we found that similar to 70 % of spines with protrusions in CA1 pyramidal neurons contained synaptopodin. Analysis of synaptopodin-deficient neurons revealed that synaptopodin is required for the stability but not the formation of SHPs. The effects of synaptopodin could be linked to its role in Ca2+ homeostasis, since spines with protrusions often contained ryanodine receptors and synaptopodin. Furthermore, disrupting Ca2+ signaling shortened protrusion lifetime. By transgenically reintroducing synaptopodin on a synaptopodin-deficient background, SHP stability could be rescued. Overall, we show that synaptopodin increases the stability of SHPs, and could potentially modulate the rewiring of microcircuitries by making synaptic reorganization more efficient. C1 [Verbich, David; McKinney, R. Anne] McGill Univ, Integrated Program Neurosci, Montreal, PQ H3G 0B1, Canada. [Becker, Denise; Vlachos, Andreas; Deller, Thomas] Goethe Univ Frankfurt, Inst Clin Neuroanat, Neurosci Ctr, D-60590 Frankfurt, Germany. [Becker, Denise; McKinney, R. Anne] McGill Univ, Dept Pharmacol & Therapeut, Bellini Life Sci Bldg,Room 167, Montreal, PQ H3G 0B1, Canada. [Mundel, Peter] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Becker, Denise] Univ Lausanne, Dept Fundamental Neurosci, CH-1005 Lausanne, Switzerland. [Vlachos, Andreas] Univ Dusseldorf, Fac Med, Inst Anat 2, D-40225 Dusseldorf, Germany. RP McKinney, RA (reprint author), McGill Univ, Integrated Program Neurosci, Montreal, PQ H3G 0B1, Canada.; McKinney, RA (reprint author), McGill Univ, Dept Pharmacol & Therapeut, Bellini Life Sci Bldg,Room 167, Montreal, PQ H3G 0B1, Canada. EM anne.mckinney@mcgill.ca OI Becker, Denise/0000-0003-0132-9986 FU Canadian Institutes of Health Research [MOP 86724] NR 69 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD APR 22 PY 2016 VL 4 AR 38 DI 10.1186/s40478-016-0311-x PG 12 WC Neurosciences SC Neurosciences & Neurology GA DK2FM UT WOS:000374730000001 PM 27102112 ER PT J AU Utter, DR Welch, JLM Borisy, GG AF Utter, Daniel R. Welch, Jessica L. Mark Borisy, Gary G. TI Individuality, Stability, and Variability of the Plaque Microbiome SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE human microbiome; 16S rRNA; community dynamics; oral microbiota; community ecology ID 16S RIBOSOMAL-RNA; HUMAN ORAL MICROBIOME; PHYLOGENETIC ANALYSIS; GENOME SEQUENCE; HUMAN-BODY; COMMUNITIES; DIVERSITY; ALIGNMENT; SHIGELLA; DYNAMICS AB Dental plaque is a bacterial biofilm composed of a characteristic set of organisms. Relatively little information from cultivation-independent, high-throughput analyses has been published on the temporal dynamics of the dental plaque microbiome. We used Minimum Entropy Decomposition, an information theory-based approach similar to oligotyping that provides single-nucleotide resolution, to analyze a previously published time series data set and investigate the dynamics of the plaque microbiome at various analytic and taxonomic levels. At both the genus and 9796 Operational Taxonomic Unit (OTU) levels of resolution, the range of variation within each individual overlapped that of other individuals in the data set. When analyzed at the oligotype level, however, the overlap largely disappeared, showing that single-nucleotide resolution enables differentiation of individuals from one another without ambiguity. The overwhelming majority of the plaque community in all samples was made up of bacteria from a moderate number of plaque-typical genera, indicating that the overall community framework is shared among individuals. Each of these genera fluctuated in abundance around a stable mean that varied between individuals, with some genera having higher inter-individual variability than others. Thus, at the genus level, differences between individuals lay not in the identity of the major genera but in consistently differing proportions of these genera from mouth to mouth. However, at the oligotype level, we detected oligotype "fingerprints," a highly individual-specific set of persistently abundant oligotypes fluctuating around a stable mean over time. For example, within the genus Corynebacterium, more than a dozen oligotypes were detectable in each individual, of which a different subset reached high abundance in any given person. This pattern suggests that each mouth contains a subtly different community of organisms. We also compared the Chinese plaque community characterized here to previously characterized Western plaque communities, as represented by analyses of data emerging from the Human Microbiome Project, and found no major differences between Chinese and Western supragingival plaque. In conclusion, we found the plaque microbiome to be highly individualized at the oligotype level and characterized by stability of community membership, with variability in the relative abundance of community members between individuals and over time. C1 [Utter, Daniel R.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Utter, Daniel R.; Welch, Jessica L. Mark; Borisy, Gary G.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Welch, Jessica L. Mark] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA. RP Utter, DR (reprint author), Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA.; Utter, DR (reprint author), Forsyth Inst, Dept Microbiol, Cambridge, MA USA. EM dutter@g.harvard.edu FU National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research Grant [DE022586]; Harvard University's Department of Organismic and Evolutionary Biology graduate program FX We thank F.E. Dewhirst, The Forsyth Institute for helpful discussions and A.M. Eren, University of Chicago for a critical reading of the manuscript. We thank W. X. Jiang, Y. J. Hu, L. Gao, Z. Y. He, C. L. Zhu, R. Ma, and Z. W. Huang, Shanghai, the researchers who collected the original data set, without whose work our re-analysis would have been impossible. Our work was supported by National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research Grant DE022586 (to GGB). Additional support was provided by Harvard University's Department of Organismic and Evolutionary Biology graduate program (to DRU). NR 49 TC 0 Z9 0 U1 7 U2 13 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD APR 22 PY 2016 VL 7 AR 564 DI 10.3389/fmicb.2016.00564 PG 13 WC Microbiology SC Microbiology GA DK0IF UT WOS:000374595700001 PM 27148241 ER PT J AU Briney, B Le, K Zhu, J Burton, DR AF Briney, Bryan Le, Khoa Zhu, Jiang Burton, Dennis R. TI Clonify: unseeded antibody lineage assignment from next-generation sequencing data SO SCIENTIFIC REPORTS LA English DT Article ID B-CELL REPERTOIRE; HIV-1-NEUTRALIZING ANTIBODIES; HIGH-THROUGHPUT; NEUTRALIZING ANTIBODIES; HIV-ANTIBODIES; GENE SEGMENT; POTENT; BROAD; RESPONSES; INSERTIONS AB Defining the dynamics and maturation processes of antibody clonal lineages is crucial to understanding the humoral response to infection and immunization. Although individual antibody lineages have been previously analyzed in isolation, these studies provide only a narrow view of the total antibody response. Comprehensive study of antibody lineages has been limited by the lack of an accurate clonal lineage assignment algorithm capable of operating on next-generation sequencing datasets. To address this shortcoming, we developed Clonify, which is able to perform unseeded lineage assignment on very large sets of antibody sequences. Application of Clonify to IgG+ memory repertoires from healthy individuals revealed a surprising lack of influence of large extended lineages on the overall repertoire composition, indicating that this composition is driven less by the order and frequency of pathogen encounters than previously thought. Clonify is freely available at www.github.com/briney/clonify-python. C1 [Briney, Bryan; Le, Khoa; Zhu, Jiang; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Briney, Bryan; Le, Khoa; Zhu, Jiang; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Briney, Bryan; Le, Khoa; Zhu, Jiang; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02142 USA. RP Briney, B; Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Briney, B; Burton, DR (reprint author), Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA.; Briney, B; Burton, DR (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA.; Burton, DR (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02142 USA. EM briney@scripps.edu; burton@scripps.edu FU NIH [T32 AI007244-32]; International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery [1UM1AI100663] FX We would like to thank all study participants and the staff at the Scripps Normal Blood Donor Service. BB was supported by NIH T32 AI007244-32. This work was supported by the International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center and the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (1UM1AI100663). NR 44 TC 5 Z9 5 U1 0 U2 2 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 APR 22 PY 2016 VL 6 AR 23901 DI 10.1038/srep23901 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ9MJ UT WOS:000374537300001 PM 27102563 ER PT J AU Pillai, PS Molony, RD Martinod, K Dong, H Pang, IK Tal, MC Solis, AG Bielecki, P Mohanty, S Trentalange, M Homer, RJ Flavell, RA Wagner, DD Montgomery, RR Shaw, AC Staeheli, P Iwasaki, A AF Pillai, Padmini S. Molony, Ryan D. Martinod, Kimberly Dong, Huiping Pang, Iris K. Tal, Michal C. Solis, Angel G. Bielecki, Piotr Mohanty, Subhasis Trentalange, Mark Homer, Robert J. Flavell, Richard A. Wagner, Denisa D. Montgomery, Ruth R. Shaw, Albert C. Staeheli, Peter Iwasaki, Akiko TI Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease SO SCIENCE LA English DT Article ID A-VIRUS-INFECTION; DENDRITIC CELLS; TOLERANCE; MICE; VACCINATION; RESPONSES; IMMUNITY; GENES; MOUSE AB Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology. C1 [Pillai, Padmini S.; Molony, Ryan D.; Dong, Huiping; Pang, Iris K.; Tal, Michal C.; Solis, Angel G.; Bielecki, Piotr; Flavell, Richard A.; Iwasaki, Akiko] Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA. [Martinod, Kimberly; Wagner, Denisa D.] Harvard Univ, Boston Childrens Hosp, Sch Med, Program Cellular & Mol Med, Boston, MA USA. [Mohanty, Subhasis; Shaw, Albert C.] Yale Univ, Sch Med, Dept Internal Med, Sect Infect Dis, 333 Cedar St, New Haven, CT 06520 USA. [Trentalange, Mark] Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St, New Haven, CT 06520 USA. [Homer, Robert J.] Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 USA. [Montgomery, Ruth R.] Yale Univ, Sch Med, Dept Internal Med, Sect Rheumatol, 333 Cedar St, New Haven, CT 06520 USA. [Staeheli, Peter] Univ Med Ctr Freiburg, Inst Virol, Inst Med Mikrobiol & Hyg, Hermann Herder Str 11, D-79104 Freiburg, Germany. [Flavell, Richard A.; Iwasaki, Akiko] Yale Univ, Sch Med, Howard Hughes Med Inst, 333 Cedar St, New Haven, CT 06520 USA. [Tal, Michal C.] Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. RP Iwasaki, A (reprint author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA.; Iwasaki, A (reprint author), Yale Univ, Sch Med, Howard Hughes Med Inst, 333 Cedar St, New Haven, CT 06520 USA. EM akiko.iwasaki@yale.edu OI Tal, Michal/0000-0003-2550-6246; Martinod, Kimberly/0000-0002-1026-6107 FU NIH [AI081884, AI062428, AI064705, HHSN272201100019C, K24 AG02489, T32 AI007019-36, T32 AI007019-38, T32 AI055403, 5T32HL066987-13, F31 AG039163, R01HL102101, R01HL125501, K24 AG042489, P30 AG21342]; Deutsche Forschungsgemeinschaft (DFG) [SFB1160/P13] FX The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Sequence data has been publicly released to the general scientific community (NCBI Sequence Read Archive ID SRR3216492). This study was supported by NIH awards AI081884, AI062428, and AI064705 (to A.I.); HHSN272201100019C (to A.C.S. and R.R.M); K24 AG02489 (to A.C.S.); T32 AI007019-36 (to P.S.P.); T32 AI007019-38 and T32 AI055403 (to R.D.M.); 5T32HL066987-13 (to K.M.); F31 AG039163 (to M.T.); R01HL102101 and R01HL125501 (to D.D.W.); K24 AG042489 (to A.C.S); P30 AG21342 (Claude D. Pepper Older Americans Independence Center at Yale) (to A.C.S.); and grant SFB1160/P13 from the Deutsche Forschungsgemeinschaft (DFG) (to P.S.). A.I. and R.A.F. are investigators of the Howard Hughes Medical Institute. NR 35 TC 13 Z9 14 U1 7 U2 19 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 APR 22 PY 2016 VL 352 IS 6284 BP 463 EP 466 DI 10.1126/science.aaf3926 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ8RH UT WOS:000374479700048 PM 27102485 ER PT J AU Narasimhan, VM Hunt, KA Mason, D Baker, CL Karczewski, KJ Barnes, MER Barnett, AH Bates, C Bellary, S Bockett, NA Giorda, K Griffiths, CJ Hemingway, H Jia, ZL Kelly, MA Khawaja, HA Lek, M McCarthy, S McEachan, R O'Donnell-Luria, A Paigen, K Parisinos, CA Sheridan, E Southgate, L Tee, L Thomas, M Xue, YL Schnall-Levin, M Petkov, PM -Smith, CT Maher, ER Trembath, RC MacArthur, DG Wright, J Durbin, R Heel, DA AF Narasimhan, Vagheesh M. Hunt, Karen A. Mason, Dan Baker, Christopher L. Karczewski, Konrad J. Barnes, Mi El R. Barnett, Anthony H. Bates, Chris Bellary, Srikanth Bockett, Nicholas A. Giorda, Kristina Griffiths, Christopher J. Hemingway, Harry Jia, Zhilong Kelly, M. Ann Khawaja, Hajrah A. Lek, Monkol McCarthy, Shane McEachan, Rosie O'Donnell-Luria, Anne Paigen, Kenneth Parisinos, Constantinos A. Sheridan, Eamonn Southgate, Laura Tee, Louise Thomas, Mark Xue, Yali Schnall-Levin, Michael Petkov, Petko M. -Smith, Chris Tyler Maher, Eamonn R. Trembath, Richard C. MacArthur, Daniel G. Wright, John Durbin, Richard van Heel, David A. TI Health and population effects of rare gene knockouts in adult humans with related parents SO SCIENCE LA English DT Article ID RECOMBINATION HOTSPOTS; MEIOTIC RECOMBINATION; PRDM9; VARIANTS; GENOME; PHENOTYPES; MUTATIONS; COSTS; MICE AB Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans. C1 [Narasimhan, Vagheesh M.; McCarthy, Shane; Thomas, Mark; Xue, Yali; -Smith, Chris Tyler; Durbin, Richard] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Hunt, Karen A.; Bockett, Nicholas A.; Griffiths, Christopher J.; Parisinos, Constantinos A.; Southgate, Laura; Trembath, Richard C.; van Heel, David A.] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London E1 2AT, England. [Mason, Dan; McEachan, Rosie; Sheridan, Eamonn; Wright, John] Bradford Teaching Hosp Natl Hlth Serv NHS Fdn Tru, Bradford Inst Hlth Res, Bradford BD9 6RJ, W Yorkshire, England. [Baker, Christopher L.; Paigen, Kenneth; Petkov, Petko M.] Jackson Lab, Ctr Genome Dynam, Bar Harbor, ME 04609 USA. [Karczewski, Konrad J.; Lek, Monkol; O'Donnell-Luria, Anne; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Karczewski, Konrad J.; Lek, Monkol; O'Donnell-Luria, Anne; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Barnes, Mi El R.; Jia, Zhilong; Khawaja, Hajrah A.] Queen Mary Univ London, Darts & London Sch Med & Dent, William Harvey Res Inst, London E1 2AT, England. [Barnett, Anthony H.] Heart England NHS Fdn Trust, Diabet & Endocrine Ctr, Birmingham B9 5SS, W Midlands, England. [Barnett, Anthony H.] Univ Birmingham, Birmingham B9 5SS, W Midlands, England. [Bates, Chris] TPP, Mill House,Troy Rd, Troy, NY USA. [Bellary, Srikanth] Aston Univ, Aston Res Ctr Healthy Ageing, Birmingham B4 7ET, W Midlands, England. [Giorda, Kristina; Schnall-Levin, Michael] 10X Genom, 7068 Koll Ctr Pkwy,Suite 415, Pleasanton, CA 94566 USA. [Hemingway, Harry] Farr Inst Hlth Informat Res, London NW1 2DA, England. [Hemingway, Harry] UCL, Inst Hlth Informat, London NW1 2DA, England. [Kelly, M. Ann; Tee, Louise] Univ Birmingham, Sch Clin & Expt Med, Birmingham B15 2TT, W Midlands, England. [Maher, Eamonn R.] Univ Cambridge, Dept Med Genet, Box 238,Cambridge Biomed Campus, Cambridge CB2 0QQ, England. [Maher, Eamonn R.] NIHR, Cambridge Biomed Res Ctr, Box 238,Cambridge Biomed Campus, Cambridge CB2 0QQ, England. [Maher, Eamonn R.] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Biomed Campus, Cambridge CB2 0QQ, England. [Trembath, Richard C.] Kings Coll London, Fac Life Sci & Med, London SE1 1UL, England. RP Durbin, R (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.; Heel, DA (reprint author), Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London E1 2AT, England. EM rd@sanger.ac.uk; d.vanheel@qmul.ac.uk RI Wright, John/H-1624-2012; MAHER, EAMONN/A-9507-2008; OI Wright, John/0000-0001-9572-7293; MAHER, EAMONN/0000-0002-6226-6918; O'Donnell-Luria, Anne/0000-0001-6418-9592; Narasimhan, Vagheesh/0000-0001-8651-8844; Karczewski, Konrad/0000-0003-2878-4671; Trembath, Richard/0000-0003-0550-3400; Southgate, Laura/0000-0002-2090-1450; McCarthy, Shane/0000-0002-2715-4187 FU Wellcome Trust [WT102627, WT098051, WT101597, WT099769]; Barts Charity [845/1796]; UK Medical Research Council [MR/M009017/1]; NIHR under its Collaboration for Applied Health Research and Care for Yorkshire and Humber; NIH National Institute of General Medical Sciences [R01GM104371]; NIHR Cambridge Biomedical Research Centre; UK Medical Research Council; Arthritis Research UK; British Heart Foundation; Cancer Research UK; Chief Scientist Office; Economic and Social Research Council; Engineering and Physical Sciences Research Council; NIHR; National Institute for Social Care and Health Research; Wellcome Trust; NIH [GM 099640]; AstraZeneca; Pfizer FX The study was funded by the Wellcome Trust (grants WT102627 and WT098051), Barts Charity (grant 845/1796), and the UK Medical Research Council (grant MR/M009017/1). This paper presents independent research funded by the NIHR under its Collaboration for Applied Health Research and Care for Yorkshire and Humber. Core support for Born in Bradford is also provided by the Wellcome Trust (grant WT101597). V.M.N. was supported by the Wellcome Trust Ph.D. Studentship (grant WT099769). D.G.M. and K.J.K. were supported by the NIH National Institute of General Medical Sciences under award R01GM104371. E.R.M. is funded by the NIHR Cambridge Biomedical Research Centre. H.H. is supported by awards to establish the Farr Institute of Health Informatics Research, London, from the UK Medical Research Council, Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Chief Scientist Office, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, NIHR, the National Institute for Social Care and Health Research, and the Wellcome Trust. C.L.B., K.P., and P.M.P. are supported by the NIH (grant GM 099640). Born in Bradford is only possible because of the enthusiasm and commitment of the children and parents who are part of the study. We are grateful to all of the participants, health professionals, and researchers who took part in the Born in Bradford study. We thank B. MacLaughlin (Queen Mary University of London) for assistance and J. Rogers (Health & Social Care Information Centre) for advice. We would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. R.D. declares that he is a founder and nonexecutive director of Congenica, owns stock in Illumina from previous consulting work, and is a scientific advisory board member of Dovetail. M.S.-L. and K.G. are employees of 10X Genomics. H.H. discloses paid consulting for AstraZeneca, and R.C.T. discloses a paid advisory role with Pfizer. Data reported in the paper are presented in the supplementary materials and are available under a data access agreement at the European Genotype-phenome Archive (www.ebi.ac.uk/ega) under accession numbers EGAS00001000462, EGAS00001000511, EGAS00001000567, EGAS00001000717, and EGAS00001001301. NR 25 TC 20 Z9 20 U1 8 U2 14 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 APR 22 PY 2016 VL 352 IS 6284 BP 474 EP 477 DI 10.1126/science.aac8624 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ8RH UT WOS:000374479700051 PM 26940866 ER PT J AU Netea, MG Joosten, LAB Latz, E Mills, KHG Natoli, G Stunnenberg, HG O'Neill, LAJ Xavier, RJ AF Netea, Mihai G. Joosten, Leo A. B. Latz, Eicke Mills, Kingston H. G. Natoli, Gioacchino Stunnenberg, Hendrik G. O'Neill, Luke A. J. Xavier, Ramnik J. TI Trained immunity: A program of innate immune memory in health and disease SO SCIENCE LA English DT Review ID NATURAL-KILLER-CELLS; MOUSE CYTOMEGALOVIRUS-INFECTION; CANDIDA-ALBICANS INFECTION; NK CELLS; HOST-DEFENSE; BONE-MARROW; NONSPECIFIC PROTECTION; INFLAMMATORY RESPONSE; MACROPHAGE ACTIVATION; CYTOKINE PRODUCTION AB The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases. C1 [Netea, Mihai G.; Joosten, Leo A. B.] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Netea, Mihai G.; Joosten, Leo A. B.] Radboud Univ Nijmegen, Radboud Ctr Infect Dis, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Latz, Eicke] Univ Bonn, Inst Innate Immun, Bonn, Germany. [Latz, Eicke] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Latz, Eicke] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Mills, Kingston H. G.; O'Neill, Luke A. J.] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. [Natoli, Gioacchino] European Inst Oncol, Dept Expt Oncol, Milan, Italy. [Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Fac Sci, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Fac Med, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. RP Netea, MG (reprint author), Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands.; Netea, MG (reprint author), Radboud Univ Nijmegen, Radboud Ctr Infect Dis, Med Ctr, NL-6525 ED Nijmegen, Netherlands. EM mihai.netea@radboudumc.nl OI Mills, Kingston/0000-0003-3646-8222 FU Netherlands Organization for Scientific Research; European Research Council (ERC) [310372]; Deutsche Forschungsgemeinschaft; Excellence Cluster ImmunoSensation; ERC; Science Foundation Ireland [11/P1/1036] FX M.G.N. is supported by a Vici grant from the Netherlands Organization for Scientific Research and a European Research Council (ERC) Consolidator Grant (310372). E.L. is supported by grants from the Deutsche Forschungsgemeinschaft and the Excellence Cluster ImmunoSensation and via an ERC Consolidator Grant. G.N.'s work on this topic was supported by an ERC grant (NORM). K.H.G.M. is supported by a PI grant from Science Foundation Ireland (11/P1/1036). We thank M. Gresnigt for the help with the figures. We apologize to the authors of studies that could not be cited due to space constraints. NR 111 TC 39 Z9 39 U1 18 U2 41 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 APR 22 PY 2016 VL 352 IS 6284 AR aaf1098 DI 10.1126/science.aaf1098 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ8RH UT WOS:000374479700037 ER PT J AU Norling, LV Headland, SE Dalli, J Arnardottir, HH Haworth, O Jones, HR Irimia, D Serhan, CN Perretti, M AF Norling, Lucy V. Headland, Sarah E. Dalli, Jesmond Arnardottir, Hildur H. Haworth, Oliver Jones, Hefin R. Irimia, Daniel Serhan, Charles N. Perretti, Mauro TI Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis SO JCI INSIGHT LA English DT Article ID INHALED CARBON-MONOXIDE; RHEUMATOID-ARTHRITIS; LIPID MEDIATORS; FATTY-ACIDS; RESOLUTION; RECEPTOR; DISEASE; TISSUE; D2; IDENTIFICATION AB Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE(2) biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor-deficient mice termed ALX/fpr2/3(-/-). These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA. C1 [Norling, Lucy V.; Headland, Sarah E.; Haworth, Oliver; Jones, Hefin R.; Perretti, Mauro] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England. [Dalli, Jesmond; Arnardottir, Hildur H.; Serhan, Charles N.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Harvard Inst Med, Ctr Expt Therapeut & Reperfus Injury, 75 Francis St, Boston, MA 02115 USA. [Dalli, Jesmond; Arnardottir, Hildur H.; Serhan, Charles N.] Harvard Med Sch, Boston, MA USA. [Irimia, Daniel] Harvard Med Sch, Massachusetts Gen Hosp, Shriners Hosp Children, Ctr Engn Med, Boston, MA USA. RP Perretti, M (reprint author), Queen Mary Univ London, William Harvey Res Inst, Charterhouse Sq, London EC1M 6BQ, England. EM m.perretti@qmul.ac.uk FU NIBIB NIH HHS [P41 EB002503]; NIGMS NIH HHS [P01 GM095467, R01 GM092804] NR 52 TC 5 Z9 5 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD APR 21 PY 2016 VL 1 IS 5 AR e85922 DI 10.1172/jci.insight.85922 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IV UT WOS:000387104600004 PM 27158677 ER PT J AU Reddy, PNG Radu, M Xu, K Wood, J Harris, CE Chernoff, J Williams, DA AF Reddy, Pavankumar N. G. Radu, Maria Xu, Ke Wood, Jenna Harris, Chad E. Chernoff, Jonathan Williams, David A. TI p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with beta-Pix SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ACTIN STRESS FIBERS; BONE-MARROW; PROGENITOR CELLS; RHO-GTPASES; RAC GTPASE; MYELOPROLIFERATIVE DISEASE; GUANOSINE TRIPHOSPHATASES; PAK KINASES; MYOSIN-II AB Cytoskeletal remodeling of hematopoietic stem and progenitor cells (HSPCs) is essential for homing to the bone marrow (BM). The Ras-related C3 botulinum toxin substrate (Rac)/cell division control protein 42 homolog (CDC42) effector p21-activated kinase (Pak2) has been implicated in HSPC homing and engraftment. However, the molecular pathways mediating Pak2 functions in HSPCs are unknown. Here, we demonstrate that both Pak2 kinase activity and its interaction with the PAK-interacting exchange factor-beta (beta-Pix) are required to reconstitute defective Pak2(Delta/Delta) HSPC homing to the BM. Pak2 serine/threonine kinase activity is required for stromal-derived factor-1 (SDF1 alpha) chemokine-induced HSPC directional migration, whereas Pak2 interaction with beta-Pix is required to regulate the velocity of HSPC migration and precise F-actin assembly. Lack of SDF1 alpha-induced filopodia and associated abnormal cell protrusions seen in Pak2(Delta/Delta) HSPCs were rescued by wild-type (WT) Pak2 but not by a Pak2-kinase dead mutant (KD). Expression of a beta-Pix interaction-defective mutant of Pak2 rescued filopodia formation but led to abnormal F-actin bundles. Although CDC42 has previously been considered an upstream regulator of Pak2, we found a paradoxical decrease in baseline activation of CDC42in Pak2(Delta/Delta) HSPCs, which was rescued by expression of Pak2-WT but not by Pak2-KD; defective homing of Pak2-deleted HSPCs was rescued by constitutive active CDC42. These data demonstrate that both Pak2 kinase activity and its interaction with beta-Pix are essential for HSPC filopodia formation, cytoskeletal integrity, and homing via activation of CDC42. Taken together, we provide mechanistic insights into the role of Pak2 in HSPC migration and homing. C1 [Reddy, Pavankumar N. G.; Xu, Ke; Wood, Jenna; Harris, Chad E.; Williams, David A.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Reddy, Pavankumar N. G.; Xu, Ke; Wood, Jenna; Harris, Chad E.; Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Radu, Maria; Chernoff, Jonathan] Fox Chase Canc Ctr, Canc Biol Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Williams, David A.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Williams, DA (reprint author), Boston Childrens Hosp, 300 Longwood Ave,Karp 08125-3, Boston, MA 02115 USA. EM dawilliams@childrens.harvard.edu OI Reddy, Pavankumar N.G./0000-0001-5980-110X FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK062757-14, P30 DK049216-21]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P30 HD18655]; National Cancer Institute [5R01CA142928]; American Society of Hematology FX This work was supported by grants from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases 5R01DK062757-14 (D.A.W.) and P30 DK049216-21 (Ronald Mathieu), Eunice Kennedy Shriver National Institute of Child Health and Human Development P30 HD18655 (Anthony Hill), and National Cancer Institute 5R01CA142928 (J.C.).; P.N.G.R. is supported by a fellowship from the American Society of Hematology. NR 53 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD APR 21 PY 2016 VL 127 IS 16 BP 1967 EP 1975 DI 10.1182/blood-2016-01-693572 PG 9 WC Hematology SC Hematology GA DJ8DE UT WOS:000374441900007 PM 26932803 ER PT J AU Wink, LK Adams, R Wang, ZM Klaunig, JE Plawecki, MH Posey, DJ McDougle, CJ Erickson, CA AF Wink, Logan K. Adams, Ryan Wang, Zemin Klaunig, James E. Plawecki, Martin H. Posey, David J. McDougle, Christopher J. Erickson, Craig A. TI A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder SO MOLECULAR AUTISM LA English DT Article DE Autism; Autism spectrum disorder; Social impairment; N-acetylcysteine; Oxidative stress ID CONTROLLED CLINICAL-TRIAL; OXIDATIVE STRESS; DOUBLE-BLIND; RISPERIDONE; CHILDREN; HOMOCYSTEINE; BEHAVIOR; PLASMA; SAMPLE; CELLS AB Background: Social impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. The goal of this study was to evaluate efficacy, safety, and tolerability of oral N-acetylcysteine (NAC), an antioxidant whose function overlaps with proposed mechanisms of ASD pathophysiology, targeting core social impairment in youth with ASD. Methods: This study was a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD. Study participants were medically healthy youth age 4 to 12 years with ASD, weighing >= 15 kg, and judged to be moderately ill based on the Clinical Global Impressions Severity scale. The participants were randomized via computer to active drug or placebo in a 1: 1 ratio, with the target dose of NAC being 60 mg/kg/day in three divided doses. The primary outcome measure of efficacy was the Clinical Global Impressions Improvement (CGI-I) scale anchored to core social impairment. To investigate the impact of NAC on oxidative stress markers in peripheral blood, venous blood samples were collected at screen and week 12. Results: Thirty-one patients were enrolled (NAC = 16, placebo = 15). Three participants were lost to follow-up, and three left the trial due to adverse effects. The average daily dose of NAC at week 12 was 56.2 mg/kg (SD = 9.7) with dose ranging from 33.6 to 64.3 mg/kg. The frequency of adverse events was so low that comparisons between groups could not be conducted. At week 12, there was no statistically significant difference between the NAC and placebo groups on the CGI-I (p > 0.69) but the glutathione (GSH) level in blood was significantly higher in the NAC group (p < 0.05). The oxidative glutathione disulfide (GSSG) level increased in the NAC group, however only at a trend level of significance (p = 0.09). There was no significant difference between the NAC and placebo groups in the GSH/GSSG ratio, DNA strand break and oxidative damage, and blood homocysteine levels at week 12 (ps > 0.16). Conclusions: The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD. C1 [Wink, Logan K.; Adams, Ryan; Erickson, Craig A.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 4002, Cincinnati, OH 45229 USA. [Wang, Zemin; Klaunig, James E.] Indiana Univ, Sch Publ Hlth, Invest Toxicol & Pathol, Bloomington, IN USA. [Plawecki, Martin H.] Indiana Univ Sch Med, Dept Psychiat, Christian Sarkine Autism Treatment Ctr, Riley Hosp Children,Indiana Univ Hlth, Indianapolis, IN 46202 USA. [McDougle, Christopher J.] Massachusetts Gen Hosp, Dept Psychiat, Lurie Ctr Autism, Boston, MA 02114 USA. [McDougle, Christopher J.] Massachusetts Gen Hosp, Dept Pediat, Lurie Ctr Autism, Boston, MA 02114 USA. [McDougle, Christopher J.] Harvard Univ, Sch Med, MassGen Hosp Children, Boston, MA USA. RP Erickson, CA (reprint author), Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 4002, Cincinnati, OH 45229 USA. EM Craig.erickson@cchmc.org OI Wang, Zemin/0000-0003-4189-578X FU Autism Speaks Treatment Grant FX Autism Speaks Treatment Grant. NR 34 TC 2 Z9 2 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD APR 21 PY 2016 VL 7 AR 26 DI 10.1186/s13229-016-0088-6 PG 9 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DJ8MG UT WOS:000374465800001 PM 27103982 ER PT J AU Song, J Swisher, CL Im, H Jeong, S Pathania, D Iwamoto, Y Pivovarov, M Weissleder, R Lee, H AF Song, Jun Swisher, Christine Leon Im, Hyungsoon Jeong, Sangmoo Pathania, Divya Iwamoto, Yoshiko Pivovarov, Misha Weissleder, Ralph Lee, Hakho TI Sparsity-Based Pixel Super Resolution for Lens-Free Digital In-line Holography SO SCIENTIFIC REPORTS LA English DT Article ID ON-CHIP MICROSCOPY; COMPRESSIVE HOLOGRAPHY; OPTIMIZATION; ALGORITHMS AB Lens-free digital in-line holography (LDIH) is a promising technology for portable, wide field-of-view imaging. Its resolution, however, is limited by the inherent pixel size of an imaging device. Here we present a new computational approach to achieve sub-pixel resolution for LDIH. The developed method is a sparsity-based reconstruction with the capability to handle the non-linear nature of LDIH. We systematically characterized the algorithm through simulation and LDIH imaging studies. The method achieved the spatial resolution down to one-third of the pixel size, while requiring only single-frame imaging without any hardware modifications. This new approach can be used as a general framework to enhance the resolution in nonlinear holographic systems. C1 [Song, Jun; Swisher, Christine Leon; Im, Hyungsoon; Jeong, Sangmoo; Pathania, Divya; Iwamoto, Yoshiko; Pivovarov, Misha; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Song, Jun] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Swisher, Christine Leon; Im, Hyungsoon; Jeong, Sangmoo; Pathania, Divya; Pivovarov, Misha; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Lee, H (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.; Lee, H (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. EM hlee@mgh.harvard.edu RI Im, Hyungsoon/A-3178-2009 OI Im, Hyungsoon/0000-0002-0626-1346 FU NIH [R01HL113156, R01EB004626, R01EB010011, HHSN268201000044C, U54-CA119349, T32-CA79443, 1K99CA201248-01, F32-CA192531]; Department of Defense Ovarian Cancer Research Program Award [W81XWH-14-1-0279] FX We thank R.M. Westervelt (Harvard), C. Vinegoni, and P.F. Feruglio for helpful discussions. This work was supported in part by NIH Grants R01HL113156, R01EB004626, R01EB010011, HHSN268201000044C, U54-CA119349, T32-CA79443, 1K99CA201248-01 and F32-CA192531; and Department of Defense Ovarian Cancer Research Program Award W81XWH-14-1-0279. NR 26 TC 0 Z9 0 U1 3 U2 12 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 APR 21 PY 2016 VL 6 AR 24681 DI 10.1038/srep24681 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ8UB UT WOS:000374487600001 PM 27098438 ER PT J AU Regan, S Meigs, JB Grinspoon, SK Triant, VA AF Regan, Susan Meigs, James B. Grinspoon, Steven K. Triant, Virginia A. TI Determinants of Smoking and Quitting in HIV-Infected Individuals SO PLOS ONE LA English DT Article ID CORONARY-HEART-DISEASE; IMMUNODEFICIENCY-VIRUS-INFECTION; MYOCARDIAL-INFARCTION RATES; RISK-FACTORS; ANTIRETROVIRAL THERAPY; GENERAL-POPULATION; CIGARETTE-SMOKING; MENTAL-ILLNESS; TOBACCO USE; CESSATION AB Background Cigarette smoking is widespread among HIV-infected patients, who confront increased risk of smoking-related co-morbidities. The effects of HIV infection and HIV-related variables on smoking and smoking cessation are incompletely understood. We investigated the correlates of smoking and quitting in an HIV-infected cohort using a validated natural language processor to determine smoking status. Method We developed and validated an algorithm using natural language processing (NLP) to ascertain smoking status from electronic health record data. The algorithm was applied to records for a cohort of 3487 HIV-infected from a large health care system in Boston, USA, and 9446 uninfected control patients matched 3: 1 on age, gender, race and clinical encounters. NLP was used to identify and classify smoking-related portions of free-text notes. These classifications were combined into patient-year smoking status and used to classify patients as ever versus never smokers and current smokers versus non-smokers. Generalized linear models were used to assess associations of HIV with 3 outcomes, ever smoking, current smoking, and current smoking in analyses limited to ever smokers (persistent smoking), while adjusting for demographics, cardiovascular risk factors, and psychiatric illness. Analyses were repeated within the HIV cohort, with the addition of CD4 cell count and HIV viral load to assess associations of these HIV-related factors with the smoking outcomes. Results Using the natural language processing algorithm to assign annual smoking status yielded sensitivity of 92.4, specificity of 86.2, and AUC of 0.89 (95% confidence interval [CI] 0.88-0.91). Ever and current smoking were more common in HIV-infected patients than controls (54% vs. 44% and 42% vs. 30%, respectively, both P< 0.001). In multivariate models HIV was independently associated with ever smoking (adjusted rate ratio [ARR] 1.18, 95% CI 1.13-1.24, P < 0.001), current smoking (ARR 1.33, 95% CI 1.25-1.40, P< 0.001), and persistent smoking (ARR 1.11, 95% CI 1.07-1.15, P< 0.001). Within the HIV cohort, having a detectable HIV RNA was significantly associated with all three smoking outcomes. Conclusions HIV was independently associated with both smoking and not quitting smoking, using a novel algorithm to ascertain smoking status from electronic health record data and accounting for multiple confounding clinical factors. Further research is needed to identify HIV-related barriers to smoking cessation and develop aggressive interventions specific to HIV-infected patients. C1 [Regan, Susan; Meigs, James B.; Triant, Virginia A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Regan, Susan; Meigs, James B.; Grinspoon, Steven K.; Triant, Virginia A.] Harvard Univ, Sch Med, Boston, MA USA. [Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Triant, Virginia A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Regan, S (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.; Regan, S (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM sregan@partners.org FU American Heart Association [10CRP2790003]; National Institutes of Health [K24 DK080140, K24 DK064545, K01 AI073109] FX This work was funded in part by American Heart Association 10CRP2790003 (VAT) and National Institutes of Health K24 DK080140 (JBM), K24 DK064545 (SKG), and K01 AI073109 (VAT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 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 APR 21 PY 2016 VL 11 IS 4 AR e0153103 DI 10.1371/journal.pone.0153103 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK4OR UT WOS:000374898500025 PM 27099932 ER PT J AU Boulias, K Lieberman, J Greer, EL AF Boulias, Konstantinos Lieberman, Judy Greer, Eric Lieberman TI An Epigenetic Clock Measures Accelerated Aging in Treated HIV Infection SO MOLECULAR CELL LA English DT Editorial Material ID AGE AB In this issue of Molecular Cell, Gross et al. (2016) find a CpG DNA methylation signature in blood cells of patients with chronic well-controlled HIV infection that correlates with accelerated aging. C1 [Boulias, Konstantinos; Greer, Eric Lieberman] Boston Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA. [Lieberman, Judy] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Lieberman, Judy; Greer, Eric Lieberman] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Greer, EL (reprint author), Boston Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA.; Greer, EL (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. EM eric.greer@childrens.harvard.edu FU NIA NIH HHS [R00 AG043550] NR 11 TC 0 Z9 0 U1 1 U2 5 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 APR 21 PY 2016 VL 62 IS 2 BP 153 EP 155 DI 10.1016/j.molcel.2016.04.008 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DK1AI UT WOS:000374643900001 PM 27105110 ER PT J AU Misra, M Sagar, P Friedmann, AM Ryan, DP Sgroi, DC AF Misra, Madhusmita Sagar, Pallavi Friedmann, Alison M. Ryan, Daniel P. Sgroi, Dennis C. TI Case 12-2016: An 8-Year-Old Boy with an Enlarging Mass in the Right Breast SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SECRETORY CARCINOMA; PREPUBERTAL GYNECOMASTIA; AROMATASE GENE; CANCER; EXCESS; HYBRIDIZATION; METASTASIS; FUSION; ADULTS; GAIN C1 [Misra, Madhusmita; Friedmann, Alison M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Sagar, Pallavi] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ryan, Daniel P.] Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA 02114 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Misra, Madhusmita; Friedmann, Alison M.] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. [Sagar, Pallavi] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Ryan, Daniel P.] Harvard Univ, Sch Med, Dept Pediat Surg, Cambridge, MA 02138 USA. [Sgroi, Dennis C.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA.; Misra, M (reprint author), Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. FU Genentech FX Dr. Misra reports receiving grant support to her institution from Genentech. No other potential conflict of interest relevant to this article was reported. NR 32 TC 0 Z9 0 U1 2 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 APR 21 PY 2016 VL 374 IS 16 BP 1565 EP 1574 DI 10.1056/NEJMcpc1503831 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DJ7IA UT WOS:000374383900012 PM 27096583 ER PT J AU Itkin, T Gur-Cohen, S Spencer, JA Schajnovitz, A Ramasamy, SK Kusumbe, AP Ledergor, G Jung, Y Milo, I Poulos, MG Kalinkovich, A Ludin, A Kollet, O Shakhar, G Butler, JM Rafii, S Adams, RH Scadden, DT Lin, CP Lapidot, T AF Itkin, Tomer Gur-Cohen, Shiri Spencer, Joel A. Schajnovitz, Amir Ramasamy, Saravana K. Kusumbe, Anjali P. Ledergor, Guy Jung, Yookyung Milo, Idan Poulos, Michael G. Kalinkovich, Alexander Ludin, Aya Kollet, Orit Shakhar, Guy Butler, Jason M. Rafii, Shahin Adams, Ralf H. Scadden, David T. Lin, Charles P. Lapidot, Tsvee TI Distinct bone marrow blood vessels differentially regulate haematopoiesis SO NATURE LA English DT Article ID STEM-CELL QUIESCENCE; PROGENITOR CELLS; RAPID MOBILIZATION; ENDOTHELIAL-CELLS; SDF-1 RELEASE; STROMAL CELLS; NICHE; MEGAKARYOCYTES; ENGRAFTMENT; INTEGRITY AB Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols. C1 [Itkin, Tomer; Gur-Cohen, Shiri; Ledergor, Guy; Milo, Idan; Kalinkovich, Alexander; Ludin, Aya; Kollet, Orit; Shakhar, Guy; Lapidot, Tsvee] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Spencer, Joel A.; Jung, Yookyung; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Spencer, Joel A.; Jung, Yookyung; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Schajnovitz, Amir; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Schajnovitz, Amir; Scadden, David T.] Harvard Stem Cell Inst, Boston, MA 02114 USA. [Schajnovitz, Amir; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Schajnovitz, Amir; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ramasamy, Saravana K.; Kusumbe, Anjali P.; Adams, Ralf H.] Univ Munster, Dept Tissue Morphogenesis, Max Planck Inst Mol Biomed, D-48149 Munster, Germany. [Ramasamy, Saravana K.; Kusumbe, Anjali P.; Adams, Ralf H.] Univ Munster, Fac Med, D-48149 Munster, Germany. [Ledergor, Guy] Tel Aviv Sourasky Med Ctr, Dept Internal Med, IL-64239 Tel Aviv, Israel. [Poulos, Michael G.; Butler, Jason M.; Rafii, Shahin] Weill Cornell Med Coll, Dept Med Genet, New York, NY 10065 USA. RP Lapidot, T (reprint author), Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel.; Lin, CP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA.; Lin, CP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM charles_lin@hms.harvard.edu; tsvee.lapidot@weizmann.ac.il FU Ministry of Science, Technology Space, Israel; DKFZ, Germany; Israel Science Foundation [851/13]; Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; EU [261387]; European Research Council [339409]; NIH [EB017274, HL100402] FX We thank G. Karsenty and M. A. Lichtman for fruitful discussions and for critically reviewing the manuscript. We thank S. Mendez-Ferrer and M. Argueta Hernandez for assistance in studies involving MSPCs and nervous system elements. We thank Z. Porat for technical assistance with ImageStream analysis and R. Rotkopf for assistance with statistical data analysis. This study was partially supported by the Ministry of Science, Technology & Space, Israel and the DKFZ, Germany, grants from the Israel Science Foundation (851/13), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine and EU FP7-HEALTH-2010 (CELL-PID #261387) (T.L.). Confocal studies were supported by the European Research Council Advanced Grant 339409, 'AngioBone' (R.H.A.). Intravital multiphoton studies were supported by NIH grants EB017274 and HL100402 (C.P.L. & D.T.S.). NR 50 TC 33 Z9 33 U1 16 U2 32 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 APR 21 PY 2016 VL 532 IS 7599 BP 323 EP + DI 10.1038/nature17624 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7WU UT WOS:000374424700024 PM 27074509 ER PT J AU Hoesl, M Deepak, S Moteabbed, M Jassens, G Orban, J Park, YK Parodi, K Bentefour, EH Lu, HM AF Hoesl, M. Deepak, S. Moteabbed, M. Jassens, G. Orban, J. Park, Y. K. Parodi, K. Bentefour, E. H. Lu, H. M. TI Clinical commissioning of an in vivo range verification system for prostate cancer treatment with anterior and anterior oblique proton beams SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton therapy; in vivo range verification; prostate cancer ID THERAPY; RADIOTHERAPY; RADIATION; TISSUE AB The purpose of this work is the clinical commissioning of a recently developed in vivo range verification system (IRVS) for treatment of prostate cancer by anterior and anterior oblique proton beams. The IRVS is designed to perform a complete workflow for pre-treatment range verification and adjustment. It contains specifically designed dosimetry and electronic hardware and a specific software for workflow control with database connection to the treatment and imaging systems. An essential part of the IRVS system is an array of Si-diode detectors, designed to be mounted to the endorectal water balloon routinely used for prostate immobilization. The diodes can measure dose rate as function of time from which the water equivalent path length (WEPL) and the dose received are extracted. The former is used for pre-treatment beam range verification and correction, if necessary, while the latter is to monitor the dose delivered to patient rectum during the treatment and serves as an additional verification. The entire IRVS workflow was tested for anterior and 30 degree inclined proton beam in both solid water and anthropomorphic pelvic phantoms, with the measured WEPL and rectal doses compared to the treatment plan. Gafchromic films were also used for measurement of the rectal dose and compared to IRVS results. The WEPL measurement accuracy was in the order of 1 mm and after beam range correction, the dose received by the rectal wall were 1.6% and 0.4% from treatment planning, respectively, for the anterior and anterior oblique field. We believe the implementation of IRVS would make the treatment of prostate with anterior proton beams more accurate and reliable. C1 [Hoesl, M.; Moteabbed, M.; Park, Y. K.; Lu, H. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Hoesl, M.; Parodi, K.] Univ Munich, Fac Phys, Munich, Germany. [Deepak, S.; Jassens, G.; Orban, J.] Catholic Univ Louvain, ICTEAM Inst, Louvain La Neuve, Belgium. [Bentefour, E. H.] Ion Beam Applicat Inc, Louvain La Neuve, Belgium. RP Lu, HM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. EM hmlu@mgh.harvard.edu RI Samuel, Deepak/B-6482-2017; OI Samuel, Deepak/0000-0002-4560-5957; Janssens, Guillaume/0000-0001-9553-6024 FU PROSA LMU foundation FX Financial support was provided from the PROSA LMU foundation. NR 20 TC 2 Z9 2 U1 0 U2 1 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 APR 21 PY 2016 VL 61 IS 8 BP 3049 EP 3062 DI 10.1088/0031-9155/61/8/3049 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DJ2EU UT WOS:000374017300007 PM 27002470 ER PT J AU Xia, D Kelleher, RJ Shen, J AF Xia, Dan Kelleher, Raymond J., III Shen, Jie TI Loss of A beta 43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain SO NEURON LA English DT Article ID GAMMA-SECRETASE ACTIVITY; FAMILIAL ALZHEIMERS-DISEASE; TRANSGENIC MICE; SYNAPTIC PLASTICITY; NEURONAL LOSS; PROTEIN; INACTIVATION; MEMORY; NEURODEGENERATION; AMYLOIDOGENICITY AB We recently reported that homozygous Presenilin-1 (Psen1) knockin (KI) mice carrying the familial Alzheimer's disease (FAD) mutation L435F or C410Y recapitulate the phenotypes of Psen1(-/-) mice. Production and steady-state levels of A beta 40 and A beta 42 are undetectable in KI/KI brains and reduced in KI/+ brains, though the A beta 42/A beta 40 ratio is slightly increased in KI/+ brains. Moreover, the FAD mutation impairs synaptic function, learning and memory, and age-dependent neuronal survival in the adult brain. Here we extend our analysis of the effects of the L435F and C410Y mutations to the generation of A beta 43. Similar to A beta 40 and A beta 42, production of A beta 43 is undetectable in KI/KI brains and reduced in KI/+ brains. These results support our previous conclusions that the L435F and C410Y mutations cause loss of Presenilin function and gamma-secretase activity, including impaired A beta production in the brain. This Matters Arising Response paper addresses the Veugelen et al. (2016) Matters Arising paper, published concurrently in Neuron. C1 [Xia, Dan; Shen, Jie] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Xia, Dan; Kelleher, Raymond J., III] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Ctr Human Genet Res, Boston, MA 02115 USA. [Kelleher, Raymond J., III; Shen, Jie] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Shen, J (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA.; Kelleher, RJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Ctr Human Genet Res, Boston, MA 02115 USA.; Kelleher, RJ; Shen, J (reprint author), Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. EM kelleher@helix.mgh.harvard.edu; jshen@rics.bwh.harvard.edu FU National Institutes of Health [R01NS041783, R01NS042818, R01NS075346]; MetLife Foundation FX We would like to thank our lab members for helpful discussions. This work was supported by grants from the National Institutes of Health (R01NS041783 and R01NS042818 to J.S., and R01NS075346 to R.J.K.) and an award from the MetLife Foundation (to J.S.). NR 32 TC 3 Z9 3 U1 3 U2 6 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 APR 20 PY 2016 VL 90 IS 2 BP 417 EP 422 DI 10.1016/j.neuron.2016.03.009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DJ8ZV UT WOS:000374504400021 PM 27100200 ER PT J AU Chen, L An, HZ Haghgooie, R Shank, AT Martel, JM Toner, M Doyle, PS AF Chen, Lynna An, Harry Z. Haghgooie, Ramin Shank, Aaron T. Martel, Joseph M. Toner, Mehmet Doyle, Patrick S. TI Flexible Octopus-Shaped Hydrogel Particles for Specific Cell Capture SO SMALL LA English DT Article DE cell capture; circulating tumor cells; hydrogels; microfluidics; microparticles ID CIRCULATING TUMOR-CELLS; STOP-FLOW LITHOGRAPHY; DRUG-DELIVERY; NONSPHERICAL BIOPARTICLES; MICROFLUIDIC DEVICE; MICROPARTICLES; BLOOD; NANOPARTICLES; SEPARATION; MICROGELS C1 [Chen, Lynna] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [An, Harry Z.; Doyle, Patrick S.] MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Haghgooie, Ramin] Gen Fluid, 34 Anderson St,Ste 5, Boston, MA 02114 USA. [Shank, Aaron T.; Martel, Joseph M.; Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Bldg 114,16th St, Charlestown, MA 02129 USA. RP Doyle, PS (reprint author), MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM pdoyle@mit.edu OI Chen, Lynna/0000-0002-2505-3657 FU MRSEC Program of the National Science Foundation [DMR-1419807]; National Science Foundation [CMMI-1120724]; Institute for Collaborative Biotechnologies through U.S. Army Research Office [W911NF-09-0001]; US National Institutes of Health (NIH) P41 Resource Center; NIH National Institute of Biomedical Imaging and Bioengineering Quantum Grant; Natural Sciences and Engineering Research Council (NSERC) of Canada FX L.C. and H.Z.A. contributed equally to this work. This work was supported in part by the MRSEC Program of the National Science Foundation under award number DMR-1419807, the National Science Foundation CMMI-1120724, and Institute for Collaborative Biotechnologies through grant W911NF-09-0001 from the U.S. Army Research Office. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. Additional support was provided by the US National Institutes of Health (NIH) P41 Resource Center and an NIH National Institute of Biomedical Imaging and Bioengineering Quantum Grant. The authors thank Octavio Hurtado for help with device microfabrication, and Aimal H. Khankhel for help with cell culture. L.C. was supported in part by a postgraduate scholarship from Natural Sciences and Engineering Research Council (NSERC) of Canada. NR 61 TC 2 Z9 2 U1 28 U2 63 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD APR 20 PY 2016 VL 12 IS 15 BP 2001 EP 2008 DI 10.1002/smll.201600163 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DJ6PE UT WOS:000374334600003 PM 26929053 ER PT J AU Wirth, LJ AF Wirth, Lori J. TI Cetuximab in Human Papillomavirus-Positive Oropharynx Carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; PLATINUM-BASED CHEMOTHERAPY; NECK-CANCER; PLUS CETUXIMAB; OPEN-LABEL; HEAD; RECURRENT; HPV; TRIAL C1 [Wirth, Lori J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wirth, LJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 18 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 APR 20 PY 2016 VL 34 IS 12 BP 1289 EP + DI 10.1200/JCO.2015.65.1414 PG 4 WC Oncology SC Oncology GA DJ6PJ UT WOS:000374335100004 PM 26884569 ER PT J AU DuBois, SG Marachelian, A Fox, E Kudgus, RA Reid, JM Groshen, S Malvar, J Bagatell, R Wagner, L Maris, JM Hawkins, R Courtier, J Lai, H Goodarzian, F Shimada, H Czarnecki, S Tsao-Wei, D Matthay, KK Mosse, YP AF DuBois, Steven G. Marachelian, Araz Fox, Elizabeth Kudgus, Rachel A. Reid, Joel M. Groshen, Susan Malvar, Jemily Bagatell, Rochelle Wagner, Lars Maris, John M. Hawkins, Randall Courtier, Jesse Lai, Hollie Goodarzian, Fariba Shimada, Hiroyuki Czarnecki, Scarlett Tsao-Wei, Denice Matthay, Katherine K. Mosse, Yael P. TI Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHILDRENS ONCOLOGY GROUP; ADVANCED SOLID TUMORS; SELECTIVE AURORA; N-MYC; MLN8237; CONSORTIUM; SCHEDULES AB Purpose Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m(2), with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion Alisertib 60 mg/m(2) per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing. (C) 2016 by American Society of Clinical Oncology C1 [DuBois, Steven G.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [DuBois, Steven G.] Harvard Univ, Sch Med, Boston, MA USA. [Marachelian, Araz; Groshen, Susan; Malvar, Jemily; Lai, Hollie; Goodarzian, Fariba; Shimada, Hiroyuki; Czarnecki, Scarlett; Tsao-Wei, Denice] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Marachelian, Araz; Groshen, Susan; Malvar, Jemily; Lai, Hollie; Goodarzian, Fariba; Shimada, Hiroyuki; Czarnecki, Scarlett; Tsao-Wei, Denice] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Hawkins, Randall; Courtier, Jesse; Matthay, Katherine K.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Hawkins, Randall; Courtier, Jesse; Matthay, Katherine K.] Benioff Childrens Hosp, San Francisco, CA USA. [Fox, Elizabeth; Bagatell, Rochelle; Maris, John M.; Mosse, Yael P.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Fox, Elizabeth; Bagatell, Rochelle; Maris, John M.; Mosse, Yael P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kudgus, Rachel A.; Reid, Joel M.] Mayo Clin, Rochester, MN USA. [Wagner, Lars] Univ Kentucky, Coll Med, Lexington, KY USA. RP DuBois, SG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 3, Boston, MA 02215 USA. EM steven_dubois@dfci.harvard.edu FU National Cancer Institute [P01 81403]; Millennium Pharmaceuticals; [NIH/NCRR UCSF-CTSI UL1 RR024131] FX Supported by Grant No. P01 81403 from the National Cancer Institute; Grant No. NIH/NCRR UCSF-CTSI UL1 RR024131; and by Millennium Pharmaceuticals. NR 32 TC 8 Z9 8 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 APR 20 PY 2016 VL 34 IS 12 BP 1368 EP + DI 10.1200/JCO.2015.65.4889 PG 10 WC Oncology SC Oncology GA DJ6PJ UT WOS:000374335100017 PM 26884555 ER PT J AU Scher, HI Morris, MJ Stadler, WM Higano, C Basch, E Fizazi, K Antonarakis, ES Beer, TM Carducci, MA Chi, KN Corn, PG de Bono, JS Dreicer, R George, DJ Heath, EI Hussain, M Kelly, WK Liu, G Logothetis, C Nanus, D Stein, MN Rathkopf, DE Slovin, SF Ryan, CJ Sartor, O Small, EJ Smith, MR Sternberg, CN Taplin, ME Wilding, G Nelson, PS Schwartz, LH Halabi, S Kantoff, PW Armstrong, AJ AF Scher, Howard I. Morris, Michael J. Stadler, Walter M. Higano, Celestia Basch, Ethan Fizazi, Karim Antonarakis, Emmanuel S. Beer, Tomasz M. Carducci, Michael A. Chi, Kim N. Corn, Paul G. de Bono, Johann S. Dreicer, Robert George, Daniel J. Heath, Elisabeth I. Hussain, Maha Kelly, Wm. Kevin Liu, Glenn Logothetis, Christopher Nanus, David Stein, Mark N. Rathkopf, Dana E. Slovin, Susan F. Ryan, Charles J. Sartor, Oliver Small, Eric J. Smith, Matthew Raymond Sternberg, Cora N. Taplin, Mary-Ellen Wilding, George Nelson, Peter S. Schwartz, Lawrence H. Halabi, Susan Kantoff, Philip W. Armstrong, Andrew J. TI Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CIRCULATING TUMOR-CELLS; PROGRESSION-FREE SURVIVAL; PLACEBO-CONTROLLED TRIAL; BONE-SCAN INDEX; PROGNOSTIC MODEL; PLUS PREDNISONE; NATURAL-HISTORY; END-POINTS; PHASE-III; MEN AB Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval. (C) 2016 by American Society of Clinical Oncology C1 [Scher, Howard I.; Morris, Michael J.; Rathkopf, Dana E.; Slovin, Susan F.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Scher, Howard I.; Morris, Michael J.; Rathkopf, Dana E.; Slovin, Susan F.] Weill Cornell Med Coll, New York, NY USA. [Nanus, David] NewYork Presbyterian Weill Cornell Med, New York, NY USA. [Schwartz, Lawrence H.] NewYork Presbyterian Columbia Univ Med Ctr, New York, NY USA. [Stadler, Walter M.] Univ Chicago Med, Chicago, IL USA. [Higano, Celestia; Nelson, Peter S.] Univ Washington, Seattle, WA 98195 USA. [Higano, Celestia; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. [Antonarakis, Emmanuel S.; Carducci, Michael A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Corn, Paul G.; Logothetis, Christopher] Univ Texas Houston, MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Dreicer, Robert] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [George, Daniel J.; Halabi, Susan; Armstrong, Andrew J.] Duke Univ, Durham, NC USA. [George, Daniel J.; Halabi, Susan; Armstrong, Andrew J.] Duke Canc Inst, Durham, NC USA. [Heath, Elisabeth I.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Hussain, Maha] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kelly, Wm. Kevin] Thomas Jefferson Univ, Sidney Kimmel Sch Med, Philadelphia, PA 19107 USA. [Liu, Glenn; Wilding, George] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Stein, Mark N.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Sartor, Oliver] Tulane Sch Med, New Orleans, LA USA. [Smith, Matthew Raymond] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Smith, Matthew Raymond; Taplin, Mary-Ellen; Kantoff, Philip W.] Harvard Univ, Sch Med, Boston, MA USA. [Taplin, Mary-Ellen; Kantoff, Philip W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fizazi, Karim] Univ Paris 11, Inst Gustave Roussy, Villejuif, France. [Chi, Kim N.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [de Bono, Johann S.] Royal Canc Hosp, London, England. [Sternberg, Cora N.] San Camillo Hosp, Rome, Italy. [Sternberg, Cora N.] Forlanini Hosp, Rome, Italy. RP Scher, HI (reprint author), Mem Sloan Kettering Canc Ctr, Genitourinary Oncol Serv, Dept Med, Sidney Kimmel Ctr Prostate & Urol Canc, 1275 York Ave, New York, NY 10065 USA. EM scherh@mskcc.org OI Morris, Michael J./0000-0002-9454-0096 FU National Cancer Institute (NCI) SPORE in Prostate Cancer [P50-CA92629]; NCI Cancer Center Support [P30 CA008748]; Department of Defense Prostate Cancer Research Program [PC071610]; Prostate Cancer Foundation; Sidney Kimmel Center for Prostate and Urologic Cancers; US Department of Defense and the Prostate Cancer Foundation FX Supported by National Cancer Institute (NCI) Grant No. P50-CA92629 SPORE in Prostate Cancer, NCI Cancer Center Support Grant No. P30 CA008748, the Department of Defense Prostate Cancer Research Program (PC071610), the Prostate Cancer Foundation, the Sidney Kimmel Center for Prostate and Urologic Cancers, and funds provided by David H. Koch through the Prostate Cancer Foundation. We thank the following institutions and individuals for their input into these recommendations: the US Food and Drug Administration, the Prostate Cancer Clinical Trials Consortium (which is supported by the US Department of Defense and the Prostate Cancer Foundation), and other international investigators in prostate cancer drug and biomarker development. NR 68 TC 32 Z9 32 U1 4 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 APR 20 PY 2016 VL 34 IS 12 BP 1402 EP + DI 10.1200/JCO.2015.64.2702 PG 25 WC Oncology SC Oncology GA DJ6PJ UT WOS:000374335100021 PM 26903579 ER PT J AU Olszewski, AJ Falah, J Castillo, JJ AF Olszewski, Adam J. Falah, Jaleh Castillo, Jorge J. TI Survival Claims From Observational Data on Cancer Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID B-CELL LYMPHOMA; TREATMENT SELECTION; RADIOTHERAPY; OUTCOMES C1 [Olszewski, Adam J.; Falah, Jaleh] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Olszewski, Adam J.; Falah, Jaleh] Brown Univ, Mem Hosp Rhode Isl, Pawtucket, RI 02860 USA. [Castillo, Jorge J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RP Olszewski, AJ (reprint author), Brown Univ, Alpert Med Sch, Providence, RI 02912 USA.; Olszewski, AJ (reprint author), Brown Univ, Mem Hosp Rhode Isl, Pawtucket, RI 02860 USA. OI Castillo, Jorge/0000-0001-9490-7532 NR 10 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 20 PY 2016 VL 34 IS 12 BP 1425 EP + DI 10.1200/JCO.2015.64.7644 PG 4 WC Oncology SC Oncology GA DJ6PJ UT WOS:000374335100027 PM 26884574 ER PT J AU Romano, O Peano, C Tagliazucchi, GM Petiti, L Poletti, V Cocchiarella, F Rizzi, E Severgnini, M Cavazza, A Rossi, C Pagliaro, P Ambrosi, A Ferrari, G Bicciato, S De Bellis, G Mavilio, F Miccio, A AF Romano, Oriana Peano, Clelia Tagliazucchi, Guidantonio Malagoli Petiti, Luca Poletti, Valentina Cocchiarella, Fabienne Rizzi, Ermanno Severgnini, Marco Cavazza, Alessia Rossi, Claudia Pagliaro, Pasqualepaolo Ambrosi, Alessandro Ferrari, Giuliana Bicciato, Silvio De Bellis, Gianluca Mavilio, Fulvio Miccio, Annarita TI Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment SO SCIENTIFIC REPORTS LA English DT Article ID LEUKEMIA-VIRUS INTEGRATION; EMBRYONIC STEM-CELLS; CHROMATIN STATE DYNAMICS; GENE-EXPRESSION PROGRAMS; SUPER-ENHANCERS; HUMAN GENOME; PROMOTER ARCHITECTURE; FETAL-HEMOGLOBIN; ACTIVE ENHANCERS; MAMMALIAN-CELLS AB Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE), ChIP-seq and Moloney leukemia virus (MLV) integration site mapping. Most promoters and transcripts were shared by HSPC and committed progenitors, while enhancers and super-enhancers consistently changed upon differentiation, indicating that lineage commitment is essentially regulated by enhancer elements. A significant fraction of CAGE promoters differentially expressed upon commitment were novel, harbored a chromatin enhancer signature, and may identify promoters and transcribed enhancers driving cell commitment. MLV-targeted genomic regions co-mapped with cell-specific active enhancers and super-enhancers. Expression analyses, together with an enhancer functional assay, indicate that MLV integration can be used to identify bona fide developmentally regulated enhancers. Overall, this study provides an overview of transcriptional and epigenetic changes associated to HSPC lineage commitment, and a novel signature for regulatory elements involved in cell identity. C1 [Romano, Oriana; Cocchiarella, Fabienne; Mavilio, Fulvio; Miccio, Annarita] Univ Modena & Reggio Emilia, Dept Life Sci, Modena, Italy. [Romano, Oriana; Tagliazucchi, Guidantonio Malagoli; Bicciato, Silvio] Univ Modena & Reggio Emilia, Ctr Genom Res, Modena, Italy. [Romano, Oriana; Miccio, Annarita] INSERM, UMR 1163, Lab Chromatin & Gene Regulat Dev, Paris, France. [Peano, Clelia; Petiti, Luca; Rizzi, Ermanno; Severgnini, Marco; De Bellis, Gianluca] CNR, Inst Biomed Technol, I-20133 Milan, Italy. [Poletti, Valentina; Mavilio, Fulvio] Genethon, Evry, France. [Rizzi, Ermanno] Telethon Fdn, Milan, Italy. [Cavazza, Alessia] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Rossi, Claudia; Ferrari, Giuliana] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy TIGET, I-20132 Milan, Italy. [Pagliaro, Pasqualepaolo] Az Osp Policlin Univ Bologna, Policlin S Orsola Malpighi, Unita Operat Immunoematol & Trasfus, Bologna, Italy. [Ambrosi, Alessandro; Ferrari, Giuliana] Univ Vita Salute San Raffaele, Milan, Italy. [Miccio, Annarita] Paris Descartes, Sorbonne Paris Cite Univ, Imagine Inst, Paris, France. RP Miccio, A (reprint author), Univ Modena & Reggio Emilia, Dept Life Sci, Modena, Italy.; Miccio, A (reprint author), INSERM, UMR 1163, Lab Chromatin & Gene Regulat Dev, Paris, France.; Miccio, A (reprint author), Paris Descartes, Sorbonne Paris Cite Univ, Imagine Inst, Paris, France. EM annarita.miccio@institutimagine.org RI ambrosi, alessandro/H-4424-2011; OI ambrosi, alessandro/0000-0003-1976-5663; Severgnini, Marco/0000-0001-8655-1206; rizzi, ermanno/0000-0002-9898-2326 FU European Research Council (ERC-AdG); Telethon Foundation (TIGET Core Grant); Italian Ministry of Education, Universities and Research [2010-RBFR10OS4G, 2012-RBFR126B8I_003] FX We thank Maria Carmela Latella and Francesco Gandolfi for technical assistance. This work was supported by grants from the European Research Council (ERC-2010-AdG, GT-SKIN), the Telethon Foundation (TIGET Core Grant) and the Italian Ministry of Education, Universities and Research (FIRB-Futuro in Ricerca 2010-RBFR10OS4G, FIRB-Futuro in Ricerca 2012-RBFR126B8I_003 and EPIGEN Epigenomics Flagship Project). NR 68 TC 0 Z9 0 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 20 PY 2016 VL 6 AR 24724 DI 10.1038/srep24724 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7HA UT WOS:000374381300001 PM 27095295 ER PT J AU Long, YM Zhao, XC Clermont, AC Zhou, QF Liu, Q Feener, EP Yan, B Jiang, GB AF Long, Yan-Min Zhao, Xing-Chen Clermont, Allen C. Zhou, Qun-Fang Liu, Qian Feener, Edward P. Yan, Bing Jiang, Gui-Bin TI Negatively charged silver nanoparticles cause retinal vascular permeability by activating plasma contact system and disrupting adherens junction SO NANOTOXICOLOGY LA English DT Article DE Cell junction; kallikrein-kinin system; retinal endothelial cell; silver NP; vascular permeability ID LIPID-BILAYER DISRUPTION; HEREDITARY ANGIOEDEMA; DIABETIC-RETINOPATHY; ENDOTHELIAL-CELLS; MOLECULAR-BASIS; MACULAR EDEMA; VE-CADHERIN; FACTOR-XII; IN-VIVO; KALLIKREIN AB Silver nanoparticles (AgNPs) have been extensively used as antibacterial component in numerous healthcare, biomedical and consumer products. Therefore, their adverse effects to biological systems have become a major concern. AgNPs have been shown to be absorbed into circulation and redistributed into various organs. It is thus of great importance to understand how these nanoparticles affect vascular permeability and uncover the underlying molecular mechanisms. A negatively charged mecaptoundeonic acid-capped silver nanoparticle (MUA@AgNP) was investigated in this work. Ex vivo experiments in mouse plasma revealed that MUA@AgNPs caused plasma prekallikrein cleavage, while positively charged or neutral AgNPs, as well as Ag ions had no effect. In vitro tests revealed that MUA@AgNPs activated the plasma kallikrein-kinin system (KKS) by triggering Hageman factor autoactivation. By using specific inhibitors aprotinin and HOE 140, we demonstrated that KKS activation caused the release of bradykinin, which activated B2 receptors and induced the shedding of adherens junction protein, VE-cadherin. These biological perturbations eventually resulted in endothelial paracellular permeability in mouse retina after intravitreal injection of MUA@AgNPs. The findings from this work provided key insights for toxicity modulation and biomedical applications of AgNPs. C1 [Long, Yan-Min; Zhao, Xing-Chen; Zhou, Qun-Fang; Liu, Qian; Jiang, Gui-Bin] Chinese Acad Sci, Ecoenvironm Sci Res Ctr, State Key Lab Environm Chem & Ecotoxicol, POB 934, Beijing, Peoples R China. [Long, Yan-Min] Jianghan Univ, Inst Environm & Hlth, Wuhan, Peoples R China. [Clermont, Allen C.; Feener, Edward P.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Yan, Bing] Shandong Univ, Sch Chem & Chem Engn, Jinan 250100, Peoples R China. RP Zhou, QF; Jiang, GB (reprint author), Chinese Acad Sci, Ecoenvironm Sci Res Ctr, State Key Lab Environm Chem & Ecotoxicol, POB 934, Beijing, Peoples R China. EM zhouqf@rcees.ac.cn; gbjiang@rcee-s.ac.cn RI Liu, Qian/K-6759-2012 OI Liu, Qian/0000-0001-8525-7961 FU National Basic Research Program of China [2011CB936001]; National Natural Science Foundation of China [21137002, 21477153, 21307151]; China Postdoctoral Science Foundation [2013M541055] FX This study was jointly supported by the National Basic Research Program of China (2011CB936001), National Natural Science Foundation of China (21137002, 21477153, 21307151) and the China Postdoctoral Science Foundation (2013M541055). The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. NR 58 TC 1 Z9 2 U1 9 U2 24 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PD APR 20 PY 2016 VL 10 IS 4 BP 501 EP 511 DI 10.3109/17435390.2015.1088589 PG 11 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA DG3TE UT WOS:000371992200012 PM 26399585 ER PT J AU Koppers-Lalic, D Hackenberg, M de Menezes, R Misovic, B Wachalska, M Geldof, A Zini, N de Reijke, T Wurdinger, T Vis, A van Moorselaar, J Pegtel, M Bijnsdorp, I AF Koppers-Lalic, Danijela Hackenberg, Michael de Menezes, Renee Misovic, Branislav Wachalska, Magda Geldof, Albert Zini, Nicoletta de Reijke, Theo Wurdinger, Thomas Vis, Andre van Moorselaar, Jeroen Pegtel, Michiel Bijnsdorp, Irene TI Non-invasive prostate cancer detection by measuring miRNA variants (isomiRs) in urine extracellular vesicles SO ONCOTARGET LA English DT Article DE liquid biopsy; isomiRs; miRNA; RNA sequencing; extracellular vesicles ID DIGITAL RECTAL EXAMINATION; TRANSFER-RNA; EXOSOMES; MICRORNAS; CELLS; ANTIGEN; BIOMARKERS; SEDIMENTS; PCA3; STABILIZATION AB In many cancer types, the expression and function of similar to 22 nucleotide-long microRNAs (miRNA) is deregulated. Mature miRNAs can be stably detected in extracellular vesicles (EVs) in biofluids, therefore they are considered to have great potential as biomarkers. In the present study, we investigated whether miRNAs have a distinct expression pattern in urine-EVs of prostate cancer (PCa) patients compared to control males. By next generation sequencing, we determined the miRNA expression in a discovery cohort of 4 control men and 9 PCa patients. miRNAs were validated by using a stemloop RT-PCR in an independent cohort of 74 patients (26 control and 48 PCa-patients). Whereas standard mapping protocols identified > 10 PCa associated miRNAs in urinary EVs, miR-21, miR-375 and miR-204 failed to robustly discriminate for disease in a validation study with RT-PCR-detection of mature miRNA sequences. In contrast, we observed that miRNA isoforms (isomiRs) with 3' end modifications were highly discriminatory between samples from control men and PCa patients. Highly differentially expressed isomiRs of miR-21, miR-204 and miR-375 were subsequently validated in an independent group of 74 patients. Receiver-operating characteristic analysis was performed to evaluate the diagnostic performance of three isomiRs, resulting in a 72.9% sensitivity with a high (88%) specificity and an area under the curve (AUC) of 0.866. In comparison, prostate specific antigen had an AUC of 0.707 and measuring the mature form of these miRNAs yielded a lower 70.8% sensitivity and 72% specificity (AUC 0.766). We propose that isomiRs may carry discriminatory information which is useful to generate stronger biomarkers. C1 [Koppers-Lalic, Danijela; Pegtel, Michiel] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Koppers-Lalic, Danijela; Wurdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Neurooncol Res Grp, Dept Neurosurg, Amsterdam, Netherlands. [Koppers-Lalic, Danijela] Exbiome BV, NL-1016 PL Amsterdam, Netherlands. [Hackenberg, Michael] Univ Granada, Dept Genet, Computat Genom & Bioinformat Grp, Granada, Spain. [de Menezes, Renee] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Misovic, Branislav] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Wachalska, Magda; Vis, Andre; van Moorselaar, Jeroen; Bijnsdorp, Irene] Vrije Univ Amsterdam, Med Ctr, Dept Urol, Amsterdam, Netherlands. [Geldof, Albert; Zini, Nicoletta] IGM, CNR, Natl Res Council Italy, Bologna, Italy. [Zini, Nicoletta] IOR IRCCS, SC Lab Musculoskeletal Cell Biol, Bologna, Italy. [de Reijke, Theo] Univ Amsterdam, Acad Med Ctr, Dept Urol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Wurdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Wurdinger, Thomas] Harvard Univ, Sch Med, Charlestown, MA USA. RP Koppers-Lalic, D (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands.; Koppers-Lalic, D (reprint author), Vrije Univ Amsterdam, Med Ctr, Neurooncol Res Grp, Dept Neurosurg, Amsterdam, Netherlands.; Koppers-Lalic, D (reprint author), Exbiome BV, NL-1016 PL Amsterdam, Netherlands.; Bijnsdorp, I (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Urol, Amsterdam, Netherlands. EM d.koppers@vumc.nl; iv.bijnsdorp@vumc.nl RI Hackenberg, Michael/A-2503-2009; OI Hackenberg, Michael/0000-0003-2248-3114; Intveld, Linda/0000-0003-0036-734X FU Stichting Urologie [1973]; VUmc-CCA; Worldwide Cancer Research (AICR) [15-1005]; [KWF-VU-5510] FX Stichting Urologie 1973 (RJvM, IB, TdR, DMP, DKL), VUmc-CCA (IB, RJvM, DMP, TW), KWF-VU-5510 (DMP), Worldwide Cancer Research (AICR #15-1005; IB). NR 46 TC 3 Z9 3 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 19 PY 2016 VL 7 IS 16 BP 22566 EP 22578 DI 10.18632/oncotarget.8124 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO3TY UT WOS:000377705900115 PM 26992225 ER PT J AU LaRochelle, JR Fodor, M Xu, X Durzynska, I Fan, L Status, T Chan, HM LaMarche, MJ Chopra, R Wang, P Fortin, PD Acker, MG Blacklow, SC AF LaRochelle, Jonathan R. Fodor, Michelle Xu, Xiang Durzynska, Izabela Fan, Lixin Status, Travis Chan, Ho Man LaMarche, Matthew J. Chopra, Rajiv Wang, Ping Fortin, Pascal D. Acker, Michael G. Blacklow, Stephen C. TI Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2 SO BIOCHEMISTRY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; X-RAY-SCATTERING; INSULIN-RECEPTOR SUBSTRATE-1; ACUTE MYELOID-LEUKEMIA; PTPN11 MUTATIONS; NOONAN-SYNDROME; MOUSE MODEL; SH-PTP2; DIFFERENTIATION; LEUKEMOGENESIS AB The proto-oncogene PTPN11 encodes a cytoplasmic protein tyrosine phosphatase, SHP2, which is required for normal development and sustained activation of the Ras-MAPK signaling pathway. Germline mutations in SHP2 cause developmental disorders, and somatic mutations have been identified in childhood and adult cancers and drive leukemia in mice. Despite our knowledge of the PTPN11 variations associated with pathology, the structural and functional consequences of many disease-associated mutants remain poorly understood. Here, we combine X-ray crystallography, small-angle X-ray scattering, and biochemistry to elucidate structural and mechanistic features of three cancer-associated SHP2 variants harboring single point mutations within the N-SH2:PTP interdomain autoinhibitory interface. Our findings directly compare the impact of each mutation on autoinhibition of the phosphatase and advance the development of structure-guided and mutation specific SHP2 therapies. C1 [LaRochelle, Jonathan R.; Xu, Xiang; Durzynska, Izabela; Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [LaRochelle, Jonathan R.; Xu, Xiang; Durzynska, Izabela; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Fodor, Michelle; Status, Travis; Chopra, Rajiv] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA 02139 USA. [Chan, Ho Man; Wang, Ping; Fortin, Pascal D.; Acker, Michael G.] Novartis Inst Biomed Res, Oncol, Cambridge, MA 02139 USA. [LaMarche, Matthew J.] Novartis Inst Biomed Res, Global Discovery Chem, Cambridge, MA 02139 USA. [Fan, Lixin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Bas Sci Program, Frederick, MD 21702 USA. RP Blacklow, SC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Blacklow, SC (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM stephen_blacklow@hms.harvard.edu FU Novartis-Dana Farber Cancer Institute Drug Development Program [250 GM10718A1]; William Lawrence-Blanche Hughes Foundation; American Cancer Society [128126] FX This work was funded in part by the Novartis-Dana Farber Cancer Institute Drug Development Program, 250 GM10718A1 (X.X. and S.C.B.), and by the William Lawrence-Blanche Hughes Foundation (to S.C.B.). M.F., T.S., H.M.C., M.J.L., RC., P.W., P.D.F., and M.G.A. are employees of Novartis. J.R.L. gratefully acknowledges postdoctoral fellowship funding from the American Cancer Society (Award 128126). NR 39 TC 0 Z9 1 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 19 PY 2016 VL 55 IS 15 BP 2269 EP 2277 DI 10.1021/acs.biochem.5b01287 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK1WX UT WOS:000374706900007 PM 27030275 ER PT J AU Platts-Mills, TF Nicholson, RJ Richmond, NL Patel, KV Simonsick, EM Domeier, RM Swor, RA Hendry, PL Peak, DA Rathlev, NK Jones, JS Lee, DC Weaver, MA Keefe, FJ McLean, SA AF Platts-Mills, Timothy F. Nicholson, Robert J. Richmond, Natalie L. Patel, Kushang V. Simonsick, Eleanor M. Domeier, Robert M. Swor, Robert A. Hendry, Phyllis L. Peak, David A. Rathlev, Niels K. Jones, Jeffrey S. Lee, David C. Weaver, Mark A. Keefe, Francis J. McLean, Samuel A. TI Restricted activity and persistent pain following motor vehicle collision among older adults: a multicenter prospective cohort study SO BMC GERIATRICS LA English DT Article DE Aged; Motor Activity; Emergency medicine; Pain; Geriatrics; Traffic accidents ID LOW-BACK-PAIN; EMERGENCY-DEPARTMENT PATIENTS; PHYSICAL-ACTIVITY SCALE; UNITED-STATES FINDINGS; 2011 NATIONAL-HEALTH; BED REST; COGNITIVE IMPAIRMENT; FUNCTIONAL DECLINE; 6-ITEM SCREENER; WHIPLASH INJURY AB Background: Restricted physical activity commonly occurs following acute musculoskeletal pain in older adults and may influence long-term outcomes. We sought to examine the relationship between restricted physical activity after motor vehicle collision (MVC) and the development of persistent pain. Methods: We examined data from a prospective study of adults >= 65 years of age presenting to the emergency department (ED) after MVC without life-threatening injuries. Restricted physical activity 6 weeks after MVC was defined in three different ways: 1) by a >= 25 point decrease in Physical Activity Scale in the Elderly (PASE) score, 2) by the answer "yes" to the question, "during the past two weeks, have you stayed in bed for at least half a day?", and 3) by the answer "yes" to the question, "during the past two weeks, have you cut down on your usual activities as compared to before the accident?" We examined relationships between each definition of restricted activity and pain severity, pain interference, and functional capacity at 6 months with adjustment for confounders. Results: Within the study sample (N = 164), adjusted average pain severity scores at 6 months did not differ between patients with and without restricted physical activity based on decreased PASE score (2.54 vs. 2.07, p = 0.32). In contrast, clinically and statistically important differences in adjusted average pain severity at 6 months were observed for patients who reported spending half a day in bed vs. those who did not (3.56 vs. 1.91, p < 0.01). In adjusted analyses, both decreased PASE score and cutting down on activity were associated with functional capacity at 6 months, but only decreased PASE score was associated with increased ADL difficulty at 6 months (0.70 vs. -0.01, p = 0.02). Conclusions: Among older adults experiencing MVC, those reporting bed rest or reduced activity 6 weeks after the collision reported higher pain and pain interference scores at 6 months. More research is needed to determine if interventions to promote activity can improve outcomes after MVC in older adults. C1 [Platts-Mills, Timothy F.; Nicholson, Robert J.; Richmond, Natalie L.] Univ N Carolina, Dept Emergency Med, 170 Manning Dr, Chapel Hill, NC USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, 1959 NE Pacific St, Seattle, WA 98195 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Domeier, Robert M.] St Joseph Mercy Hlth Syst, Dept Emergency Med, 5301 McAuley Dr, Ypsilanti, MI USA. [Swor, Robert A.] William Beaumont Hosp, Dept Emergency Med, 3601 W 13 Mile Rd, Royal Oak, MI 48072 USA. [Hendry, Phyllis L.] Univ Florida, Coll Med Jacksonville, Dept Emergency Med, 1515 SW Archer Rd, Gainesville, FL USA. [Peak, David A.] Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St, Boston, MA 02114 USA. [Rathlev, Niels K.] Baystate Med Ctr, Dept Emergency Med, 759 Chestnut St, Springfield, MA USA. [Jones, Jeffrey S.] Spectrum Hlth, Dept Emergency Med, Butterworth Campus,100 Michigan St NE, Grand Rapids, MI 49503 USA. [Lee, David C.] N Shore Univ Hosp, Dept Emergency Med, 300 Community Dr, Manhasset, NY USA. [Weaver, Mark A.] Univ N Carolina, Dept Med, 170 Manning Dr, Chapel Hill, NC USA. [Keefe, Francis J.] Duke Univ, Dept Psychiat, 17 Chapel Dr, Durham, NC 27706 USA. [McLean, Samuel A.] Univ N Carolina, Dept Anesthesiol, 170 Manning Dr, Chapel Hill, NC USA. RP Platts-Mills, TF (reprint author), Univ N Carolina, Dept Emergency Med, 170 Manning Dr, Chapel Hill, NC USA. EM tplattsm@med.unc.edu FU National Institute on Aging [K23AG038548] FX Dr. Platts-Mills is supported by grant K23AG038548 from the National Institute on Aging. The National Institute on Aging had no role in the design of the study, the collection, analysis, and interpretation of data, or the writing of the manuscript. NR 48 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2318 J9 BMC GERIATR JI BMC Geriatr. PD APR 19 PY 2016 VL 16 AR 86 DI 10.1186/s12877-016-0260-z PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK1KK UT WOS:000374670800003 PM 27094038 ER PT J AU Valdez, IA Dirice, E Gupta, MK Shirakawa, J Teo, AKK Kulkarni, RN AF Valdez, Ivan Achel Dirice, Ercument Gupta, Manoj K. Shirakawa, Jun Teo, Adrian Kee Keong Kulkarni, Rohit N. TI Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation SO CELL REPORTS LA English DT Article ID GAMMA TRANSGENIC MICE; IFN-GAMMA; ADULT PANCREAS; BETA-CELLS; INSULIN-RESISTANCE; PROGENITOR CELLS; IN-VITRO; PROLIFERATION; REGENERATION; NEOGENESIS AB A major goal of diabetes research is to develop strategies that replenish pancreatic insulin-producing beta cells. One emerging strategy is to harness pancreatic plasticity-the ability of pancreatic cells to undergo cellular interconversions-a phenomenon implicated in physiological stress and pancreatic injury. Here, we investigate the effects of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line, in mouse ductal cells by pancreatic intraductal injection, and during the progression of autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. Furthermore, we show that inflammatory cytokines activate ductal-to-endocrine cell reprogramming in vivo independent of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal-to-endocrine cell differentiation, with implications for beta cell regeneration. C1 [Valdez, Ivan Achel; Dirice, Ercument; Gupta, Manoj K.; Shirakawa, Jun; Teo, Adrian Kee Keong; Kulkarni, Rohit N.] Brigham & Womens Hosp, Harvard Stem Cell Inst, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. [Valdez, Ivan Achel; Dirice, Ercument; Gupta, Manoj K.; Shirakawa, Jun; Teo, Adrian Kee Keong; Kulkarni, Rohit N.] Brigham & Womens Hosp, Harvard Stem Cell Inst, Dept Med, Boston, MA 02215 USA. [Valdez, Ivan Achel; Dirice, Ercument; Gupta, Manoj K.; Shirakawa, Jun; Teo, Adrian Kee Keong; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Valdez, Ivan Achel] Harvard Univ, Grad Sch Arts & Sci, Program Biol & Biomed Sci, Dept Cell Biol, Cambridge, MA 02138 USA. [Teo, Adrian Kee Keong] Proteos, Inst Mol & Cell Biol, Discovery Res Div, Singapore 138673, Singapore. [Teo, Adrian Kee Keong] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore. [Teo, Adrian Kee Keong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117596, Singapore. [Teo, Adrian Kee Keong] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 308232, Singapore. RP Teo, AKK; Kulkarni, RN (reprint author), Brigham & Womens Hosp, Harvard Stem Cell Inst, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA.; Teo, AKK; Kulkarni, RN (reprint author), Brigham & Womens Hosp, Harvard Stem Cell Inst, Dept Med, Boston, MA 02215 USA.; Teo, AKK; Kulkarni, RN (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA.; Teo, AKK (reprint author), Proteos, Inst Mol & Cell Biol, Discovery Res Div, Singapore 138673, Singapore.; Teo, AKK (reprint author), Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.; Teo, AKK (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117596, Singapore.; Teo, AKK (reprint author), Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 308232, Singapore. EM ateo@imcb.a-star.edu.sg; rohit.kulkarni@joslin.harvard.edu RI Dirice, Ercument/B-2825-2017; OI Shirakawa, Jun/0000-0002-0822-8750; Teo, Adrian/0000-0001-5901-7075 FU NIH [F31DK098931, P01 DK036836, R01 DK67536, R01 DK103215, R01 DK055523]; Juvenile Diabetes Research Foundation [3APF-2014-220-A-N, 3-2013-236]; Institute of Molecular and Cell Biology, A*STAR, NHG-KTPH [SIG/14033]; NUHS-CG Metabolic In-Vitro Core Seed; JCO Career Development Award, A*STAR [15302FG148]; Harvard Stem Cell Institute [SG-0078-12-00] FX We are grateful to Dr. Susan Bonner-Weir and Brooke Sullivan for kindly providing an aliquot of the Ngn3 antibody and advice and assistance with immunostaining protocols. I.A.V. is supported by an NIH F31DK098931 award. E.D. was supported by the Juvenile Diabetes Research Foundation postdoctoral fellowship 3APF-2014-220-A-N. A.K.K.T. was supported by the Juvenile Diabetes Research Foundation postdoctoral fellowship 3-2013-236 and is currently supported by the Institute of Molecular and Cell Biology, A*STAR, NHG-KTPH SIG/14033, the NUHS-CG Metabolic In-Vitro Core Seed Funding, and JCO Career Development Award 15302FG148, A*STAR. R.N.K. is supported by Harvard Stem Cell Institute Award SG-0078-12-00 and NIH grants P01 DK036836, R01 DK67536, R01 DK103215, and R01 DK055523. NR 55 TC 3 Z9 5 U1 3 U2 5 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 APR 19 PY 2016 VL 15 IS 3 BP 460 EP 470 DI 10.1016/j.celrep.2016.03.036 PG 11 WC Cell Biology SC Cell Biology GA DJ8XX UT WOS:000374498900002 PM 27068459 ER PT J AU Marmarelis, ME Davis, MR Sethi, NS Krajewksi, KM McKay, RR Choueiri, TK Ott, PA AF Marmarelis, Melina E. Davis, Meredith R. Sethi, Nilay S. Krajewksi, Katherine M. McKay, Rana R. Choueiri, Toni K. Ott, Patrick A. TI Tumor control with PD-1 inhibition in a patient with concurrent metastatic melanoma and renal cell carcinoma SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE PD-1; Immune checkpoint blockade; Antibody therapy; Melanoma; Renal cell cancer; Immunotherapy; Concurrent cancer ID PHASE-II; IPILIMUMAB; CANCER; BLOCKADE; ANTIBODY; BEVACIZUMAB; SAFETY AB Blockade of the immunological checkpoint programmed death 1 (PD-1) using monoclonal antibodies has shown robust anti-tumor activity across a broad range of solid and hematological malignancies including melanoma and renal cell carcinoma (RCC). Characteristic markers such as the presence of tumor infiltrating lymphocytes, PD-L1 status, and mutational load may be equally or even more important in predicting clinical benefit from PD-1 pathway blockade than tumor histology. This case of a patient with concurrent metastatic melanoma and metastatic RCC, both of which were controlled for more than a year after a single dose of the anti-PD-1 antibody pembrolizumab, illustrates the potential to simultaneously treat distinct immunogenic tumors with anti-PD-1 agents. C1 [Marmarelis, Melina E.; Davis, Meredith R.; Sethi, Nilay S.; McKay, Rana R.; Choueiri, Toni K.; Ott, Patrick A.] Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Marmarelis, Melina E.; Davis, Meredith R.; Sethi, Nilay S.; Krajewksi, Katherine M.; McKay, Rana R.; Choueiri, Toni K.; Ott, Patrick A.] Harvard Univ, Sch Med, Boston, MA USA. [Krajewksi, Katherine M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Imaging, 75 Francis St, Boston, MA 02115 USA. RP Ott, PA (reprint author), Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA.; Ott, PA (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM Patrick_Ott@dfci.harvard.edu NR 15 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD APR 19 PY 2016 VL 4 AR 26 DI 10.1186/s40425-016-0129-x PG 5 WC Oncology SC Oncology GA DK2JJ UT WOS:000374740300001 PM 27099755 ER PT J AU Klein, SR Jiang, H Hossain, MB Fan, XJ Gumin, J Dong, A Alonso, MM Gomez-Manzano, C Fueyo, J AF Klein, Sarah R. Jiang, Hong Hossain, Mohammad B. Fan, Xuejun Gumin, Joy Dong, Andrew Alonso, Marta M. Gomez-Manzano, Candelaria Fueyo, Juan TI Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens SO PLOS ONE LA English DT Article ID MHC CLASS-II; N-TERMINAL KINASE; EFFECT IN-VIVO; SELECTIVE AUTOPHAGY; ANTIGLIOMA ACTIVITY; IMMUNE-RESPONSES; NUCLEAR ANTIGEN; GENE-THERAPY; CELL-DEATH; PHOSPHORYLATION AB Adenoviruses are highly immunogenic and are being examined as potential vectors for immunotherapy. Infection by oncolytic adenovirus is followed by massive autophagy in cancer cells. Here, we hypothesize that autophagy regulates the processing of adenoviral proteins for antigen presentation. To test this hypothesis, we first examined the presentation of viral antigens by infected cells using an antibody cocktail of viral capsid proteins. We found that viral antigens were processed by JNK-mediated autophagy, and that autophagy was required for their presentation. Consistent with these results, splenocytes isolated from virus-immunized mice were activated by infected cells in an MHC II-dependent manner. We then hypothesize that this mechanism can be utilized to generate an efficient cancer vaccine. To this end, we constructed an oncolytic virus encompassing an EGFRvIII cancer-specific epitope in the adenoviral fiber. Infection of cancer cells with this fiber-modified adenovirus resulted in recognition of infected cancer cells by a specific anti-EGFRvIII antibody. However, inhibition of autophagy drastically decreased the capability of the specific antibody to detect the cancer-related epitope in infected cells. Our data suggest that combination of adenoviruses with autophagy inducers may enhance the processing and presentation of cancer-specific antigens incorporated into capsid proteins. C1 [Klein, Sarah R.; Jiang, Hong; Hossain, Mohammad B.; Fan, Xuejun; Dong, Andrew; Gomez-Manzano, Candelaria; Fueyo, Juan] Univ Texas MD Anderson Canc Ctr, Brain Tumor Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Klein, Sarah R.; Gomez-Manzano, Candelaria; Fueyo, Juan] Univ Texas Grad Sch Biomed Sci Houston, Canc Biol Program, Houston, TX USA. [Gumin, Joy; Fueyo, Juan] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Brain Tumor Ctr, Houston, TX 77030 USA. [Alonso, Marta M.] Univ Navarra, Univ Navarra Clin, Dept Med Oncol, E-31080 Pamplona, Spain. [Gomez-Manzano, Candelaria] Univ Texas MD Anderson Canc Ctr, Dept Genet, Brain Tumor Ctr, Houston, TX 77030 USA. [Klein, Sarah R.] Dana Farber Canc Inst, Dept Neurooncol, Boston, MA USA. RP Fueyo, J (reprint author), Univ Texas MD Anderson Canc Ctr, Brain Tumor Ctr, Dept Neurooncol, Houston, TX 77030 USA.; Fueyo, J (reprint author), Univ Texas Grad Sch Biomed Sci Houston, Canc Biol Program, Houston, TX USA.; Fueyo, J (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Brain Tumor Ctr, Houston, TX 77030 USA. EM jfueyo@mdanderson.org FU NIH (Cancer Center Support Grant-Sequencing and Microarray Facility and Research Animal Support Facilities) [P30CA016672, P50CA127001, R01NS069964]; Marnie Rose Foundation; Will Power Foundation; Schissler Foundation; American Legion Auxiliary FX This work was supported by grants from the NIH (P50CA127001; R01NS069964; Cancer Center Support Grant P30CA016672-Sequencing and Microarray Facility and Research Animal Support Facilities), the Marnie Rose Foundation, the Will Power Foundation, the Schissler Foundation, and the American Legion Auxiliary. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 1 Z9 2 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 APR 19 PY 2016 VL 11 IS 4 AR e0153814 DI 10.1371/journal.pone.0153814 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ9NW UT WOS:000374541200045 PM 27093696 ER PT J AU Kim, KS Kim, H Park, Y Kong, WH Lee, SW Kwok, SJJ Hahn, SK Yun, SH AF Kim, Ki Su Kim, Hyemin Park, Yunji Kong, Won Ho Lee, Seung Woo Kwok, Sheldon J. J. Hahn, Sei Kwang Yun, Seok Hyun TI Noninvasive Transdermal Vaccination Using Hyaluronan Nanocarriers and Laser Adjuvant SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article ID DERMAL DENDRITIC CELLS; INFLUENZA VACCINATION; TRANSCUTANEOUS DRUG; LANGERHANS CELLS; IMMUNE-SYSTEM; NEEDLE PHOBIA; DELIVERY; SKIN; IMMUNIZATION; ACID AB Vaccines are commonly administered by injection using needles. Although transdermal microneedles are less invasive promising alternatives, needle-free topical vaccination without involving physical damage to the natural skin barrier is still sought after as it can further reduce needle-induced anxiety and is simple to administer. However, this long-standing goal has been elusive since the intact skin is impermeable to most macromolecules. Here, we show an efficient, noninvasive transdermal vaccination by employing two key innovations: the use of hyaluronan (HA) as vaccine carriers and non-ablative laser adjuvants. Conjugates of a model vaccine ovalbumin (OVA) and HAHA-OVA conjugates-induced more effective maturation of dendritic cells in vitro, compared to OVA. Following topical administration in the skin, HA-OVA conjugates penetrated into the epidermis and dermis in murine and porcine skins, as revealed by intravital microscopy and fluorescence assay. Topical administration of HA-OVA conjugates significantly elevated both humoral and mucosal antibodies, with peak levels at four weeks. An OVA challenge at week eight elicited strong immune-recall responses. With pretreatment of the skin using non-ablative fractional laser beams as adjuvant, strong immunization was achieved with much reduced doses of HA-OVA (1 mg kg(-1) OVA). Our results demonstrate the potential of the noninvasive patch-type transdermal vaccination platform. C1 [Kim, Ki Su; Kwok, Sheldon J. J.; Hahn, Sei Kwang; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St,UP-5, Cambridge, MA 02139 USA. [Kim, Ki Su; Kwok, Sheldon J. J.; Hahn, Sei Kwang; Yun, Seok Hyun] Harvard Univ, Sch Med, Dept Dermatol, 40 Blossom St, Boston, MA 02140 USA. [Kim, Hyemin; Kong, Won Ho; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 790784, Gyeongbuk, South Korea. [Park, Yunji; Lee, Seung Woo] POSTECH, Div Integrat Biosci & Biotechnol, 77 Cheongam Ro, Pohang 790784, Gyeongbuk, South Korea. [Lee, Seung Woo] POSTECH, Dept Life Sci, 77 Cheongam Ro, Pohang 790784, Gyeongbuk, South Korea. RP Hahn, SK; Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St,UP-5, Cambridge, MA 02139 USA.; Hahn, SK; Yun, SH (reprint author), Harvard Univ, Sch Med, Dept Dermatol, 40 Blossom St, Boston, MA 02140 USA.; Hahn, SK (reprint author), Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 790784, Gyeongbuk, South Korea. EM skhanb@postech.edu; syun@hms.harvard.edu FU Mid-career Researcher Program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012R1A2A2A06045773]; National Institutes of Health [P41-EB015903, R01-CA192878, P01-HL120839] FX K.S.K. and H.K. contributed equally to this work. The authors thank Dr. Myunghwan Choi and Dr. Jie Zhao for help in intravital imaging and histological analysis, Dr. Mark Randolph for providing access to experimental pigs, Dr. Jeesoo An for help in interpretation of histology, and Dr. Ji Wang and Prof. Mei Wu for discussion. This study was supported by Mid-career Researcher Program through the National Research Foundation of Korea grant funded by the Ministry of Education, Science and Technology (Grant No. 2012R1A2A2A06045773) and in part by National Institutes of Health (Grant Nos. P41-EB015903, R01-CA192878, P01-HL120839). NR 63 TC 4 Z9 4 U1 13 U2 25 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1616-301X EI 1616-3028 J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD APR 19 PY 2016 VL 26 IS 15 BP 2512 EP 2522 DI 10.1002/adfm.201504879 PG 11 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DK7SQ UT WOS:000375126400012 PM 27833475 ER PT J AU Weiss, MD Macklin, EA Simmons, Z Knox, AS Greenblatt, DJ Atassi, N Graves, M Parziale, N Salameh, JS Quinn, C Brown, RH Distad, JB Trivedi, J Shefner, JM Barohn, RJ Pestronk, A Swenson, A Cudkowicz, ME AF Weiss, Michael D. Macklin, Eric A. Simmons, Zachary Knox, Angela S. Greenblatt, David J. Atassi, Nazem Graves, Michael Parziale, Nicholas Salameh, Johnny S. Quinn, Colin Brown, Robert H. Distad, Jane B. Trivedi, Jaya Shefner, Jeremy M. Barohn, Richard J. Pestronk, Alan Swenson, Andrea Cudkowicz, Merit E. CA Mexiletine ALS Study Grp TI A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; PLACEBO-CONTROLLED TRIAL; QUALITY STANDARDS SUBCOMMITTEE; PRACTICE PARAMETER UPDATE; DOUBLE-BLIND; CORTICAL HYPEREXCITABILITY; CORTICOMOTOR THRESHOLD; AMERICAN ACADEMY; RILUZOLE; PATIENT AB Objective:To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).Methods:Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.Results:The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p < 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005).Conclusions:Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study.Classification of evidence:This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose. C1 [Weiss, Michael D.; Distad, Jane B.] Univ Washington, Med Ctr, Dept Neurol, Seattle, WA 98195 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Macklin, Eric A.] Harvard Univ, Sch Med, Boston, MA USA. [Simmons, Zachary] Penn State Hershey Med Ctr, Dept Neurol, Hershey, PA USA. [Knox, Angela S.; Atassi, Nazem; Cudkowicz, Merit E.] Massachusetts Gen Hosp, Neurol Clin Res Inst, Dept Neurol, Boston, MA 02114 USA. [Greenblatt, David J.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Graves, Michael; Parziale, Nicholas] Univ Calif Los Angeles, Med Ctr, Dept Neurol, Los Angeles, CA 90024 USA. [Salameh, Johnny S.; Quinn, Colin; Brown, Robert H.] Univ Massachusetts, Mem Med Ctr, Dept Neurol, Worcester, MA 01605 USA. [Trivedi, Jaya] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Shefner, Jeremy M.] Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. [Barohn, Richard J.] Univ Kansas, Med Ctr, Dept Neurol, Lawrence, KS 66045 USA. [Pestronk, Alan] Washington Univ, Med Ctr, Dept Neurol, St Louis, MO USA. [Swenson, Andrea] Univ Iowa Hosp & Clin, Dept Neurol, Iowa City, IA 52242 USA. RP Weiss, MD (reprint author), Univ Washington, Med Ctr, Dept Neurol, Seattle, WA 98195 USA. EM mdweiss@uw.edu FU ALS Therapy Alliance and Neurology Clinical Research Institute/Northeast ALS Consortium FX Supported by funding from the ALS Therapy Alliance and Neurology Clinical Research Institute/Northeast ALS Consortium. NR 32 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD APR 19 PY 2016 VL 86 IS 16 BP 1474 EP 1481 DI 10.1212/WNL.0000000000002507 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DK4KS UT WOS:000374887700008 PM 26911633 ER PT J AU Napoles, AM Appelle, N Kalkhoran, S Vijayaraghavan, M Alvarado, N Satterfield, J AF Napoles, Anna Maria Appelle, Nicole Kalkhoran, Sara Vijayaraghavan, Maya Alvarado, Nicholas Satterfield, Jason TI Perceptions of clinicians and staff about the use of digital technology in primary care: qualitative interviews prior to implementation of a computer-facilitated 5As intervention SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article DE Smoking cessation counseling; 5As; Computer technology; Primary care; Tobacco addiction ID SMOKING-CESSATION INTERVENTIONS; HEALTH-CARE; INFORMATION-TECHNOLOGY; PRACTICE GUIDELINE; TOBACCO; ADULTS; ACCEPTANCE; UPDATE AB Background: Digital health interventions using hybrid delivery models may offer efficient alternatives to traditional behavioral counseling by addressing obstacles of time, resources, and knowledge. Using a computer-facilitated 5As (ask, advise, assess, assist, arrange) model as an example (CF5As), we aimed to identify factors from the perspectives of primary care providers and clinical staff that were likely to influence introduction of digital technology and a CF5As smoking cessation counseling intervention. In the CF5As model, patients self-administer a tablet intervention that provides 5As smoking cessation counseling, produces patient and provider handouts recommending next steps, and is followed by a patient-provider encounter to reinforce key cessation messages, provide assistance, and arrange follow-up. Methods: Semi-structured in-person interviews of administrative and clinical staff and primary care providers from three primary care clinics. Results: Thirty-five interviews were completed (12 administrative staff, ten clinical staff, and 13 primary care providers). Twelve were from an academic internal medicine practice, 12 from a public hospital academic general medicine clinic, and 11 from a public hospital HIV clinic. Most were women (91 %); mean age (SD) was 42 years (11.1). Perceived usefulness of the CF5As focused on its relevance for various health behavior counseling purposes, potential gains in counseling efficiency, confidentiality of data collection, occupying patients while waiting, and serving as a cue to action. Perceived ease of use was viewed to depend on the ability to accommodate: clinic workflow; heavy patient volumes; and patient characterisitics, e.g., low literacy. Social norms potentially affecting implementation included beliefs in the promise/burden of technology, priority of smoking cessation counseling relative to other patient needs, and perception of CF5As as just "one more thing to do" in an overburdened system. The most frequently cited facilitating conditions were staffing levels and smoking cessation resources and training; the most cited hindering factors were visit time constraints and patients' complex health care needs. Conclusions: Integrating CF5As and other technology-enhanced behavioral counseling interventions in primary care requires flexibility to accommodate work flow and perceptions of overload in dynamic environments. Identifying factors that promote and hinder CF5As adoption could inform implementation of other CF behavioral health interventions in primary care. C1 [Napoles, Anna Maria] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, Box 08563333 Calif St,Suite 335, San Francisco, CA 94118 USA. [Appelle, Nicole] UCSF, Dept Med, Div Gen Internal Med, Box 03201545 Divisadero St, San Francisco, CA 94115 USA. [Kalkhoran, Sara] Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Vijayaraghavan, Maya] UCSF, San Francisco Gen Hosp, Box 13641001 Potrero Ave,90 Room 1311E, San Francisco, CA USA. [Alvarado, Nicholas] UCSF, Dept Med, Div Gen Internal Med, Box 03202200 Post St,MZ Bldg C Room C126B, San Francisco, CA 94115 USA. [Satterfield, Jason] UCSF, Dept Med, Div Gen Internal Med, Box 17311701 Divisadero St,Room 500, San Francisco, CA 94115 USA. RP Napoles, AM (reprint author), Univ Calif San Francisco, Dept Med, Div Gen Internal Med, Box 08563333 Calif St,Suite 335, San Francisco, CA 94118 USA. EM anapoles@ucsf.edu FU NIH/NIDA [R01DA034253]; NIH/NIA [P30 AG15272] FX This research was supported by NIH/NIDA Grant No. R01DA034253 awarded to Dr. Jason Satterfield. Dr. Napoles' time was supported also by NIH/NIA Grant No. P30 AG15272. Funding agencies were not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. NR 33 TC 1 Z9 1 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD APR 19 PY 2016 VL 16 AR 44 DI 10.1186/s12911-016-0284-5 PG 13 WC Medical Informatics SC Medical Informatics GA DK1FA UT WOS:000374656700002 PM 27094928 ER PT J AU Yeh, JE Frank, DA AF Yeh, Jennifer E. Frank, David A. TI STAT3-Interacting Proteins as Modulators of Transcription Factor Function: Implications to Targeted Cancer Therapy SO CHEMMEDCHEM LA English DT Review DE cancer; drug discovery; gene expression; protein-protein interactions; signal transduction ID SMALL-MOLECULE INHIBITOR; STAT3 NUCLEAR IMPORT; N-TERMINAL DOMAIN; BREAST-CANCER; SIGNAL TRANSDUCER; GROWTH-FACTOR; MULTIPLE-MYELOMA; IN-VITRO; PRECURSOR EXPRESSION; S-GLUTATHIONYLATION AB The oncogenic transcription factor STAT3 is inappropriately activated in multiple hematopoietic and solid malignancies, in which it drives the expression of genes involved in cell proliferation, differentiation, survival, and angiogenesis. Thus far, strategies to inhibit the function of STAT3 have focused on blocking the function of its activating kinases or sequestering its DNA binding ability. A less well-explored aspect of STAT3 function is its interaction with other proteins, which can modulate the oncogenic activity of STAT3 via its subcellular localization, DNA binding ability, and recruitment of transcriptional machinery. Herein we summarize what is currently known about STAT3-interacting proteins and describe the utility of a proteomics-based approach for successfully identifying and characterizing novel STAT3-interacting proteins that affect STAT3 transcriptional activity and oncogenic function. C1 [Yeh, Jennifer E.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM david_frank@dfci.harvard.edu NR 88 TC 3 Z9 3 U1 4 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD APR 19 PY 2016 VL 11 IS 8 SI SI BP 795 EP 801 DI 10.1002/cmdc.201500482 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK1SE UT WOS:000374693500006 PM 26662504 ER PT J AU O'Donoghue, ML Glaser, R Cavender, MA Aylward, PE Bonaca, MP Budaj, A Davies, RY Dellborg, M Fox, KAA Gutierrez, JAT Hamm, C Kiss, RG Kovar, F Kuder, JF Im, KA Lepore, JJ Lopez-Sendon, JL Ophuis, TO Parkhomenko, A Shannon, JB Spinar, J Tanguay, JF Ruda, M Steg, PG Theroux, P Wiviott, SD Laws, I Sabatine, MS Morrow, DA AF O'Donoghue, Michelle L. Glaser, Ruchira Cavender, Matthew A. Aylward, Philip E. Bonaca, Marc P. Budaj, Andrzej Davies, Richard Y. Dellborg, Mikael Fox, Keith A. A. Gutierrez, Jorge Antonio T. Hamm, Christian Kiss, Robert G. Kovar, Frantisek Kuder, Julia F. Im, Kyung Ah Lepore, John J. Lopez-Sendon, Jose L. Ophuis, Ton Oude Parkhomenko, Alexandr Shannon, Jennifer B. Spinar, Jindrich Tanguay, Jean-Francois Ruda, Mikhail Steg, P. Gabriel Theroux, Pierre Wiviott, Stephen D. Laws, Ian Sabatine, Marc S. Morrow, David A. CA LATITUDE-TIMI 60 Investigators TI Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACTIVATED PROTEIN-KINASE; ACUTE CORONARY SYNDROME; HEART-FAILURE; RHEUMATOID-ARTHRITIS; IN-VIVO; DISEASE; INHIBITION; APOPTOSIS; PATHWAY; EVENTS AB IMPORTANCE p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes inmyocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acutemyocardial infarction. DESIGN, SETTING, AND PATIENTS LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS Patients were randomized to either twice-daily losmapimod (7.5mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS In part A, among the 3503 patients randomized (median age, 66 years; 1036 [ 29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P =.24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. C1 [O'Donoghue, Michelle L.; Cavender, Matthew A.; Bonaca, Marc P.; Gutierrez, Jorge Antonio T.; Kuder, Julia F.; Im, Kyung Ah; Wiviott, Stephen D.; Sabatine, Marc S.; Morrow, David A.] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 350 Longwood Ave,First Floor, Boston, MA 02115 USA. [Glaser, Ruchira; Davies, Richard Y.; Lepore, John J.; Laws, Ian] GlaxoSmithKline, Res & Dev, Metab Pathways & Cardiovasc Unit, Collegeville, PA USA. [Aylward, Philip E.] Flinders Univ S Australia, Med Ctr, South Australian Hlth & Med Res Inst, Adelaide, SA 5001, Australia. [Budaj, Andrzej] Grochowski Hosp, Postgrad Med Sch, Warsaw, Poland. [Dellborg, Mikael] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Dellborg, Mikael] Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden. [Fox, Keith A. A.] Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Hamm, Christian] Kerckhoff Heart Ctr, Bad Nauheim, Germany. [Hamm, Christian] Univ Giessen, D-35390 Giessen, Germany. [Kiss, Robert G.] Mil Hosp, Dept Cardiol, Budapest, Hungary. [Kovar, Frantisek] Comenius Univ, Jessenius Fac Med Martin, Dept Internal Med 1, Martin, Slovakia. [Lopez-Sendon, Jose L.] Univ Hosp La Paz, Cardiovasc Div, Madrid, Spain. [Ophuis, Ton Oude] Canisius Wilhelmina Hosp, Nijmegen, Netherlands. [Parkhomenko, Alexandr] Ukranian Strazhesko Inst Cardiol, Kiev, Ukraine. [Shannon, Jennifer B.] PAREXEL Int, Durham, NC USA. [Spinar, Jindrich] Univ Hosp, Brno, Czech Republic. [Tanguay, Jean-Francois; Theroux, Pierre] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Tanguay, Jean-Francois; Theroux, Pierre] Univ Montreal, Montreal, PQ, Canada. [Ruda, Mikhail] Cardiol Res Ctr, Moscow 121552, Russia. [Steg, P. Gabriel] Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75877 Paris, France. [Steg, P. Gabriel] Univ Paris Diderot, Paris, France. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 350 Longwood Ave,First Floor, Boston, MA 02115 USA. EM modonoghue@partners.org RI Nicolau, Jose/E-1487-2012; OI Apartsin, Konstantin/0000-0003-0577-9001 FU GlaxoSmithKline FX The LATITUDE-TIMI 60 trial was funded by GlaxoSmithKline. NR 17 TC 19 Z9 19 U1 2 U2 5 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 APR 19 PY 2016 VL 315 IS 15 BP 1591 EP 1599 DI 10.1001/jama.2016.3609 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DJ5ZK UT WOS:000374289300019 PM 27043082 ER PT J AU Ribas, A Hamid, O Daud, A Hodi, FS Wolchok, JD Kefford, R Joshua, AM Patnaik, A Hwu, WJ Weber, JS Gangadhar, TC Hersey, P Dronca, R Joseph, RW Zarour, H Chmielowski, B Lawrence, DP Algazi, A Rizvi, NA Hoffner, B Mateus, C Gergich, K Lindia, JA Giannotti, M Li, XN Ebbinghaus, S Kang, SP Robert, C AF Ribas, Antoni Hamid, Omid Daud, Adil Hodi, F. Stephen Wolchok, Jedd D. Kefford, Richard Joshua, Anthony M. Patnaik, Amita Hwu, Wen-Jen Weber, Jeffrey S. Gangadhar, Tara C. Hersey, Peter Dronca, Roxana Joseph, Richard W. Zarour, Hassane Chmielowski, Bartosz Lawrence, Donald P. Algazi, Alain Rizvi, Naiyer A. Hoffner, Brianna Mateus, Christine Gergich, Kevin Lindia, Jill A. Giannotti, Maxine Li, Xiaoyun Nicole Ebbinghaus, Scot Kang, S. Peter Robert, Caroline TI Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BRAF INHIBITORS; T-CELLS; IPILIMUMAB; IMMUNOTHERAPY; NIVOLUMAB; CRITERIA; CANCER; SAFETY; TRIAL; PD-1 AB IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35%(95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. C1 [Ribas, Antoni; Chmielowski, Bartosz] Univ Calif Los Angeles, Div Hematol & Oncol, 10833 Le Conte Ave,11-934 Factor Bldg, Los Angeles, CA 90095 USA. [Hamid, Omid; Hoffner, Brianna] Angeles Clin & Res Inst, Dept Hematol Oncol, Los Angeles, CA USA. [Daud, Adil; Algazi, Alain] Univ Calif San Francisco, Dept Hematol Oncol, San Francisco, CA 94143 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolchok, Jedd D.; Rizvi, Naiyer A.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Kefford, Richard] Westmead Hosp, Crown Princess Mary Canc Ctr, Dept Med Oncol, Sydney, NSW, Australia. [Kefford, Richard] Melanoma Inst Australia, Sydney, NSW, Australia. [Kefford, Richard] Macquarie Univ, Dept Clin Med, Sydney, NSW 2109, Australia. [Joshua, Anthony M.] Princess Margaret Canc Ctr, Dept Med Oncol, Toronto, ON, Canada. [Patnaik, Amita] South Texas Accelerated Res Therapeut, Dept Clin Res, San Antonio, TX USA. [Hwu, Wen-Jen] Univ Texas MD Anderson Canc Ctr, Dept Melanoma, Houston, TX 77030 USA. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Cutaneous Oncol, Tampa, FL 33682 USA. [Gangadhar, Tara C.] Univ Penn, Abramson Canc Ctr, Div Hematol & Oncol, Philadelphia, PA 19104 USA. [Hersey, Peter] Univ Sydney, Dept Med, Sydney, NSW 2006, Australia. [Dronca, Roxana] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Joseph, Richard W.] Mayo Clin, Dept Hematol Oncol, Jacksonville, FL 32224 USA. [Zarour, Hassane] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Lawrence, Donald P.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA USA. [Mateus, Christine; Robert, Caroline] Gustave Roussy Canc Campus, Dept Med Oncol, Villejuif Paris Sud, France. [Mateus, Christine; Robert, Caroline] Univ Paris Sud, Villejuif Paris Sud, France. [Gergich, Kevin; Lindia, Jill A.; Giannotti, Maxine; Ebbinghaus, Scot; Kang, S. Peter] Merck & Co Inc, Dept Clin Oncol, Kenilworth, NJ USA. [Li, Xiaoyun Nicole] Merck & Co Inc, BARDS, Kenilworth, NJ USA. RP Ribas, A (reprint author), Univ Calif Los Angeles, Div Hematol & Oncol, 10833 Le Conte Ave,11-934 Factor Bldg, Los Angeles, CA 90095 USA. EM aribas@mednet.ucla.edu FU Merck Co, Inc. FX This study was supported by Merck & Co, Inc. NR 24 TC 46 Z9 47 U1 8 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 19 PY 2016 VL 315 IS 15 BP 1600 EP 1609 DI 10.1001/jama.2016.4059 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DJ5ZK UT WOS:000374289300020 PM 27092830 ER PT J AU Wakabayashi, A Ulirsch, JC Ludwig, LS Fiorini, C Yasuda, M Choudhuri, A McDonel, P Zon, LI Sankaran, VG AF Wakabayashi, Aoi Ulirsch, Jacob C. Ludwig, Leif S. Fiorini, Claudia Yasuda, Makiko Choudhuri, Avik McDonel, Patrick Zon, Leonard I. Sankaran, Vijay G. TI Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE GATA1; cis-regulatory elements; noncoding mutations; Mendelian erythroid disorders ID PYRUVATE-KINASE DEFICIENCY; GENOME-WIDE ANALYSIS; DYSERYTHROPOIETIC ANEMIA; SIDEROBLASTIC ANEMIA; REGULATORY ELEMENT; GENETIC-VARIATION; HUMAN-DISEASE; MUTATIONS; DNA; DIFFERENTIATION AB Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. C1 [Wakabayashi, Aoi; Ulirsch, Jacob C.; Ludwig, Leif S.; Fiorini, Claudia; Choudhuri, Avik; Zon, Leonard I.; Sankaran, Vijay G.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol Oncol, Boston, MA 02115 USA. [Wakabayashi, Aoi; Ulirsch, Jacob C.; Ludwig, Leif S.; Fiorini, Claudia; Choudhuri, Avik; Zon, Leonard I.; Sankaran, Vijay G.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wakabayashi, Aoi; Ulirsch, Jacob C.; Ludwig, Leif S.; Fiorini, Claudia; McDonel, Patrick; Sankaran, Vijay G.] Broad Inst, Cambridge, MA 02142 USA. [Ludwig, Leif S.] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany. [Ludwig, Leif S.] Charite, D-10117 Berlin, Germany. [Yasuda, Makiko] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Choudhuri, Avik; Zon, Leonard I.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Zon, Leonard I.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol Oncol, Boston, MA 02115 USA.; Sankaran, VG (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Sankaran, VG (reprint author), Broad Inst, Cambridge, MA 02142 USA. EM sankaran@broadinstitute.org OI Ludwig, Leif/0000-0002-2916-2164; Fiorini, Claudia/0000-0003-4878-2438 FU National Institutes of Health [R01 DK103794, R21 HL120791] FX We thank B. Cleary, C. Fulco, R. Tewhey, D. Bishop, and members of the V.G.S. laboratory for valuable comments and discussions. This work was supported by National Institutes of Health Grants R01 DK103794 and R21 HL120791 (to V.G.S.). NR 65 TC 7 Z9 7 U1 1 U2 3 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 APR 19 PY 2016 VL 113 IS 16 BP 4434 EP 4439 DI 10.1073/pnas.1521754113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800058 PM 27044088 ER PT J AU Peterson, TE Kirkpatrick, ND Huang, YH Farrar, CT Marijt, KA Kloepper, J Datta, M Amoozgar, Z Seano, G Jung, K Kamoun, WS Vardam, T Snuderl, M Goveia, J Chatterjee, S Batista, A Muzikansky, A Leow, CC Xu, L Batchelor, TT Duda, DG Fukumura, D Jain, RK AF Peterson, Teresa E. Kirkpatrick, Nathaniel D. Huang, Yuhui Farrar, Christian T. Marijt, Koen A. Kloepper, Jonas Datta, Meenal Amoozgar, Zohreh Seano, Giorgio Jung, Keehoon Kamoun, Walid S. Vardam, Trupti Snuderl, Matija Goveia, Jermaine Chatterjee, Sampurna Batista, Ana Muzikansky, Alona Leow, Ching Ching Xu, Lei Batchelor, Tracy T. Duda, Dan G. Fukumura, Dai Jain, Rakesh K. TI Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anti-angiogenic therapy; tumor microenvironment; tumor immunity; colony-stimulating factor 1; macrophage ID ENDOTHELIAL GROWTH-FACTOR; NEWLY-DIAGNOSED GLIOBLASTOMA; BEVACIZUMAB PLUS IRINOTECAN; PHASE-II TRIAL; RECURRENT GLIOBLASTOMA; ANTIANGIOGENIC THERAPY; ANGIOPOIETIN-2 FUNCTIONS; KINASE INHIBITOR; RANDOMIZED-TRIAL; BLOOD PERFUSION AB Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti-Ang-2-neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti-colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells. C1 [Peterson, Teresa E.; Kirkpatrick, Nathaniel D.; Huang, Yuhui; Marijt, Koen A.; Kloepper, Jonas; Datta, Meenal; Amoozgar, Zohreh; Seano, Giorgio; Jung, Keehoon; Kamoun, Walid S.; Vardam, Trupti; Snuderl, Matija; Goveia, Jermaine; Chatterjee, Sampurna; Batista, Ana; Muzikansky, Alona; Xu, Lei; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. [Peterson, Teresa E.; Kirkpatrick, Nathaniel D.; Huang, Yuhui; Marijt, Koen A.; Kloepper, Jonas; Datta, Meenal; Amoozgar, Zohreh; Seano, Giorgio; Jung, Keehoon; Kamoun, Walid S.; Vardam, Trupti; Snuderl, Matija; Goveia, Jermaine; Chatterjee, Sampurna; Batista, Ana; Xu, Lei; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Peterson, Teresa E.] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Farrar, Christian T.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Farrar, Christian T.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Datta, Meenal] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA. [Muzikansky, Alona] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Muzikansky, Alona; Batchelor, Tracy T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Leow, Ching Ching] MedImmune, Dept Translat Med Oncol, Gaithersburg, MD 20878 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Dept Neurol, Boston, MA 02114 USA. [Peterson, Teresa E.] Wilson Sonsini Goodrich & Rosati, Palo Alto, CA 94304 USA. [Kirkpatrick, Nathaniel D.] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA. [Huang, Yuhui] Soochow Univ, Cyrus Tang Hematol Ctr, Suzhou 215123, Peoples R China. [Marijt, Koen A.] Leiden Univ, Dept Clin Oncol, Med Ctr, NL-2333 Leiden, Netherlands. [Kamoun, Walid S.] Merrimack Pharmaceut, Cambridge, MA 02139 USA. [Vardam, Trupti] Mayo Clin, Coll Med, Dept Immunol, Scottsdale, AZ 85259 USA. [Snuderl, Matija] NYU, Langone Med Ctr, New York, NY 10016 USA. [Snuderl, Matija] NYU, Sch Med, New York, NY 10016 USA. [Goveia, Jermaine] Katholieke Univ Leuven, Dept Oncol, Vesalius Res Ctr, B-3000 Leuven, Belgium. [Batista, Ana] Trends Canc, Cambridge, MA 02139 USA. RP Fukumura, D; Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA.; Fukumura, D; Jain, RK (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM dai@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu RI Seano, Giorgio/R-6611-2016; OI Seano, Giorgio/0000-0002-7294-302X; Snuderl, Matija/0000-0003-0752-0917 FU NIH [P01-CA080124, P50CA165962, R01CA126642, R35CA197743, R01-CA096915, S10-RR027070, R01-CA159258]; National Cancer Institute/Federal Share Proton Beam Program Income; Department of Defense Breast Cancer Research Innovator Award [W81XWH-10-1-0016]; MedImmune; National Foundation for Cancer Research; Children's Tumor Foundation (CTF) Clinical Research Award; American Cancer Society Research Scholar Award; Ira Spiro Award; CTF Drug Discovery Initiative; German Research Foundation; Solidar-Immun Foundation Fellowships; Aid for Cancer Research Foundation Fellowship; Susan G. Komen Postdoctoral Fellowship; Tosteson Fund; Affymetrix; CTF Clinical Research Award; American Cancer Society FX We thank S. Roberge for outstanding technical support for mouse studies; P. Huang for managing the mouse colony and generating mice for the paper; and E. Ager, S. Goel, and C. Kesler for valuable discussions and experimental assistance. The investigators' research was supported by NIH Grants P01-CA080124 (to R.K.J., D.G.D., and D.F.), P50CA165962 (to T.T.B. and R.K.J.), R01CA126642 and R35CA197743 (to R.K.J.), R01-CA096915 and S10-RR027070 (to D.F.), and R01-CA159258 (to D.G.D.); by National Cancer Institute/Federal Share Proton Beam Program Income (R.K.J. and D.F.); by Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016 (to R.K.J.); by grants from MedImmune and the National Foundation for Cancer Research (to R.K.J.); by a Children's Tumor Foundation (CTF) Clinical Research Award, an American Cancer Society Research Scholar Award, and an Ira Spiro Award (all to L.X.); and by the CTF Drug Discovery Initiative (L.X.). Additional support was provided by German Research Foundation and Solidar-Immun Foundation Fellowships (to J.K.); an Aid for Cancer Research Foundation Fellowship (to Z.A.); a Susan G. Komen Postdoctoral Fellowship (to G.S.); a Tosteson & Fund for Medical Discovery Fellowship (to T.V.); Affymetrix (M.S.); a CTF Clinical Research Award, an American Cancer Society Research Scholar Award, and an Ira Spiro Award (all to L.X.); and the CTF Drug Discovery Initiative (L.X.). NR 69 TC 10 Z9 10 U1 4 U2 14 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 APR 19 PY 2016 VL 113 IS 16 BP 4470 EP 4475 DI 10.1073/pnas.1525349113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800064 PM 27044097 ER PT J AU Kloepper, J Riedemann, L Amoozgar, Z Seano, G Susek, K Yu, V Dalvie, N Amelung, RL Datta, M Song, JW Askoxylakis, V Taylor, JW Lu-Emerson, C Batista, A Kirkpatrick, ND Jung, K Snuderl, M Muzikansky, A Stubenrauch, KG Krieter, O Wakimoto, H Xu, L Munn, LL Duda, DG Fukumura, D Batchelor, TT Jain, RK AF Kloepper, Jonas Riedemann, Lars Amoozgar, Zohreh Seano, Giorgio Susek, Katharina Yu, Veronica Dalvie, Nisha Amelung, Robin L. Datta, Meenal Song, Jonathan W. Askoxylakis, Vasileios Taylor, Jennie W. Lu-Emerson, Christine Batista, Ana Kirkpatrick, Nathaniel D. Jung, Keehoon Snuderl, Matija Muzikansky, Alona Stubenrauch, Kay G. Krieter, Oliver Wakimoto, Hiroaki Xu, Lei Munn, Lance L. Duda, Dan G. Fukumura, Dai Batchelor, Tracy T. Jain, Rakesh K. TI Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anti-angiogenic therapy; tumor microenvironment; anti-tumor immunity; macrophage polarization; microglia reprogramming ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-ASSOCIATED MACROPHAGES; NEWLY-DIAGNOSED GLIOBLASTOMA; TIE2-EXPRESSING MONOCYTES; IN-VIVO; RECURRENT GLIOBLASTOMA; BLOOD-VESSELS; RANDOMIZED-TRIAL; THERAPY; CANCER AB Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth. C1 [Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh; Seano, Giorgio; Susek, Katharina; Yu, Veronica; Dalvie, Nisha; Amelung, Robin L.; Datta, Meenal; Song, Jonathan W.; Askoxylakis, Vasileios; Taylor, Jennie W.; Lu-Emerson, Christine; Batista, Ana; Kirkpatrick, Nathaniel D.; Jung, Keehoon; Snuderl, Matija; Munn, Lance L.; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. [Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh; Seano, Giorgio; Susek, Katharina; Yu, Veronica; Dalvie, Nisha; Amelung, Robin L.; Datta, Meenal; Song, Jonathan W.; Askoxylakis, Vasileios; Taylor, Jennie W.; Lu-Emerson, Christine; Batista, Ana; Kirkpatrick, Nathaniel D.; Jung, Keehoon; Snuderl, Matija; Muzikansky, Alona; Wakimoto, Hiroaki; Munn, Lance L.; Duda, Dan G.; Fukumura, Dai; Batchelor, Tracy T.; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Datta, Meenal] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA. [Taylor, Jennie W.; Lu-Emerson, Christine; Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Snuderl, Matija] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Muzikansky, Alona] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Stubenrauch, Kay G.; Krieter, Oliver] Roche Pharma Res & Early Dev, Roche Innovat Ctr Munich, D-82377 Penzberg, Germany. [Wakimoto, Hiroaki] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Riedemann, Lars] Univ Heidelberg Hosp, Neurol Clin, D-69120 Heidelberg, Germany. [Riedemann, Lars] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Riedemann, Lars] German Canc Res Ctr, Clin Cooperat Unit Neurooncol, German Canc Consortium, D-69120 Heidelberg, Germany. [Song, Jonathan W.] Ohio State Univ, Dept Mech & Aerosp Engn, Columbus, OH 43210 USA. [Taylor, Jennie W.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Lu-Emerson, Christine] Maine Med Ctr, Dept Neurol, Portland, ME 04102 USA. [Batista, Ana] Trends Canc, Cell Press, Cambridge, MA 02139 USA. [Kirkpatrick, Nathaniel D.] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA. [Snuderl, Matija] NYU, Dept Pathol, Langone Med Ctr, New York, NY 10016 USA. [Snuderl, Matija] Sch Med, New York, NY 10016 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA.; Batchelor, TT; Jain, RK (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA.; Batchelor, TT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. EM tbatchelor@mgh.harvard.edu; jain@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016; Riedemann, Lars/J-5725-2014; Song, Jonathan/C-1922-2013; Seano, Giorgio/R-6611-2016; OI Munn, Lance/0000-0003-0698-7232; Riedemann, Lars/0000-0002-9510-1845; Song, Jonathan/0000-0002-6991-5298; Seano, Giorgio/0000-0002-7294-302X; Snuderl, Matija/0000-0003-0752-0917 FU NIH [P50CA165962, P01CA080124, KCA125440, R01CA126642, R35CA197743, R01CA159258, R01CA096915, R01HL106584, S10-RR027070, T32-CA073479, K12CA090354]; National Cancer Institute/Federal Share Proton Beam Program Income; Department of Defense Breast Cancer Research Innovator Award [W81XWH-10-1-0016]; National Foundation for Cancer Research Fellow Award; Hoffmann-La Roche; German Research Foundation (DFG); Solidar-Immun Foundation; Mildred Scheel Fellowship (Deutsche Krebshilfe); Aid for Cancer Research Foundation; Susan G. Komen Postdoctoral Fellowship [PDF14301739]; Affymetrix; DFG FX We thank T. J. Diefenbach and the Ragon Institute Imaging Core (Harvard Center for AIDS Research Immunology Core) for technical and instrumental support for microscopy; B. A. Tannous for technical support with the Gluc-GFP reporter system; M. Duquette, S. Roberge, P. Huang, A. Khachatryan, M. Tedy, O. Pulluqi, I. Gorr, S. Imhof-Jung, H. Durr, T. v. Hirschheydt, M. Molhoj, H. Kettenberger, J. Moelleken, and H. Auer for outstanding technical assistance; and S. Chatterjee, M. Badeaux, S. Babykutty, T. Hato, D. Kodack, G. B. Ferraro, S. S. Islam, T. Mempel, T. Padera, Y. Huang, T. Peterson, S. M. Chin, S. Kozin, M. Thomas, K. Munro, M. Weidner, and H. J. Mueller for invaluable suggestions and experimental assistance. The study was supported in part by NIH Grants P50CA165962 (to T. T. B and R.K.J.), P01CA080124 (to R.K.J., D.G.D., D.F., and L.L.M.), KCA125440 (to T.T.B.), R01CA126642 and R35CA197743 (to R.K.J.), R01CA159258 (to D. G.D.), R01CA096915 (to D.F.), R01HL106584 (to L.L.M.), and S10-RR027070 (to D.F.); National Cancer Institute/Federal Share Proton Beam Program Income (R.K.J.); Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016 and National Foundation for Cancer Research Fellow Award (to R.K.J.); and a research grant from Hoffmann-La Roche. N.D.K. was supported by NIH Training Grant T32-CA073479. M.S., C.L.-E., and J.W.T. were supported by NIH Training Grant K12CA090354. J.K. received fellowships from the German Research Foundation (DFG) and the Solidar-Immun Foundation. L.R. received a Mildred Scheel Fellowship (Deutsche Krebshilfe). Z.A. received a fellowship from the Aid for Cancer Research Foundation. G. S. was supported by Susan G. Komen Postdoctoral Fellowship PDF14301739. M.S. received research support from Affymetrix. V.A. received financial support from the DFG. NR 67 TC 14 Z9 14 U1 4 U2 18 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 APR 19 PY 2016 VL 113 IS 16 BP 4476 EP 4481 DI 10.1073/pnas.1525360113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800065 PM 27044098 ER PT J AU Krager, SC Prochazka, AV AF Krager, Steven C. Prochazka, Allan V. TI Review: In women 50 to 69 y of age at average risk, mammography screening reduces breast cancer mortality SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID FORCE RECOMMENDATION STATEMENT; TRIAL C1 [Krager, Steven C.; Prochazka, Allan V.] Denver VA Med Ctr, Denver, CO USA. RP Krager, SC (reprint author), Denver VA Med Ctr, Denver, CO USA. NR 7 TC 0 Z9 0 U1 3 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 19 PY 2016 VL 164 IS 8 BP JC38 EP JC39 DI 10.7326/ACPJC-2016-164-8-038 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DJ5OH UT WOS:000374257900001 PM 27089086 ER PT J AU Prochazka, AV AF Prochazka, Allan V. TI Varenicline increased smoking cessation at 24 weeks in patients hospitalized with ACS and motivated to quit SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Prochazka, Allan V.] Denver VA Med Ctr, Denver, CO USA. RP Prochazka, AV (reprint author), Denver VA Med Ctr, Denver, CO USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 19 PY 2016 VL 164 IS 8 BP JC43 EP JC43 DI 10.7326/ACPJC-2016-164-6-043 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DJ5OH UT WOS:000374257900005 PM 27089093 ER PT J AU Dec, GW AF Dec, G. William TI How Should We Diagnose Myocarditis, and Is its Recognition Really Clinically Relevant? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE endomyocardial biopsy; extracellular volume; mapping; myocardial inflammation ID CARDIOMYOPATHY; THERAPY C1 [Dec, G. William] Massachusetts Gen Hosp, Div Cardiol, Yawkey 5B,55 Fruit St, Boston, MA 02114 USA. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5B,55 Fruit St, Boston, MA 02114 USA. EM gdec@partners.org NR 11 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 19 PY 2016 VL 67 IS 15 BP 1812 EP 1814 DI 10.1016/j.jacc.2016.02.036 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI8FC UT WOS:000373735800008 PM 27081021 ER PT J AU Iki, N Boros, E Nakamura, M Baba, R Caravan, P AF Iki, Nobuhiko Boros, Eszter Nakamura, Mami Baba, Ryo Caravan, Peter TI Gd(3)TCAS(2): An Aquated Gd3+-Thiacalix[4]arene Sandwich Cluster with Extremely Slow Ligand Substitution Kinetics SO INORGANIC CHEMISTRY LA English DT Article ID CONTRAST AGENTS; O-17 NMR; WATER-MOLECULES; GD3+ COMPLEXES; SERUM-ALBUMIN; MRI CONTRAST; COORDINATION SPHERE; PARACEST AGENTS; EXCHANGE; RELAXATION AB In aqueous solution, Gd3+ and thiacalix[4]arene-p-tetrasulfonate (TCAS) form the complex [Gd(3)TCAS(2)](7-), in which a trinuclear Gd3+ core is sandwiched by two TCAS ligands. Acid-catalyzed dissociation reactions, as well as transmetalation and ligand exchange with physiological concentrations of Zn2+ and phosphate, showed [Gd(3)TCAS(2)](7-) to be extremely inert compared to other Gd complexes. Luminescence lifetime measurements of the Tb analogue Tb(3)TCAS(2) allowed estimation of the mean hydration number q to be 2.4 per Tb ion. The longitudinal relaxivity of [Gd(3)TCAS(2)](7-) (per Gd3+) was r(1) = 5.83 mM(-1) s(-1) at 20 Hz (37 degrees C, pH 7.4); however, this relaxivity was limited by an extremely slow water exchange rate that was 5 orders of magnitude slower than the Gd3+ aqua ion. Binding to serum albumin resulted in no relaxivity increase owing to the extremely slow water exchange kinetics. The slow dissociation and water exchange kinetics of [Gd(3)TCAS(2)](7-) can be attributed to the very rigid coordination geometry. C1 [Iki, Nobuhiko; Nakamura, Mami; Baba, Ryo] Tohoku Univ, Grad Sch Environm Studies, Aoba Ku, 6-6-07 Aramaki Aoba, Sendai, Miyagi 9808579, Japan. [Boros, Eszter; Caravan, Peter] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. RP Iki, N (reprint author), Tohoku Univ, Grad Sch Environm Studies, Aoba Ku, 6-6-07 Aramaki Aoba, Sendai, Miyagi 9808579, Japan.; Caravan, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM iki@m.tohoku.ac.jp; caravan@nmr.mgh.harvard.edu FU National Institute for Biomedical Imaging and Bioengineering [R01EB009062]; National Center for Research Resources [S10OD010650, S10RR023385, P41RR14075]; Swiss National Science Foundation; NIH [K99HL125728]; JSPS [25288061] FX No competing financial interests have been declared. This work was supported in part by Award No. R01EB009062 from the National Institute for Biomedical Imaging and Bioengineering and the National Center for Research Resources for instrumentation (Grant Nos. S10OD010650, S10RR023385, and P41RR14075). E.B. thanks the Swiss National Science Foundation (advanced postdoc mobility fellowship) as well as the NIH (K99HL125728) for support. N.I. thanks JSPS for KAKENHI (Grant No. 25288061). NR 31 TC 2 Z9 2 U1 15 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 EI 1520-510X J9 INORG CHEM JI Inorg. Chem. PD APR 18 PY 2016 VL 55 IS 8 BP 4000 EP 4005 DI 10.1021/acs.inorgchem.6b00241 PG 6 WC Chemistry, Inorganic & Nuclear SC Chemistry GA DJ9BI UT WOS:000374508600035 PM 27018719 ER PT J AU Segata, N Baldini, F Pompon, J Garrett, WS Truong, DT Dabire, RK Diabate, A Levashina, EA Catteruccia, F AF Segata, Nicola Baldini, Francesco Pompon, Julien Garrett, Wendy S. Duy Tin Truong Dabire, Roch K. Diabate, Abdoulaye Levashina, Elena A. Catteruccia, Flaminia TI The reproductive tracts of two malaria vectors are populated by a core microbiome and by gender-and swarm-enriched microbial biomarkers SO SCIENTIFIC REPORTS LA English DT Article ID ANOPHELES-GAMBIAE; SP-NOV; MOLECULAR-FORMS; DROSOPHILA-MELANOGASTER; PLASMODIUM INFECTION; SYMBIOTIC BACTERIA; FIELD POPULATIONS; GENOME SEQUENCES; BURKINA-FASO; MOSQUITOS AB Microbes play key roles in shaping the physiology of insects and can influence behavior, reproduction and susceptibility to pathogens. In Sub-Saharan Africa, two major malaria vectors, Anopheles gambiae and An. coluzzii, breed in distinct larval habitats characterized by different microorganisms that might affect their adult physiology and possibly Plasmodium transmission. We analyzed the reproductive microbiomes of male and female An. gambiae and An. coluzzii couples collected from natural mating swarms in Burkina Faso. 16S rRNA sequencing on dissected tissues revealed that the reproductive tracts harbor a complex microbiome characterized by a large core group of bacteria shared by both species and all reproductive tissues. Interestingly, we detected a significant enrichment of several gender-associated microbial biomarkers in specific tissues, and surprisingly, similar classes of bacteria in males captured from one mating swarm, suggesting that these males originated from the same larval breeding site. Finally, we identified several endosymbiotic bacteria, including Spiroplasma, which have the ability to manipulate insect reproductive success. Our study provides a comprehensive analysis of the reproductive microbiome of important human disease vectors, and identifies a panel of core and endosymbiotic bacteria that can be potentially exploited to interfere with the transmission of malaria parasites by the Anopheles mosquito. C1 [Segata, Nicola; Duy Tin Truong] Univ Trento, Ctr Integrat Biol, Trento, Trento, Italy. [Baldini, Francesco; Garrett, Wendy S.; Catteruccia, Flaminia] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Baldini, Francesco] Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Glasgow G12 8QQ, Lanark, Scotland. [Baldini, Francesco; Catteruccia, Flaminia] Univ Perugia, Dipartimento Med Sperimentale & Sci Biochim, I-06100 Perugia, Italy. [Pompon, Julien; Levashina, Elena A.] Univ Strasbourg, INSERM, CNRS, UPR9022,U963, 15 Rue R Descartes, F-67084 Strasbourg, France. [Pompon, Julien] CNRS, IRD, UMR,UM1,UM2, MIVEGEC,Malad Infect & Vecteurs Ecol Genet Evolut, F-34394 Montpellier, France. [Pompon, Julien] Duke NUS Grad Med Sch, Programme Emerging Infect Dis, Singapore 169857, Singapore. [Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Dabire, Roch K.; Diabate, Abdoulaye] Ctr Muraz, Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso. [Levashina, Elena A.] Max Planck Inst Infect Biol, Vector Biol Unit, Charitepl 1, D-10117 Berlin, Germany. RP Catteruccia, F (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.; Catteruccia, F (reprint author), Univ Perugia, Dipartimento Med Sperimentale & Sci Biochim, I-06100 Perugia, Italy.; Levashina, EA (reprint author), Univ Strasbourg, INSERM, CNRS, UPR9022,U963, 15 Rue R Descartes, F-67084 Strasbourg, France.; Levashina, EA (reprint author), Max Planck Inst Infect Biol, Vector Biol Unit, Charitepl 1, D-10117 Berlin, Germany. EM levashina@mpiib-berlin.mpg.de; fcatter@hsph.harvard.edu OI Baldini, Francesco/0000-0002-5904-4070; Segata, Nicola/0000-0002-1583-5794 NR 62 TC 2 Z9 2 U1 5 U2 17 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 APR 18 PY 2016 VL 6 AR 24207 DI 10.1038/srep24207 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ5DD UT WOS:000374226100001 PM 27086581 ER PT J AU Pilliod, RA Feinberg, BB Burwick, RM AF Pilliod, Rachel A. Feinberg, Bruce B. Burwick, Richard M. TI Maternal and feto-placental phenotypes of early-onset severe preeclampsia SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Disease phenotype; HELLP; histopathology; obstetrics; placenta ID ANGIOGENIC FACTORS; HELLP-SYNDROME; PRE-ECLAMPSIA; MANAGEMENT; HYPERTENSION; GENETICS AB Objective: To characterize maternal and feto-placental phenotypes of severe preeclampsia that trigger early-onset delivery.Methods: A retrospective cohort review of pregnant women receiving care from 2000 to 2010. Subjects with early-onset severe preeclampsia delivering between 20 and 32 weeks were identified excluding multiple gestations or major anomalies. We defined indications for delivery as maternal (i.e. severe headache or abnormal laboratory parameters), feto-placental (i.e. non-reassuring tracing) or mixed (i.e. both maternal and feto-placental factors). To characterize the groups, demographic, clinical, laboratory, ultrasound and pathology data were abstracted. Statistical analysis was conducted.Results: We identified 164 subjects meeting inclusion criteria. Indications for delivery were maternal (57.3%), feto-placental (29.9%) or mixed (12.8%). Compared to neonates delivered for maternal indications, birthweight was significantly lower among neonates delivered for feto-placental or mixed indications (p<0.001). While placental findings were largely similar between groups, abnormal cord insertion was more common in subjects delivered for feto-placental factors (p=0.02). Women delivered for maternal indications had more significant lab abnormalities than women delivered for feto-placental or mixed indications.Conclusion: In attempting to classify early-onset severe preeclampsia by delivery indication, we found patterns to suggest that feto-placental and maternal phenotypes of disease may have distinct pathophysiologic underpinnings. C1 [Pilliod, Rachel A.] Brigham & Womens & Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA USA. [Feinberg, Bruce B.] Columbia Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, New York, NY USA. [Burwick, Richard M.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, Portland, OR 97201 USA. RP Pilliod, RA (reprint author), Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. EM rpilliod@partners.org NR 30 TC 0 Z9 0 U1 4 U2 18 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD APR 17 PY 2016 VL 29 IS 8 BP 1209 EP 1213 DI 10.3109/14767058.2015.1045867 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DB7TJ UT WOS:000368718700004 PM 25983137 ER PT J AU Schffoeffski, P Chawla, S Maki, RG Italiano, A Gelderblom, H Choy, E Grignani, G Camargo, V Bauer, S Rha, SY Blay, JY Hohenberger, P D'Adamo, D Guo, M Chmielowski, B Le Cesne, A Demetri, GD Patel, SR AF Schffoeffski, Patrick Chawla, Sant Maki, Robert G. Italiano, Antoine Gelderblom, Hans Choy, Edwin Grignani, Giovanni Camargo, Veridiana Bauer, Sebastian Rha, Sun Young Blay, Jean-Yves Hohenberger, Peter D'Adamo, David Guo, Matthew Chmielowski, Bartosz Le Cesne, Axel Demetri, George D. Patel, Shreyaskumar R. TI Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial SO LANCET LA English DT Article ID SOFT-TISSUE SARCOMA; DOUBLE-BLIND; MESYLATE; GEMCITABINE; ANTHRACYCLINE; CHEMOTHERAPY; IFOSFAMIDE; DOCETAXEL; PAZOPANIB AB Background A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). Methods We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1.4 mg/m(2) intravenously on days 1 and 8) or dacarbazine (850 mg/m(2), 1000 mg/m(2), or 1200 mg/m(2) [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue. Findings Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13.5 months [95% CI 10.9-15.6] vs 11.5 months [9.6-13.0]; hazard ratio 0.77 [95% CI 0.62-0.95]; p=0.0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators. Interpretation Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma. C1 [Schffoeffski, Patrick] Univ Hosp Leuven, Leuven Canc Inst, Dept Gen Med Oncol, B-3000 Leuven, Belgium. [Chawla, Sant] Sarcoma Oncol Ctr, Santa Monica, CA USA. [Maki, Robert G.] Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. [Italiano, Antoine] Inst Bergonie, Dept Oncol, Bordeaux, France. [Gelderblom, Hans] Leiden Univ, Med Ctr, Dept Med Oncol, Leiden, Netherlands. [Choy, Edwin] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Grignani, Giovanni] Fdn Piemonte Oncol IRCCS, Dept Med Oncol, Candiolo, Italy. [Camargo, Veridiana] Hosp Sirio Libanes, Dept Med Oncol, Sao Paulo, Brazil. [Camargo, Veridiana] Inst Canc Estado Sao Paulo, Sao Paulo, Brazil. [Bauer, Sebastian] Univ Duisburg Essen, West German Canc Ctr, Essen, Germany. [Rha, Sun Young] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. [Blay, Jean-Yves] Univ Lyon 1, LYRIC INCa DGOS 4664, F-69365 Lyon, France. [Blay, Jean-Yves] Ctr Leon Berard, F-69373 Lyon, France. [Hohenberger, Peter] Univ Mannheim, Med Ctr, Dept Surg, Div Surg Oncol & Thorac Surg, D-68131 Mannheim, Germany. [D'Adamo, David] Eisai & Co Ltd, Woodcliff Lake, NJ USA. [Chmielowski, Bartosz] Univ Calif Los Angeles, Jonsson Comprehens Canc, Dept Hematol, Los Angeles, CA USA. [Le Cesne, Axel] Gustave Roussy, Villejuif, France. [Demetri, George D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Sarcoma Ctr, 44 Binney St, Boston, MA 02115 USA. [Demetri, George D.] Harvard Univ, Sch Med, Ludwig Ctr, Boston, MA USA. [Patel, Shreyaskumar R.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. RP Schffoeffski, P (reprint author), Univ Hosp Leuven, Leuven Canc Inst, Dept Gen Med Oncol, B-3000 Leuven, Belgium. EM patrick.schoffski@uzleuven.be RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU Eisai FX Eisai. NR 26 TC 2 Z9 2 U1 4 U2 12 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 APR 16 PY 2016 VL 387 IS 10028 BP 1629 EP 1637 DI 10.1016/S0140-6736(15)01283-0 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3ZL UT WOS:000374145100030 ER PT J AU Brumpton, BM Langhammer, A Henriksen, AH Camargo, CA Chen, Y Romundstad, PR Mai, XM AF Brumpton, Ben Michael Langhammer, Arnulf Henriksen, Anne Hildur Camargo, Carlos Arturo, Jr. Chen, Yue Romundstad, Pal Richard Mai, Xiao-Mei TI Vitamin D and Lung Function Decline in Adults With Asthma SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE asthma; 25-hydroxyvitamin D; lung function; spirometry; vitamin D ID SERUM 25-HYDROXYVITAMIN D; D DEFICIENCY; PULMONARY-FUNCTION; D INSUFFICIENCY; HUNT; SMOKING; ASSOCIATION; COHORT; HEALTH AB We investigated whether low 25-hydroxyvitamin D (25(OH)D) levels were associated with more lung function decline in adults with asthma and whether this association was modified by smoking status or inhaled corticosteroid (ICS) use. We analyzed data on 395 adults with asthma from the Nord-Trondelag Health Study (1995-2008), Norway. Plasma 25(OH)D and lung function were measured at baseline, and lung function measurements were repeated at follow-up, approximately 11 years later. Linear regression was used to estimate lung function decline. Participants with low 25(OH)D (< 50 nmol/L) had more decline in lung function measurements for forced expiratory volume in 1 second (FEV1) (388 mL), forced vital capacity (298 mL), and the FEV1/forced vital capacity ratio (3.7%) over the follow-up, compared with those with high 25(OH)D (a parts per thousand yen50 nmol/L) who declined 314 mL, 246 mL, and 3.0%, respectively (P = 0.08, 0.30, and 0.23, respectively). The associations were stronger in never smokers and non-ICS users. In never smokers, low 25(OH)D levels were associated with more decline in FEV1 (445 vs. 222 mL) (P = 0.01). In non-ICS users, low 25(OH)D levels were associated with more decline in FEV1 (467 vs. 320 mL) (P = 0.02). Low serum 25(OH)D levels were weakly associated with more lung function decline in adults with asthma, and stronger associations were observed in never smokers and non-ICS users. C1 [Brumpton, Ben Michael; Langhammer, Arnulf; Romundstad, Pal Richard; Mai, Xiao-Mei] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Fac Med, NO-7491 Trondheim, Norway. [Henriksen, Anne Hildur] Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, NO-7491 Trondheim, Norway. [Henriksen, Anne Hildur] Univ Trondheim Hosp, Dept Thorac & Occupat Med, Trondheim, Norway. [Camargo, Carlos Arturo, Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Camargo, Carlos Arturo, Jr.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chen, Yue] Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada. RP Brumpton, BM (reprint author), Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, MTFS, Postbox 8905, NO-7491 Trondheim, Norway. EM ben.brumpton@ntnu.no FU Liaison Committee FX B.M.B. was supported by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. The Nord-Trondelag Health Study (The HUNT Study) is a collaboration among the HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology), the Nord-Trondelag County Council, the Central Norway Health Authority, and the Norwegian Institute of Public Health. NR 29 TC 0 Z9 0 U1 2 U2 2 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 APR 15 PY 2016 VL 183 IS 8 BP 739 EP 746 DI 10.1093/aje/kwv243 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DJ8PT UT WOS:000374475100008 PM 26994061 ER PT J AU Smirnov, P Safikhani, Z El-Hachem, N Wang, D She, A Olsen, C Freeman, M Selby, H Gendoo, DMA Grossmann, P Beck, AH Aerts, HJWL Lupien, M Goldenberg, A Haibe-Kains, B AF Smirnov, Petr Safikhani, Zhaleh El-Hachem, Nehme Wang, Dong She, Adrian Olsen, Catharina Freeman, Mark Selby, Heather Gendoo, Deena M. A. Grossmann, Patrick Beck, Andrew H. Aerts, Hugo J. W. L. Lupien, Mathieu Goldenberg, Anna Haibe-Kains, Benjamin TI PharmacoGx: an R package for analysis of large pharmacogenomic datasets SO BIOINFORMATICS LA English DT Article ID DRUG-SENSITIVITY AB Pharmacogenomics holds great promise for the development of biomarkers of drug response and the design of new therapeutic options, which are key challenges in precision medicine. However, such data are scattered and lack standards for efficient access and analysis, consequently preventing the realization of the full potential of pharmacogenonnics. To address these issues, we implemented PharmacoGx, an easy-to-use, open source package for integrative analysis of multiple pharnnacogenomic datasets. We demonstrate the utility of our package in comparing large drug sensitivity datasets, such as the Genomics of Drug Sensitivity in Cancer and the Cancer Cell Line Encyclopedia. Moreover, we show how to use our package to easily perform Connectivity Map analysis. With increasing availability of drug -related data, our package will open new avenues of research for meta-analysis of pharmacogenomic data. C1 [Smirnov, Petr; Safikhani, Zhaleh; Wang, Dong; She, Adrian; Olsen, Catharina; Freeman, Mark; Gendoo, Deena M. A.; Lupien, Mathieu; Haibe-Kains, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Safikhani, Zhaleh; Gendoo, Deena M. A.; Lupien, Mathieu; Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [El-Hachem, Nehme] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Olsen, Catharina] Interuniv Inst Bioinformat Brussels IB 2, Brussels, Belgium. [Olsen, Catharina] Univ Libre Bruxelles, Dept Informat, MLG, Brussels, Belgium. [Selby, Heather; Grossmann, Patrick; Aerts, Hugo J. W. L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Selby, Heather] Boston Univ, Dept Bioinformat, Boston, MA 02215 USA. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Lupien, Mathieu] Ontario Inst Canc Res, Toronto, ON, Canada. [Goldenberg, Anna] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Goldenberg, Anna] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. RP Haibe-Kains, B (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. EM bhaibeka@uhnresearch.ca RI Haibe-Kains, Benjamin/D-3702-2011; Aerts, Hugo/P-6350-2015; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Aerts, Hugo/0000-0002-2122-2003; Smirnov, Petr/0000-0001-9395-8450 FU Canadian Cancer Research Society; Ontario Institute for Cancer Research; CIHR-IG Computational Biology Undergraduate Summer Student Health Research Award; CIBC-Brain Canada Brain Cancer Research Training Award; Gattuso-Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre FX This work was supported by the Canadian Cancer Research Society and the Ontario Institute for Cancer Research. D.W. was supported by a CIHR-IG Computational Biology Undergraduate Summer Student Health Research Award. D.M.A.G. was supported by a CIBC-Brain Canada Brain Cancer Research Training Award. B.H.K. was supported by the Gattuso-Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre. NR 9 TC 4 Z9 4 U1 0 U2 2 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 APR 15 PY 2016 VL 32 IS 8 BP 1244 EP 1246 DI 10.1093/bioinformatics/btv723 PG 3 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 DJ8QJ UT WOS:000374476800024 PM 26656004 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Arnold M. Katz, MD: 1932-2016 In Memoriam SO CIRCULATION RESEARCH LA English DT Biographical-Item ID DOG C1 [Braunwald, Eugene] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Braunwald, E (reprint author), TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 7 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD APR 15 PY 2016 VL 118 IS 8 BP 1192 EP 1193 DI 10.1161/CIRCRESAHA.116.308448 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DK2YB UT WOS:000374779300004 PM 27540607 ER PT J AU Abers, MS Sandvall, BP Sampath, R Zuno, C Uy, N Yu, VL Stager, CE Musher, DM AF Abers, Michael S. Sandvall, Barcleigh P. Sampath, Rahul Zuno, Carlo Uy, Natalie Yu, Victor L. Stager, Charles E. Musher, Daniel M. TI Postobstructive Pneumonia: An Underdescribed Syndrome SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE community-acquired pneumonia; pneumonia; postobstructive pneumonia ID COMMUNITY-ACQUIRED PNEUMONIA; OBSTRUCTIVE PNEUMONITIS; BACTERIAL-COLONIZATION; ANTIBIOTIC-THERAPY; LUNG-CANCER; PROCALCITONIN; CARCINOMA; INFECTIONS; DISEASE AB Background. Postobstructive community-acquired pneumonia (PO-CAP) is relatively common in clinical practice. The clinical syndrome is poorly defined, and the role of infection as a cause of the infiltrate is uncertain. We prospectively studied patients with PO-CAP and compared them to a cohort of patients with bacterial community-acquired pneumonia (B-CAP). Methods. We prospectively studied patients hospitalized for CAP; 5.4% had PO-CAP, defined as a pulmonary infiltrate occurring distal to an obstructed bronchus. Sputum and blood cultures, viral polymerase chain reaction, urinary antigen tests, and serum procalcitonin (PCT) were done in nearly all cases. Clinical and laboratory characteristics of patients with PO-CAP were compared to those of patients with B-CAP. Results. In a 2-year period, we identified 30 patients with PO-CAP. Compared to patients with B-CAP, patients with PO-CAP had longer duration of symptoms (median, 14 vs 5 days; P < .001). Weight loss and cavitary lesions were more common (P < .01 for both comparisons) and leukocytosis was less common (P < .01) in patients with PO-CAP. A bacterial pathogen was implicated in only 3 (10%) PO-CAP cases. PCT was <0.25 ng/mL in 19 (63.3%) patients. Although no differences were observed in disease severity or rates of intensive care unit admissions, 30-day mortality was significantly higher in PO-CAP vs B-CAP (40.0% vs 11.7%; P < .01). Conclusions. Although there is substantial overlap, PO-CAP is a clinical entity distinct from B-CAP; a bacterial cause was identified in only 10% of patients. Our study has important implications for the clinical recognition of patients with PO-CAP, the role of microorganisms as etiologic agents, and the use of antibiotic therapy. C1 [Abers, Michael S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Abers, Michael S.] Harvard Univ, Sch Med, Boston, MA USA. [Sandvall, Barcleigh P.] Kaiser Permanente Med Ctr, Dept Head & Neck Surg, Oakland, CA USA. [Sampath, Rahul] Mayo Clin, Div Infect Dis, Rochester, MN USA. [Zuno, Carlo; Uy, Natalie; Stager, Charles E.; Musher, Daniel M.] Michael E DeBakey VA Med Ctr, Med Care Line Infect Dis Sect, Houston, TX USA. [Zuno, Carlo; Uy, Natalie; Stager, Charles E.; Musher, Daniel M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Zuno, Carlo; Uy, Natalie; Stager, Charles E.; Musher, Daniel M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Yu, Victor L.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. RP Abers, MS (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM mabers@partners.org FU National Institutes of Health [HHSN272201000040C] FX This work was supported by the National Institutes of Health (contract # HHSN272201000040C). Viral polymerase chain reaction assays were donated by BioFire Diagnostics. Assays for Legionella and pneumococcal antigen were donated by BinaxNOW. Procalcitonin kits were donated by bioMerieux. NR 25 TC 3 Z9 3 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2016 VL 62 IS 8 BP 957 EP 961 DI 10.1093/cid/civ1212 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DK7EU UT WOS:000375088500006 PM 26908806 ER PT J AU Baek, JI Kwon, SH Zuo, XF Choi, SY Kim, SH Lipschutz, JH AF Baek, Jeong-In Kwon, Sang-Ho Zuo, Xiaofeng Choi, Soo Young Kim, Seok-Hyung Lipschutz, Joshua H. TI Dynamin Binding Protein (Tuba) Deficiency Inhibits Ciliogenesis and Nephrogenesis in Vitro and in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE CDC42; cilia; guanine nucleotide exchange factor (GEF); kidney; membrane trafficking ID NUCLEOTIDE EXCHANGE FACTORS; EPITHELIAL-CELLS; CDC42 GEF; ZEBRAFISH PRONEPHROS; PRIMARY CILIUM; FACIOGENITAL DYSPLASIA; INDUCED TUBULOGENESIS; EXTRACELLULAR-MATRIX; SPINDLE ORIENTATION; ACTIN CYTOSKELETON AB Dysfunction of renal primary cilia leads to polycystic kidney disease. We previously showed that the exocyst, a protein trafficking complex, is essential for ciliogenesis and regulated by multiple Rho and Rab family GTPases, such as Cdc42. Cdc42 deficiency resulted in a disruption of renal ciliogenesis and a polycystic kidney disease phenotype in zebrafish and mice. Here we investigate the role of Dynamin binding protein (also known as Tuba), a Cdc42-specific guanine nucleotide exchange factor, in ciliogenesis and nephrogenesis using Tuba knockdown Madin-Darby canine kidney cells and tuba knockdown in zebrafish. Tuba depletion resulted in an absence of cilia, with impaired apical polarization and inhibition of hepatocyte growth factor-induced tubulogenesis in Tuba knockdown Madin-Darby canine kidney cell cysts cultured in a collagen gel. In zebrafish, tuba was expressed in multiple ciliated organs, and, accordingly, tuba start and splice site morphants showed various ciliary mutant phenotypes in these organs. Co-injection of tuba and cdc42 morpholinos at low doses, which alone had no effect, resulted in genetic synergy and led to abnormal kidney development with highly disorganized pronephric duct cilia. Morpholinos targeting two other guanine nucleotide exchange factors not known to be in the Cdc42/ciliogenesis pathway and a scrambled control morpholino showed no phenotypic effect. Given the molecular nature of Cdc42 and Tuba, our data strongly suggest that tuba and cdc42 act in the same ciliogenesis pathway. Our study demonstrates that Tuba deficiency causes an abnormal renal ciliary and morphogenetic phenotype. Tuba most likely plays a critical role in ciliogenesis and nephrogenesis by regulating Cdc42 activity. C1 [Baek, Jeong-In; Kwon, Sang-Ho; Zuo, Xiaofeng; Choi, Soo Young; Kim, Seok-Hyung; Lipschutz, Joshua H.] Med Univ S Carolina, Dept Med, Clin Sci Bldg 829,96 Jonathan Lucas St, Charleston, SC 29425 USA. [Lipschutz, Joshua H.] Ralph H Johnson Vet Affairs Med Ctr, Dept Med, Charleston, SC 29401 USA. RP Lipschutz, JH (reprint author), Med Univ S Carolina, Dept Med, Clin Sci Bldg 829,96 Jonathan Lucas St, Charleston, SC 29425 USA. EM Lipschut@musc.edu FU Department of Veterans Affairs Merit Award [2I01BX000820]; National Institutes of Health [2P30DK074038]; PKD Foundation fellowship award FX This work was supported in part by Department of Veterans Affairs Merit Award 2I01BX000820 (to J. H. L.), National Institutes of Health Grant 2P30DK074038 (to J. H. L.), and a PKD Foundation fellowship award (to J. I. B.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 74 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 15 PY 2016 VL 291 IS 16 BP 8632 EP 8643 DI 10.1074/jbc.M115.688663 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2VT UT WOS:000374773200026 PM 26895965 ER PT J AU Echeverri-Chacon, S Restrepo, R Cuartas-Velez, C Uribe-Patarroyo, N AF Echeverri-Chacon, Santiago Restrepo, Rene Cuartas-Velez, Carlos Uribe-Patarroyo, Nestor TI Vortex-enhanced coherent-illumination phase diversity for phase retrieval in coherent imaging systems SO OPTICS LETTERS LA English DT Article AB We propose a phase-retrieval method based on the numerical optimization of a new objective function using coherent phase-diversity images as inputs for the characterization of aberrations in coherent imaging systems. By employing a spatial light modulator to generate multiple-order spiral phase masks as diversities, we obtain an increase in the accuracy of the retrieved phase compared with similar state-of-the-art phase-retrieval techniques that use the same number of input images. We present simulations that show a consistent advantage of our technique, and experimental validation where our implementation is used to characterize a highly aberrated 4F optical system. (C) 2016 Optical Society of America C1 [Echeverri-Chacon, Santiago; Restrepo, Rene; Cuartas-Velez, Carlos] Univ EAFIT, Appl Opt Grp, Carrera 49 7 Sur 50, Medellin, Colombia. [Uribe-Patarroyo, Nestor] Harvard Univ, Sch Med, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. [Uribe-Patarroyo, Nestor] Massachusetts Gen Hosp, 40 Blossom St, Boston, MA 02114 USA. RP Echeverri-Chacon, S (reprint author), Univ EAFIT, Appl Opt Grp, Carrera 49 7 Sur 50, Medellin, Colombia. EM sechev14@eafit.edu.co OI Restrepo Gomez, Rene/0000-0002-3874-3032 FU National Institutes of Health (NIH) [P41EB015903] FX National Institutes of Health (NIH) (P41EB015903). NR 13 TC 0 Z9 0 U1 1 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 EI 1539-4794 J9 OPT LETT JI Opt. Lett. PD APR 15 PY 2016 VL 41 IS 8 BP 1817 EP 1820 DI 10.1364/OL.41.001817 PG 4 WC Optics SC Optics GA DJ7LC UT WOS:000374391900033 PM 27082353 ER PT J AU Stelloh, C Reimer, MH Pulakanti, K Blinka, S Peterson, J Pinello, L Jia, S Roumiantsev, S Hessner, MJ Milanovich, S Yuan, GC Rao, S AF Stelloh, Cary Reimer, Michael H. Pulakanti, Kirthi Blinka, Steven Peterson, Jonathan Pinello, Luca Jia, Shuang Roumiantsev, Sergei Hessner, Martin J. Milanovich, Samuel Yuan, Guo-Cheng Rao, Sridhar TI The cohesin-associated protein Wapal is required for proper Polycomb-mediated gene silencing SO EPIGENETICS & CHROMATIN LA English DT Article DE Cohesin complex; Epigenetics; Embryonic stem cells; Wapal; Polycomb complex ID EMBRYONIC STEM-CELLS; DE-LANGE-SYNDROME; GENOME-WIDE; CHROMATIN-STRUCTURE; CHROMOSOME ARMS; SELF-RENEWAL; CTCF; EXPRESSION; PLURIPOTENCY; DIFFERENTIATION AB Background: The cohesin complex consists of multiple core subunits that play critical roles in mitosis and transcriptional regulation. The cohesin-associated protein Wapal plays a central role in off-loading cohesin to facilitate sister chromatid separation, but its role in regulating mammalian gene expression is not understood. We used embryonic stem cells as a model, given that the well-defined transcriptional regulatory circuits were established through master transcription factors and epigenetic pathways that regulate their ability to maintain a pluripotent state. Results: RNAi-mediated depletion of Wapal causes a loss of pluripotency, phenocopying loss of core cohesin subunits. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), we determine that Wapal occupies genomic sites distal to genes in combination with CTCF and core cohesin subunits such as Rad21. Interestingly, genomic sites occupied by Wapal appear enriched for cohesin, implying that Wapal does not off-load cohesin at regions it occupies. Wapal depletion induces derepression of Polycomb group (PcG) target genes without altering total levels of Polycomb-mediated histone modifications, implying that PcG enzymatic activity is preserved. By integrating ChIP-seq and gene expression changes data, we identify that Wapal binding is enriched at the promoters of PcG-silenced genes and is required for proper Polycomb repressive complex 2 (PRC2) recruitment. Lastly, we demonstrate that Wapal is required for the interaction of a distal cis-regulatory element (CRE) with the c-Fos promoter. Conclusions: Collectively, this work indicates that Wapal plays a critical role in silencing of PcG target genes through the interaction of distal CREs with promoters. C1 [Stelloh, Cary; Reimer, Michael H.; Pulakanti, Kirthi; Blinka, Steven; Peterson, Jonathan; Rao, Sridhar] BloodCtr Wisconsin, Blood Res Inst, 8727 West Watertown Plank Rd, Milwaukee, WI 53226 USA. [Reimer, Michael H.; Blinka, Steven; Rao, Sridhar] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. [Pinello, Luca; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. [Jia, Shuang; Hessner, Martin J.; Rao, Sridhar] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Roumiantsev, Sergei] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Milanovich, Samuel] Univ S Dakota, Sanford Sch Med, Sanford Res Ctr, Sioux Falls, SD USA. RP Rao, S (reprint author), BloodCtr Wisconsin, Blood Res Inst, 8727 West Watertown Plank Rd, Milwaukee, WI 53226 USA. EM sridhar.rao@bcw.edu FU NHBLI [HL087951]; American Cancer Society (Institutional Research Grant) [86004]; Children's Research Institute; Midwest Athletes against Childhood Cancer; Hyundai Hope on Wheels FX This work was supported in part by funding from NHBLI (HL087951), a pilot grant from the American Cancer Society (Institutional Research Grant #86004), the Children's Research Institute, the Midwest Athletes against Childhood Cancer, and Hyundai Hope on Wheels, and generous philanthropic support from Mr. Douglas Ziegler, all to S. Rao. NR 76 TC 1 Z9 1 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD APR 15 PY 2016 VL 9 AR 14 DI 10.1186/s13072-016-0063-7 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA DK1LD UT WOS:000374672900001 PM 27087855 ER PT J AU Lennon, FE Cianci, GC Kanteti, R Riehm, JJ Arif, Q Poroyko, VA Lupovitch, E Vigneswaran, W Husain, A Chen, P Liao, JK Sattler, M Kindler, HL Salgia, R AF Lennon, Frances E. Cianci, Gianguido C. Kanteti, Rajani Riehm, Jacob J. Arif, Qudsia Poroyko, Valeriy A. Lupovitch, Eitan Vigneswaran, Wickii Husain, Aliya Chen, Phetcharat Liao, James K. Sattler, Martin Kindler, Hedy L. Salgia, Ravi TI Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma SO SCIENTIFIC REPORTS LA English DT Article ID BREAST-CANCER CELLS; PLEURAL MESOTHELIOMA; LUNG-CANCER; DRP1 RECRUITMENT; FISSION; METFORMIN; DYNAMICS; METABOLISM; MIGRATION; PATHOLOGY AB Malignant mesothelioma (MM), is an intractable disease with limited therapeutic options and grim survival rates. Altered metabolic and mitochondrial functions are hallmarks of MM and most other cancers. Mitochondria exist as a dynamic network, playing a central role in cellular metabolism. MM cell lines display a spectrum of altered mitochondrial morphologies and function compared to control mesothelial cells. Fractal dimension and lacunarity measurements are a sensitive and objective method to quantify mitochondrial morphology and most importantly are a promising predictor of response to mitochondrial inhibition. Control cells have high fractal dimension and low lacunarity and are relatively insensitive to mitochondrial inhibition. MM cells exhibit a spectrum of sensitivities to mitochondrial inhibitors. Low mitochondrial fractal dimension and high lacunarity correlates with increased sensitivity to the mitochondrial inhibitor metformin. Lacunarity also correlates with sensitivity to Mdivi-1, a mitochondrial fission inhibitor. MM and control cells have similar sensitivities to cisplatin, a chemotherapeutic agent used in the treatment of MM. Neither oxidative phosphorylation nor glycolytic activity, correlated with sensitivity to either metformin or mdivi-1. Our results suggest that mitochondrial inhibition may be an effective and selective therapeutic strategy in mesothelioma, and identifies mitochondrial morphology as a possible predictor of response to targeted mitochondrial inhibition. C1 [Lennon, Frances E.; Kanteti, Rajani; Riehm, Jacob J.; Kindler, Hedy L.; Salgia, Ravi] Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Lennon, Frances E.; Kanteti, Rajani; Riehm, Jacob J.; Kindler, Hedy L.; Salgia, Ravi] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Cianci, Gianguido C.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Arif, Qudsia; Husain, Aliya] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Poroyko, Valeriy A.] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. [Lupovitch, Eitan] Univ Maryland, College Pk, MD 20742 USA. [Vigneswaran, Wickii] Univ Chicago, Dept Surg, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Chen, Phetcharat; Liao, James K.] Univ Chicago, Dept Med, Cardiol Sect, Chicago, IL 60637 USA. [Sattler, Martin] Dana Farber Canc Inst, Hematol Oncol, Dept Med, Boston, MA 02215 USA. [Salgia, Ravi] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut, 1500 E Duarte Rd, Duarte, CA 91010 USA. RP Salgia, R (reprint author), Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM rsalgia@coh.org FU CRF; MARF; NCI; NIH [HL052233, DK085006] FX This work was supported by CRF, MARF and NCI grants to RS, and NIH grants HL052233 and DK085006 to JKL. NR 67 TC 0 Z9 0 U1 2 U2 8 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 APR 15 PY 2016 VL 6 AR 24578 DI 10.1038/srep24578 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ5BL UT WOS:000374221700003 PM 27080907 ER PT J AU Maatuf, Y Stern, EA Slovin, H AF Maatuf, Yossi Stern, Edward A. Slovin, Hamutal TI Abnormal Population Responses in the Somatosensory Cortex of Alzheimer's Disease Model Mice SO SCIENTIFIC REPORTS LA English DT Article ID MILD COGNITIVE IMPAIRMENT; NEURONS IN-VIVO; APPSWE/PS1DE9 MOUSE MODEL; RAT BARREL CORTEX; AMYLOID-BETA DEPOSITION; SPATIOTEMPORAL DYNAMICS; CORTICAL DYNAMICS; MEMORY DEFICITS; EEG SYNCHRONIZATION; SENSORY RESPONSES AB Alzheimer's disease (AD) is the most common form of dementia. One of the neuropathological hallmarks of AD is the accumulation of amyloid-beta plaques. Overexpression of human amyloid precursor protein in transgenic mice induces hippocampal and neocortical amyloid-beta accumulation and plaque deposition that increases with age. The impact of these effects on neuronal population responses and network activity in sensory cortex is not well understood. We used Voltage Sensitive Dye Imaging, to investigate at high spatial and temporal resolution, the sensory evoked population responses in the barrel cortex of aged transgenic (Tg) mice and of age-matched non-transgenic littermate controls (Ctrl) mice. We found that a whisker deflection evoked abnormal sensory responses in the barrel cortex of Tg mice. The response amplitude and the spatial spread of the cortical responses were significantly larger in Tg than in Ctrl mice. At the network level, spontaneous activity was less synchronized over cortical space than in Ctrl mice, however synchronization during evoked responses induced by whisker deflection did not differ between the two groups. Thus, the presence of elevated A beta and plaques may alter population responses and disrupts neural synchronization in large-scale networks, leading to abnormalities in sensory processing. C1 [Maatuf, Yossi] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel. [Stern, Edward A.; Slovin, Hamutal] Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, IL-5290002 Ramat Gan, Israel. [Stern, Edward A.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Slovin, H (reprint author), Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, IL-5290002 Ramat Gan, Israel. EM Hamutal.Slovin@biu.ac.il NR 102 TC 0 Z9 0 U1 1 U2 7 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 APR 15 PY 2016 VL 6 AR 24560 DI 10.1038/srep24560 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ5BH UT WOS:000374221300002 PM 27079783 ER PT J AU Karacsonyi, J Karatasakis, A Karmpaliotis, D Alaswad, K Yeh, RW Jaffer, FA Wyman, MR Lombardi, WL Grantham, JA Kandzari, DE Lembo, N Moses, JW Kirtane, AJ Parikh, MA Green, P Finn, M Garcia, S Doing, A Patel, M Bahadorani, J Parachini, JRM Resendes, E Rangan, BV Ungi, I Thompson, CA Banerjee, S Brilakis, ES AF Karacsonyi, Judit Karatasakis, Aris Karmpaliotis, Dimitri Alaswad, Khaldoon Yeh, Robert W. Jaffer, Farouc A. Wyman, Michael R. Lombardi, William L. Grantham, J. Aaron Kandzari, David E. Lembo, Nicholas Moses, Jeffrey W. Kirtane, Ajay J. Parikh, Manish A. Green, Philip Finn, Matthew Garcia, Santiago Doing, Anthony Patel, Mitul Bahadorani, John Parachini, Jose Roberto Martinez Resendes, Erica Rangan, Bavana V. Ungi, Imre Thompson, Craig A. Banerjee, Subhash Brilakis, Emmanouil S. TI Effect of Previous Failure on Subsequent Procedural Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention (from a Contemporary Multicenter Registry) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID US REGISTRY; HYBRID APPROACH; CTO REGISTRY; INSIGHTS; SCORE; VALIDATION; EFFICACY; SUCCESS; JAPAN AB We sought to examine the impact of previous failure on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We examined the clinical and angiographic characteristics and procedural outcomes of 1,213 consecutive patients who underwent 1,232 CTO PCIs from 2012 to 2015 at 12 US centers. Mean age was 65 10 years, and 84.8% of patients were men. A previously failed attempt had been performed in 215 patients (17.5%). As compared with patients without previous CTO PCI failure, patients with previous failure had higher Multicenter CTO Registry in Japan CTO score (2.40 +/- 1.13 vs 3.28 +/- 1.29, p <0.0001) and were more likely to have in-stent restenosis (10.5% vs 28.4%, p <0.0001) and to undergo recanalization attempts using the retrograde approach (41% vs 50%, p = 0.011). Technical (90% vs 88%, p = 0.390) and procedural (89% vs 86%, p = 0.184) success were similar in the 2 study groups; however, median procedure time (125 vs 142 minutes, p = 0.026) and fluoroscopy time (45 vs 55 minutes, p = 0.015) were longer in the previous failure group. In conclusion, a previously failed CTO PCI attempt is associated with higher angiographic complexity, longer procedural duration, and fluoroscopy time, but not with the success and complication rates of subsequent CTO PCI attempts. Published by Elsevier Inc. C1 [Karacsonyi, Judit; Karatasakis, Aris; Parachini, Jose Roberto Martinez; Resendes, Erica; Rangan, Bavana V.; Banerjee, Subhash; Brilakis, Emmanouil S.] Univ Texas SW Med Ctr Dallas, Vet Affairs North Texas Hlth Care Syst, Dallas, TX 75390 USA. [Karacsonyi, Judit; Ungi, Imre] Univ Szeged, Dept Internal Med 2, Div Invas Cardiol, Szeged, Hungary. [Karmpaliotis, Dimitri; Moses, Jeffrey W.; Kirtane, Ajay J.; Parikh, Manish A.; Green, Philip; Finn, Matthew] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA. [Alaswad, Khaldoon] Henry Ford Hosp, Dept Cardiol, Detroit, MI 48202 USA. [Yeh, Robert W.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiol, Boston, MA USA. [Wyman, Michael R.] Torrance Mem Med Ctr, Dept Cardiol, Torrance, CA USA. [Lombardi, William L.] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Grantham, J. Aaron] St Lukes Hosp, Mid Amer Heart Inst, Dept Cardiol, Kansas City, MO 64111 USA. [Kandzari, David E.; Lembo, Nicholas] Piedmt Heart Inst, Intervent Cardiol, Atlanta, GA USA. [Garcia, Santiago] Univ Minnesota, Dept Med, Minneapolis Vet Affairs Hlth Care Syst, Box 736 UMHC, Minneapolis, MN 55455 USA. [Doing, Anthony] Med Ctr Rockies, Dept Cardiol, Loveland, CO USA. [Patel, Mitul; Bahadorani, John] Univ Calif San Diego, Vet Affairs San Diego Hlth Care Syst, Dept Cardiol, San Diego, CA 92103 USA. [Thompson, Craig A.] Boston Sci, Natick, MA USA. RP Brilakis, ES (reprint author), Univ Texas SW Med Ctr Dallas, Vet Affairs North Texas Hlth Care Syst, Dallas, TX 75390 USA. EM esbrilakis@gmail.com FU CTSA NIH [UL1-RR024982] FX Supported by CTSA NIH Grant UL1-RR024982. NR 16 TC 3 Z9 3 U1 1 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 15 PY 2016 VL 117 IS 8 BP 1267 EP 1271 DI 10.1016/j.amjcard.2016.01.021 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DJ1NC UT WOS:000373968500011 PM 26899493 ER PT J AU Ferrario, CM VonCannon, J Jiao, Y Ahmad, S Bader, M Dell'Italia, LJ Groban, L Varagic, J AF Ferrario, Carlos M. VonCannon, Jessica Jiao, Yan Ahmad, Sarfaraz Bader, Michael Dell'Italia, Louis J. Groban, Leanne Varagic, Jasmina TI Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE angiotensin converting enzyme inhibitors; angiotensin II; angiotensinogen; cardiac angiotensins; chymase; angiotensin-(1-12); renin ID CONVERTING ENZYME; HUMAN RENIN; BLOOD-PRESSURE; II GENERATION; CHYMASE; HEART; INTRACRINE; PROANGIOTENSIN-12; IDENTIFICATION; METABOLISM AB Angiotensin-(1-12) [ANG-(1-12)] is processed into ANG II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human ANG-(1-12) render the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin-dependent effects of increased hAGT expression on heart function and arterial pressure. Compared with Sprague-Dawley (SD) control rats (n = 11), male homozygous TGR(hAGT)L1623 (n = 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human ANG-(1-12) immunofluorescence within myocytes of TGR(hAGT) L1623 rats was associated with a fourfold increase in cardiac ANG II content. Chymase enzymatic activity, using the rat or human ANG-(1-12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac angiotensin-converting enzyme (ACE) and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular ANG II content might be a product of an increased cardiac expression of ANG II generated through a non-renin-dependent mechanism. The data also underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function. C1 [Ferrario, Carlos M.; VonCannon, Jessica; Jiao, Yan; Varagic, Jasmina] Wake Forest Sch Med, Dept Surg, Winston Salem, NC USA. [VonCannon, Jessica; Ahmad, Sarfaraz; Groban, Leanne; Varagic, Jasmina] Wake Forest Sch Med, Hypertens & Vasc Res Ctr, Winston Salem, NC USA. [Bader, Michael] Max Delbruck Ctr Mol Med MDC, Berlin, Germany. [Dell'Italia, Louis J.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Dept Vet Affairs, Birmingham, AL USA. [Groban, Leanne] Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC USA. [Ferrario, Carlos M.; Varagic, Jasmina] Wake Forest Sch Med, Dept Med Nephrol, Winston Salem, NC USA. [Ferrario, Carlos M.; Varagic, Jasmina] Wake Forest Sch Med, Dept Physiol Pharmacol, Winston Salem, NC USA. RP Varagic, J (reprint author), Wake Forest Sch Med, Hypertens & Vasc Res Ctr, Div Surg Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jvaragic@wakehealth.edu FU National Heart, Lung, and Blood Institute [P01-HL-051952]; Wake Forest University TSC-Reynolda Grant [U01079] FX This research was supported by National Heart, Lung, and Blood Institute Grant P01-HL-051952 (to C. M. Ferrario) and Wake Forest University TSC-Reynolda Grant U01079 (to J. Varagic). NR 39 TC 2 Z9 2 U1 2 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD APR 15 PY 2016 VL 310 IS 8 BP H995 EP H1002 DI 10.1152/ajpheart.00833.2015 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DJ3IY UT WOS:000374099500005 PM 26873967 ER PT J AU Shahid, M Spagnolli, E Ernande, L Thoonen, R Kolodziej, SA Leyton, PA Cheng, J Tainsh, RET Mayeur, C Rhee, DK Wu, MX Scherrer-Crosbie, M Buys, ES Zapol, WM Bloch, KD Bloch, DB AF Shahid, Mohd Spagnolli, Ester Ernande, Laura Thoonen, Robrecht Kolodziej, Starsha A. Leyton, Patricio A. Cheng, Juan Tainsh, Robert E. T. Mayeur, Claire Rhee, David K. Wu, Mei. X. Scherrer-Crosbie, Marielle Buys, Emmanuel S. Zapol, Warren M. Bloch, Kenneth D. Bloch, Donald B. TI BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE cardiac hypertrophy; BMP signaling; calcineurin; BMP type I receptor; ALK2 ID SIGNAL-TRANSDUCTION; MICE; CARDIOMYOPATHY; GROWTH; CELLS; APOPTOSIS; ATROGIN-1; CHANNELS; ATROPHY; KINASE AB Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. C1 [Shahid, Mohd; Spagnolli, Ester; Kolodziej, Starsha A.; Leyton, Patricio A.; Tainsh, Robert E. T.; Mayeur, Claire; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.; Bloch, Donald B.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Shahid, Mohd; Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A.; Leyton, Patricio A.; Cheng, Juan; Tainsh, Robert E. T.; Mayeur, Claire; Rhee, David K.; Wu, Mei. X.; Scherrer-Crosbie, Marielle; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.; Bloch, Donald B.] Harvard Univ, Sch Med, Boston, MA USA. [Ernande, Laura; Thoonen, Robrecht; Cheng, Juan; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Shahid, Mohd; Wu, Mei. X.] Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St,Thier 320, Boston, MA 02114 USA. [Rhee, David K.; Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Shahid, M (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St,Thier 320, Boston, MA 02114 USA. EM mshahid.mgh@gmail.com FU National Institute of Diabetes and Digestive and Kidney Diseases [R01DK082971]; Leducq Foundation; LaDue Memorial Fellowship Award; French Federation of Cardiology FX This work was supported by grants from National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082971 to K. D. Bloch, D. B. Bloch), the Leducq Foundation (C.Mayeur, P.A. Leyton, K. D. Bloch, D. B. Bloch), a LaDue Memorial Fellowship Award (D. K. Rhee), and from the French Federation of Cardiology (L. Ernande). NR 27 TC 0 Z9 0 U1 2 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD APR 15 PY 2016 VL 310 IS 8 BP H984 EP H994 DI 10.1152/ajpheart.00879.2015 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DJ3IY UT WOS:000374099500004 PM 26873969 ER PT J AU Ligibel, JA Giobbie-Hurder, A Shockro, L Campbell, N Partridge, AH Tolaney, SM Lin, NU Winer, EP AF Ligibel, Jennifer A. Giobbie-Hurder, Anita Shockro, Laura Campbell, Nancy Partridge, Ann H. Tolaney, Sara M. Lin, Nancy U. Winer, Eric P. TI Randomized trial of a physical activity intervention in women with metastatic breast cancer SO CANCER LA English DT Article DE breast cancer; exercise; metastatic; physical function; quality of life ID QUALITY-OF-LIFE; EXERCISE; SURVIVORS; OUTCOMES; FATIGUE; METAANALYSIS; DIAGNOSIS; THERAPY; COLLEGE; DISEASE AB BACKGROUNDExercise interventions improve fitness, functional capacity, and quality of life in patients with early-stage breast cancer, but to the authors' knowledge there are few data regarding the feasibility or potential benefits of exercise in women with metastatic breast cancer. METHODSIndividuals with metastatic breast cancer were randomized 1:1 to a 16-week moderate-intensity exercise intervention or wait-list control group. Intervention goals included 150 minutes of moderate-intensity aerobic exercise per week. The baseline and 16-week evaluations included a modified Bruce Ramp treadmill test, 7-day Physical Activity Recall interview, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C-30) questionnaire. RESULTSA total of 101 participants were randomized (48 to the intervention group and 53 to the control group). The median age of the participants was 49 years, the median time since the diagnosis of metastatic breast cancer was 1.1 years, and approximately 42% of participants were undergoing chemotherapy at the time of enrollment. Study attrition was higher in the intervention arm (14 participants vs 8 participants; P = .15). Women randomized to the exercise intervention experienced a nonsignificant increase with regard to minutes of weekly exercise (62.4 minutes vs 46.0 minutes; P = .17) and physical functioning (EORTC QLQ C30: 4.79 vs 0.93 [P = .23] and Bruce Ramp Treadmill test: 0.61 minutes vs 0.37 minutes [P = .35]) compared with control participants. CONCLUSIONSParticipation in an exercise intervention did not appear to result in significant improvements in physical functioning in a heterogeneous group of women living with advanced breast cancer. Given the significant benefits of exercise in women with early-stage breast cancer, more work is needed to explore alternative interventions to determine whether exercise could help women with metastatic disease live more fully with fewer symptoms from disease and treatment. Cancer 2016;122:1169-77. (c) 2016 American Cancer Society. Participation in an exercise intervention appears to be safe for women living with advanced breast cancer, but was not found to result in significant improvements in physical functioning or quality of life. More work, focusing on women with newly diagnosed metastatic disease, is needed to determine whether exercise interventions can help women with metastatic breast cancer to live more fully with fewer symptoms from disease and treatment. C1 [Ligibel, Jennifer A.; Shockro, Laura; Campbell, Nancy; Partridge, Ann H.; Tolaney, Sara M.; Lin, Nancy U.; Winer, Eric P.] Harvard Univ, Sch Med, Breast Oncol Ctr, Dana Farber Canc Inst, 450 Brookline Ave,Yawkey 1234, Boston, MA 02215 USA. [Giobbie-Hurder, Anita] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Stat & Computat Biol, 450 Brookline Ave,Yawkey 1234, Boston, MA 02215 USA. RP Ligibel, JA (reprint author), Harvard Univ, Sch Med, Breast Oncol Ctr, Dana Farber Canc Inst, 450 Brookline Ave,Yawkey 1234, Boston, MA 02215 USA. EM jligibel@partners.org FU McMackin Foundation FX Supported by a grant from the McMackin Foundation. NR 22 TC 2 Z9 2 U1 5 U2 5 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 APR 15 PY 2016 VL 122 IS 8 BP 1169 EP 1177 DI 10.1002/cncr.29899 PG 9 WC Oncology SC Oncology GA DJ1IZ UT WOS:000373957800008 PM 26872302 ER PT J AU Fletcher, SA Cronin, AM Zeidan, AM Odejide, OO Gore, SD Davidoff, AJ Steensma, DP Abel, GA AF Fletcher, Sean A. Cronin, Angel M. Zeidan, Amer M. Odejide, Oreofe O. Gore, Steven D. Davidoff, Amy J. Steensma, David P. Abel, Gregory A. TI Intensity of end-of-life care for patients with myelodysplastic syndromes: Findings from a large national database SO CANCER LA English DT Article DE end-of-life care; health services; hematologic malignancies; myelodysplastic syndromes; quality ID HEMATOLOGIC MALIGNANCIES; ETHNIC-DIFFERENCES; CANCER-PATIENTS; UNITED-STATES; HOSPICE USE; THERAPY; EPIDEMIOLOGY; CHEMOTHERAPY; BARRIERS; QUALITY AB BACKGROUNDAs the population ages, the prevalence of myelodysplastic syndromes (MDS) will increase, and many patients with MDS will require end-of-life (EOL) care. Little is known about the intensity of EOL care received by patients with these malignancies. METHODSUsing the Surveillance, Epidemiology, and End Results-Medicare database and standard EOL quality measures, we assessed the prevalence and predictors of intensive care unit (ICU) admission in the last 30 days of life, chemotherapy in the last 14 days of life, and hospice enrollment among MDS patients who were 65 years old or older and died between 2006 and 2011. RESULTSOf 6,955 patients, 28% were admitted to the ICU and 7% received chemotherapy near the EOL, while 49% enrolled in hospice. In multivariable models, patients dependent on red blood cell or platelet transfusions at the EOL were less likely to enroll in hospice (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.61-0.78). Nonwhite patients were less likely to enroll in hospice (OR, 0.77; 95% CI, 0.67-0.89) and more likely to be admitted to the ICU near the EOL (OR, 1.19; 95% CI, 1.03-1.38). Finally, the prevalence of hospice enrollment increased in later years (P < .001). CONCLUSIONSThe intensity of EOL care for patients with MDS varies but is potentially suboptimal with respect to the traditional measure of hospice use. The lower odds of enrollment for transfusion-dependent patients suggest that the current hospice model, which largely disallows transfusions, may not be meeting the palliative needs of this population. Cancer 2016;122:1209-15. (c) 2016 American Cancer Society. A large database analysis demonstrates that the intensity of end-of-life care for patients with myelodysplastic syndromes varies but is potentially suboptimal with respect to hospice use. The lower odds of enrollment for transfusion-dependent patients suggest that the current hospice model, which largely disallows transfusions, may not be meeting the palliative needs of this population. C1 [Fletcher, Sean A.; Cronin, Angel M.; Odejide, Oreofe O.; Steensma, David P.; Abel, Gregory A.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Zeidan, Amer M.; Gore, Steven D.; Davidoff, Amy J.] Yale Canc Ctr, New Haven, CT USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM gregory_abel@dfci.harvard.edu FU American Society of Hematology Minority Medical Student Award Program; American Cancer Society Clinical Scholar Award; Aplastic Anemia & MDS International Foundation/Evans Foundation; Dennis Cooper Hematology Young Investigator Award FX This study was funded by the American Society of Hematology Minority Medical Student Award Program (to Sean A. Fletcher), the American Cancer Society Clinical Scholar Award (to Gregory A. Abel), the Aplastic Anemia & MDS International Foundation/Evans Foundation (to David P. Steensma), and the Dennis Cooper Hematology Young Investigator Award (to Amer M. Zeidan). NR 35 TC 1 Z9 1 U1 2 U2 2 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 APR 15 PY 2016 VL 122 IS 8 BP 1209 EP 1215 DI 10.1002/cncr.29913 PG 7 WC Oncology SC Oncology GA DJ1IZ UT WOS:000373957800012 PM 26914833 ER PT J AU DePeralta, DK Wei, L Ghoshal, S Schmidt, B Lauwers, GY Lanuti, M Chung, RT Tanabe, KK Fuchs, BC AF DePeralta, Danielle K. Wei, Lan Ghoshal, Sarani Schmidt, Benjamin Lauwers, Gregory Y. Lanuti, Michael Chung, Raymond T. Tanabe, Kenneth K. Fuchs, Bryan C. TI Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis SO CANCER LA English DT Article DE hepatocellular carcinoma (HCC); liver; oval cells; prevention; receptor for advanced glycation end products (RAGE) ID CANCER STEM-CELLS; CHRONIC LIVER-DISEASE; TUMOR-INITIATING CELLS; DIABETIC-PATIENTS; PANCREATIC-CANCER; RESPIRATORY-CHAIN; BREAST-CANCER; REDUCED RISK; RECEPTOR; TUMORIGENESIS AB BACKGROUNDHepatocellular carcinoma (HCC)-associated mortality is increasing at an alarming rate, and there is a readily identifiable cohort of at-risk patients with cirrhosis, viral hepatitis, nonalcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention because it is inexpensive, has a favorable safety profile, and is well tolerated over long time periods. METHODSThe authors studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, in which tumors develop in the setting of chronic inflammation and cirrhosis. Repeated injections of diethylnitrosamine were used to induce sequential cirrhosis and HCC, and metformin was administered at the first signs of either fibrosis or cirrhosis. RESULTSProlonged metformin exposure was safe and was associated with decreases in fibrotic and inflammatory markers, especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, whereas tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. It is noteworthy that activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis; therefore, only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells. CONCLUSIONSThe current results are the first to demonstrate an effect on progenitor/stem cells in the setting of chemoprevention and provide further rationale to explore metformin as an early intervention in clinical trials of patients with chronic liver disease at high risk for HCC. Cancer 2016;122:1216-27. (c) 2016 American Cancer Society. This is the first report to demonstrate that chemopreventive effects of metformin are mediated through progenitor/stem cells. The results provide further evidence that early and long-term treatment with metformin is a promising strategy for the prevention of tumors in the liver: its main site of action. C1 [DePeralta, Danielle K.; Wei, Lan; Ghoshal, Sarani; Schmidt, Benjamin; Tanabe, Kenneth K.; Fuchs, Bryan C.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, 55 Fruit St,WRN 401, Boston, MA 02114 USA. [DePeralta, Danielle K.; Wei, Lan; Ghoshal, Sarani; Schmidt, Benjamin; Lauwers, Gregory Y.; Lanuti, Michael; Chung, Raymond T.; Tanabe, Kenneth K.; Fuchs, Bryan C.] Harvard Univ, Sch Med, Boston, MA USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, 55 Fruit St,WRN 401, Boston, MA 02114 USA. [Lanuti, Michael] Massachusetts Gen Hosp, Ctr Canc, Div Thorac Surg, 55 Fruit St,WRN 401, Boston, MA 02114 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, 55 Fruit St,WRN 401, Boston, MA 02114 USA. RP Fuchs, BC (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WRN 401, Boston, MA 02114 USA. EM bfuchs@partners.org FU National Institutes of Health [T32CA071345, K01CA140861]; Massachusetts General Hospital Department of Surgery FX This work was supported by the National Institutes of Health (grants T32CA071345 to Danielle K. DePeralta, Benjamin Schmidt, and Kenneth K. Tanabe; and grant K01CA140861 to Bryan C. Fuchs) and the Massachusetts General Hospital Department of Surgery (Kenneth K. Tanabe). NR 48 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 15 PY 2016 VL 122 IS 8 BP 1216 EP 1227 DI 10.1002/cncr.29912 PG 12 WC Oncology SC Oncology GA DJ1IZ UT WOS:000373957800013 PM 26914713 ER PT J AU Krishnatry, R Zhukova, N Stucklin, ASG Pole, JD Mistry, M Fried, I Ramaswamy, V Bartels, U Huang, A Laperriere, N Dirks, P Nathan, PC Greenberg, M Malkin, D Hawkins, C Bandopadhayay, P Kieran, MW Manley, PE Bouffet, E Tabori, U AF Krishnatry, Rahul Zhukova, Nataliya Stucklin, Ana S. Guerreiro Pole, Jason D. Mistry, Matthew Fried, Iris Ramaswamy, Vijay Bartels, Ute Huang, Annie Laperriere, Normand Dirks, Peter Nathan, Paul C. Greenberg, Mark Malkin, David Hawkins, Cynthia Bandopadhayay, Pratiti Kieran, Mark W. Manley, Peter E. Bouffet, Eric Tabori, Uri TI Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study SO CANCER LA English DT Article DE children; glioma; low-grade; neurofibromatosis type 1 (NF1); outcome; radiation ID CENTRAL-NERVOUS-SYSTEM; CONFORMAL RADIATION-THERAPY; CHILDRENS ONCOLOGY GROUP; CANCER SURVIVOR; PILOMYXOID ASTROCYTOMA; PILOCYTIC ASTROCYTOMAS; HYPOTHALAMIC GLIOMAS; BRAIN-STEM; PHASE-II; CHEMOTHERAPY AB BACKGROUNDThe determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. METHODSThis study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n=1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTSAt a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1%1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P<.001) and a thalamic location (P<.001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P=.001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P=.013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P=.012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P=0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P<.001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONSThe course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. Cancer 2016;122:1261-9. (c) 2016 American Cancer Society. This is a large population-based study looking at long-term survivors of childhood low-grade glioma. Although the course of pediatric low-grade glioma is associated with excellent long-term survival, this study unravels worrisome information about late deaths for patients receiving upfront radiation therapy. C1 [Krishnatry, Rahul; Zhukova, Nataliya; Stucklin, Ana S. Guerreiro; Ramaswamy, Vijay; Bartels, Ute; Huang, Annie; Laperriere, Normand; Nathan, Paul C.; Greenberg, Mark; Malkin, David; Bouffet, Eric; Tabori, Uri] Univ Toronto, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Krishnatry, Rahul; Zhukova, Nataliya; Mistry, Matthew; Huang, Annie; Dirks, Peter; Hawkins, Cynthia; Tabori, Uri] Univ Toronto, Labatt Brain Tumor Res Ctr, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Krishnatry, Rahul; Mistry, Matthew; Laperriere, Normand] Univ Toronto, Princess Margaret Hosp, Radiat Med Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Zhukova, Nataliya; Mistry, Matthew; Malkin, David] Univ Toronto, Program Genet & Genome Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Zhukova, Nataliya; Pole, Jason D.; Greenberg, Mark; Malkin, David] Pediat Oncol Grp Ontario, Toronto, ON, Canada. [Mistry, Matthew; Fried, Iris; Tabori, Uri] Univ Toronto, Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Mistry, Matthew; Tabori, Uri] Univ Toronto, Inst Med Sci, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Fried, Iris] Hadassah Med Ctr, Kiryat Haddasah, IL-91120 Jerusalem, Israel. [Ramaswamy, Vijay; Bartels, Ute; Huang, Annie; Nathan, Paul C.; Greenberg, Mark; Malkin, David; Bouffet, Eric; Tabori, Uri] Univ Toronto, Dept Pediat, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Dirks, Peter] Univ Toronto, Div Neurosurg, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Hawkins, Cynthia] Univ Toronto, Div Pathol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Bandopadhayay, Pratiti; Kieran, Mark W.; Manley, Peter E.] Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Pediat Hematol Oncol, Boston, MA USA. [Bandopadhayay, Pratiti] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Tabori, U (reprint author), Univ Toronto, Hosp Sick Children, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM uri.tabori@sickkids.ca OI Guerreiro Stucklin, Ana S./0000-0003-3136-9241 FU B.R.A.I.N. (Brain Tumor Research Assistance and Information Network) Child Canada; Pediatric Low-Grade Astrocytoma Foundation; Stop and Shop Pediatric Brain Tumor Program; St. Baldrick's Foundation; Society for NeuroOncology; Pediatric Oncology Group of Ontario FX This work was supported by grants from B.R.A.I.N. (Brain Tumor Research Assistance and Information Network) Child Canada, the Pediatric Low-Grade Astrocytoma Foundation, the Stop and Shop Pediatric Brain Tumor Program, and the St. Baldrick's Foundation. Rahul Krishnatry was supported by the Society for NeuroOncology through an international research development fellowship. Nataliya Zhukova was supported by the Pediatric Oncology Group of Ontario through a fellowship. NR 44 TC 2 Z9 2 U1 3 U2 5 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 APR 15 PY 2016 VL 122 IS 8 BP 1261 EP 1269 DI 10.1002/cncr.29907 PG 9 WC Oncology SC Oncology GA DJ1IZ UT WOS:000373957800018 PM 26970559 ER PT J AU Maus, MV June, CH AF Maus, Marcela V. June, Carl H. TI Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MULTIPLE-MYELOMA; GENETIC-MODIFICATION; ANTITUMOR-ACTIVITY; CD28 COSTIMULATION; ENHANCED SURVIVAL; SUPPRESSOR-CELLS; PROSTATE-CANCER; TUMOR STROMA; CAR-T AB Chimeric antigen receptors (CAR) are engineered fusion proteins constructed from antigen recognition, signaling, and costimulatory domains that can be expressed in cytotoxic T cells with the purpose of reprograming the T cells to specifically target tumor cells. CAR T-cell therapy uses gene transfer technology to reprograma patient's own T cells to stably express CARs, thereby combining the specificity of an antibody with the potent cytotoxic and memory functions of a T cell. In early-phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses within a population of otherwise refractory patients with B-cell malignancies and, more specifically, have shown complete response rates of approximately 90% in patients with relapsed or refractory acute lymphoblastic leukemia. Given this clinical efficacy, preclinical development of CAR T-cell therapy for a number of cancer indications has been actively investigated, and the future of the CAR T-cell field is extensive and dynamic. Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into the mechanisms regulating the persistence of CAR T cells. In addition, numerous early-phase clinical trials are now investigating CAR T-cell therapy beyond targeting CD19, especially in solid tumors. Trials investigating combinations of CAR T cells with immune checkpoint blockade therapies are now beginning and results are eagerly awaited. This review evaluates several of the ongoing and future directions of CAR T-cell therapy. (C) 2016 AACR. C1 [Maus, Marcela V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [June, Carl H.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Maus, MV (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bldg 149,Room 7-219,13th St, Charlestown, MA 02129 USA.; June, CH (reprint author), Smilow Ctr Translat Res, Ctr Cellular Immunotherapies, Room 8-123,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM mvmaus@mgh.harvard.edu; cjune@exchange.upenn.edu FU NCI NIH HHS [K08 CA166039]; PHS HHS [K08166039] NR 90 TC 21 Z9 24 U1 15 U2 61 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2016 VL 22 IS 8 BP 1875 EP 1884 DI 10.1158/1078-0432.CCR-15-1433 PG 10 WC Oncology SC Oncology GA DJ3JP UT WOS:000374101400008 PM 27084741 ER PT J AU Land, SR Toll, BA Moinpour, CM Mitchell, SA Ostroff, JS Hatsukami, DK Duffy, SA Gritz, ER Rigotti, NA Brandon, TH Prindiville, SA Sarna, LP Schnoll, RA Herbst, RS Cinciripini, PM Leischow, SJ Dresler, CM Fiore, MC Warren, GW AF Land, Stephanie R. Toll, Benjamin A. Moinpour, Carol M. Mitchell, Sandra A. Ostroff, Jamie S. Hatsukami, Dorothy K. Duffy, Sonia A. Gritz, Ellen R. Rigotti, Nancy A. Brandon, Thomas H. Prindiville, Sheila A. Sarna, Linda P. Schnoll, Robert A. Herbst, Roy S. Cinciripini, Paul M. Leischow, Scott J. Dresler, Carolyn M. Fiore, Michael C. Warren, Graham W. TI Research Priorities, Measures, and Recommendations for Assessment of Tobacco Use in Clinical Cancer Research SO CLINICAL CANCER RESEARCH LA English DT Article ID SELF-REPORTED SMOKING; RESEARCH POLICY STATEMENT; LUNG-CANCER; AMERICAN ASSOCIATION; CESSATION SUPPORT; DIAGNOSIS; TRIALS; ONCOLOGY; OPPORTUNITIES; ACCURACY AB There is strong evidence that cigarette smoking causes adverse outcomes in people with cancer. However, more research is needed regarding those effects and the effects of alternative tobacco products and of secondhand smoke, the effects of cessation (before diagnosis, during treatment, or during survivorship), the biologic mechanisms, and optimal strategies for tobacco dependence treatment in oncology. Fundamentally, tobacco is an important source of variation in clinical treatment trials. Nevertheless, tobacco use assessment has not been uniform in clinical trials. Progress has been impeded by a lack of consensus regarding tobacco use assessment suitable for cancer patients. The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified priority research areas and developed recommendations for assessment items and timing of assessment in cancer research. A cognitive interview study was conducted with 30 cancer patients at the NIH Clinical Center to evaluate and improve the measurement items. The resulting Cancer Patient Tobacco Use Questionnaire (C-TUQ) includes "Core" items for minimal assessment of tobacco use at initial and follow-up time points, and an "Extension" set. Domains include the following: cigarette and other tobacco use status, intensity, and past use; use relative to cancer diagnosis and treatment; cessation approaches and history; and secondhand smoke exposure. The Task Force recommends that assessment occur at study entry and, at a minimum, at the end of protocol therapy in clinical trials. Broad adoption of the recommended measures and timing protocol, and pursuit of the recommended research priorities, will help us to achieve a clearer understanding of the significance of tobacco use and cessation for cancer patients. (C) 2016 AACR. C1 [Land, Stephanie R.; Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. [Toll, Benjamin A.; Warren, Graham W.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. [Ostroff, Jamie S.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Hatsukami, Dorothy K.] Univ Minnesota DKH, Masonic Canc Ctr, Minneapolis, MN USA. [Duffy, Sonia A.] Ohio State Univ, Coll Nursing, Columbus, OH 43210 USA. [Duffy, Sonia A.] Ohio State Univ, HSR&D Ctr Excellence, VA Ctr Clin Management Res, Columbus, OH 43210 USA. [Gritz, Ellen R.; Cinciripini, Paul M.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. [Brandon, Thomas H.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hlth Outcomes & Behav, Tampa, FL 33682 USA. [Prindiville, Sheila A.] NCI, Coordinating Ctr Clin Trials, Bethesda, MD 20892 USA. [Sarna, Linda P.] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. [Schnoll, Robert A.] Univ Penn, Philadelphia, PA 19104 USA. [Herbst, Roy S.] Yale Univ, Sch Med, New Haven, CT USA. [Leischow, Scott J.] Mayo Clin, Ctr Canc, Coll Med, Phoenix, AZ USA. [Fiore, Michael C.] Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, Madison, WI USA. [Warren, Graham W.] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Warren, Graham W.] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. RP Land, SR (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM landsr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [P30 CA008748] NR 53 TC 3 Z9 3 U1 4 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2016 VL 22 IS 8 BP 1907 EP 1913 DI 10.1158/1078-0432.CCR-16-0104 PG 7 WC Oncology SC Oncology GA DJ3JP UT WOS:000374101400011 PM 26888828 ER PT J AU Nilsson, MB Giri, U Gudikote, J Tang, XM Lu, W Tran, H Fan, YH Koo, A Diao, LX Tong, P Wang, J Herbst, R Johnson, BE Ryan, A Webster, A Rowe, P Wistuba, II Heymach, JV AF Nilsson, Monique B. Giri, Uma Gudikote, Jayanthi Tang, Ximing Lu, Wei Tran, Hai Fan, Youhong Koo, Andrew Diao, Lixia Tong, Pan Wang, Jing Herbst, Roy Johnson, Bruce E. Ryan, Andy Webster, Alan Rowe, Philip Wistuba, Ignacio I. Heymach, John V. TI KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; PROTEIN-KINASE; TUMOR ANGIOGENESIS; ANTIANGIOGENIC THERAPY; 2ND-LINE TREATMENT; CARCINOMA-CELLS; FACTOR RECEPTOR; PHASE-3 TRIAL AB Purpose: VEGF pathway inhibitors have been investigated as therapeutic agents in the treatment of non-small cell lung cancer (NSCLC) because of its central role in angiogenesis. These agents have improved survival in patients with advanced NSCLC, but the effects have been modest. Although VEGFR2/KDR is typically localized to the vasculature, amplification of KDR has reported to occur in 9% to 30% of the DNA from different lung cancers. We investigated the signaling pathways activated downstream of KDR and whether KDR amplification is associated with benefit in patients with NSCLC treated with the VEGFR inhibitor vandetanib. Methods: NSCLC cell lines with or without KDR amplification were studied for the effects of VEGFR tyrosine kinase inhibitors (TKI) on cell viability and migration. Archival tumor samples collected from patients with platinum-refractory NSCLC in the phase III ZODIAC study of vandetanib plus docetaxel or placebo plus docetaxel (N = 294) were screened for KDR amplification by FISH. Results: KDR amplification was associated with VEGF-induced activation of mTOR, p38, and invasiveness in NSCLC cell lines. However, VEGFR TKIs did not inhibit proliferation of NSCLC cell lines with KDR amplification. VEGFR inhibition decreased cell motility as well as expression of HIF1a in KDR-amplified NSCLC cells. In the ZODIAC study, KDR amplification was observed in 15% of patients and was not associated with improved progression-free survival, overall survival, or objective response rate for the vandetanib arm. Conclusions: Preclinical studies suggest KDR activates invasion but not survival pathways in KDR-amplified NSCLC models. Patients with NSCLC whose tumor had KDR amplification were not associated with clinical benefit for vandetanib in combination with docetaxel. (C) 2015 AACR. C1 [Nilsson, Monique B.; Giri, Uma; Gudikote, Jayanthi; Tran, Hai; Fan, Youhong; Koo, Andrew; Wistuba, Ignacio I.; Heymach, John V.] Univ Texas MD Anderson Canc Ctr, Dept Thoracic Head & Neck Med Oncol, Unit 432,1515 Holcombe Blvd, Houston, TX 77030 USA. [Tang, Ximing; Lu, Wei; Wistuba, Ignacio I.] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Unit 432,1515 Holcombe Blvd, Houston, TX 77030 USA. [Diao, Lixia; Tong, Pan; Wang, Jing] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Unit 432,1515 Holcombe Blvd, Houston, TX 77030 USA. [Herbst, Roy] Yale Canc Ctr, Sect Med Oncol, New Haven, CT USA. [Herbst, Roy] Smilow Canc Hosp, New Haven, CT USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Johnson, Bruce E.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Ryan, Andy] Univ Oxford, Dept Oncol, Oxford, England. [Webster, Alan; Rowe, Philip] AstraZeneca, Cambridge, England. RP Heymach, JV (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac & Head & Neck Med, Unit 432,1515 Holcombe Blvd, Houston, TX 77030 USA.; Heymach, JV (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Unit 432,1515 Holcombe Blvd, Houston, TX 77030 USA. EM jheymach@mdanderson.org FU NCI NIH HHS [5P50CA070907, 1R01 CA168484-01, CA016672, P30 CA016672, P50 CA070907, R01 CA168484, R01 CA205150] NR 62 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2016 VL 22 IS 8 BP 1940 EP 1950 DI 10.1158/1078-0432.CCR-15-1994 PG 11 WC Oncology SC Oncology GA DJ3JP UT WOS:000374101400015 PM 26578684 ER PT J AU Garcia, JS Huang, M Medeiros, BC Mitchell, BS AF Garcia, Jacqueline S. Huang, Min Medeiros, Bruno C. Mitchell, Beverly S. TI Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; HISTONE DEACETYLASE INHIBITOR; ANTIOXIDANT RESPONSE ELEMENT; RELAPSED/REFRACTORY MULTIPLE-MYELOMA; SUBEROYLANILIDE HYDROXAMIC ACID; ORAL PROTEASOME INHIBITOR; TRANSCRIPTION FACTOR NRF2; NF-KAPPA-B; PHASE-I AB Purpose: This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action. Experimental Design: The cytotoxic effects of ixazomib treatment were analyzed in human acute myelogenous leukemia (AML) cell lines and primary AML samples expressing wild-type or mutatedNPM1(NPMc(+)). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and Western blots. Results: Apoptosis induced by ixazomib was abrogated by knockdown of NPM1/NPMc(+) expression using an inducible shRNA construct and enhanced by NPMc(+) overexpression. Cytotoxicity was associated with superoxide generation and was reduced by the addition of the antioxidant N-acetylcys-teine. AML cells expressing NPMc(+) had significantly reduced levels of intracellular glutathione and NADPH associated with reduced antioxidant responses to drug treatment. Treatment of 3 patients with relapsed NPMc(+) AML resulted in an antileukemic effect in 1 patient as demonstrated by a marked reduction of leukemic blasts in the peripheral blood. Efficacy was associated with superoxide generation, reduced glutathione levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells. Conclusions: In this study, a direct association was observed between NPMc(+) expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib. (C) 2015 AACR. C1 [Garcia, Jacqueline S.; Medeiros, Bruno C.; Mitchell, Beverly S.] Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA. [Huang, Min; Medeiros, Bruno C.; Mitchell, Beverly S.] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA. RP Garcia, JS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM jacqueline_garcia@dfci.harvard.edu NR 43 TC 1 Z9 1 U1 5 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2016 VL 22 IS 8 BP 1978 EP 1988 DI 10.1158/1078-0432.CCR-15-1440 PG 11 WC Oncology SC Oncology GA DJ3JP UT WOS:000374101400019 PM 26634271 ER PT J AU Ernande, L Stanford, KI Thoonen, R Zhang, HH Clerte, M Hirshman, MF Goodyear, LJ Bloch, KD Buys, ES Scherrer-Crosbie, M AF Ernande, Laura Stanford, Kristin I. Thoonen, Robrecht Zhang, Haihua Clerte, Maeva Hirshman, Michael F. Goodyear, Laurie J. Bloch, Kenneth D. Buys, Emmanuel S. Scherrer-Crosbie, Marielle TI Relationship of brown adipose tissue perfusion and function: a study through beta 2-adrenoreceptor stimulation SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE brown adipose tissue; perfusion; blood flow; beta 2-adrenoreceptor agonist; glucose uptake ID BETA-ADRENOCEPTOR SUBTYPES; DIET-INDUCED THERMOGENESIS; BLOOD-FLOW; GLUCOSE-UPTAKE; INSULIN SENSITIVITY; FAT-CELLS; NONSHIVERING THERMOGENESIS; CONTRAST ULTRASOUND; ADULT HUMANS; IN-VIVO AB Brown adipose tissue (BAT) activation increases glucose and lipid consumption; as such, it is been considered as a potential therapy to decrease obesity. BAT is highly vascularized and its activation is associated with a necessary increase in blood flow. However, whether increasing BAT blood flow per se increases BAT activity is unknown. To examine this hypothesis, we investigated whether an isolated increase in BAT blood flow obtained by beta 2-adrenoreceptor (beta 2-AR) stimulation with salbutamol increased BAT activity. BAT blood flow was estimated in vivo in mice using contrast-enhanced ultrasound. The absence of direct effect of salbutamol on the function of isolated brown adipocytes was assessed by measuring oxygen consumption. The effect of salbutamol on BAT activity was investigated by measuring BAT glucose uptake in vivo. BAT blood flow increased by 2.3 +/- 0.6-fold during beta 2-AR stimulation using salbutamol infusion in mice (P = 0.003). beta 2-AR gene expression was detectable in BAT but was extremely low in isolated brown adipocytes. Oxygen consumption of isolated brown adipocytes did not change with salbutamol exposure, confirming the absence of a direct effect of beta 2-AR agonist on brown adipocytes. Finally, beta 2-AR stimulation by salbutamol increased BAT glucose uptake in vivo (991 +/- 358 vs. 135 +/- 49 ng glucose/mg tissue/45 min in salbutamol vs. saline injected mice, respectively, P = 0.046). In conclusion, an increase in BAT blood flow without direct stimulation of the brown adipocytes is associated with increased BAT metabolic activity. Increasing BAT blood flow might represent a new therapeutic target in obesity. C1 [Ernande, Laura; Thoonen, Robrecht; Zhang, Haihua; Clerte, Maeva; Scherrer-Crosbie, Marielle] Harvard Univ, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. [Ernande, Laura; Thoonen, Robrecht; Zhang, Haihua; Clerte, Maeva; Scherrer-Crosbie, Marielle] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Cardiovasc Res Ctr,Div Car, Boston, MA USA. [Ernande, Laura] Hop Henri Mondor, Assistance Publ Hop Paris, DHU Ageing Thorax Vessel Blood, F-94010 Creteil, France. [Stanford, Kristin I.; Hirshman, Michael F.; Goodyear, Laurie J.] Brigham & Womens Hosp, Joslin Diabet Ctr, Div Res, 75 Francis St, Boston, MA 02115 USA. [Stanford, Kristin I.; Hirshman, Michael F.] Harvard Univ, Sch Med, Boston, MA USA. [Goodyear, Laurie J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Bloch, Kenneth D.; Buys, Emmanuel S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med,Anesthesia C, Boston, MA USA. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Blake 254,55 Fruit St, Boston, MA 02114 USA. EM marielle@crosbie.com FU National Institute of Diabetes and Digestive and Kidney Diseases [R21-DK092909, R01-AR42238, R01-DK099511, 5P30DK036836-27]; French Federation of Cardiology Grant (Federation Francaise de Cardiologie); American College of Sports Medicine Research Endowment Grant; Mary K. Iacocca Fellowship FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R21-DK092909 (to M.S.-C.), R01-AR42238, R01-DK099511, and 5P30DK036836-27 (to L.J.G.); French Federation of Cardiology Grant (Federation Francaise de Cardiologie, to L.E.); American College of Sports Medicine Research Endowment Grant (to K.I.S.) and Mary K. Iacocca Fellowship (to K.I.S.). NR 54 TC 2 Z9 2 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD APR 15 PY 2016 VL 120 IS 8 BP 825 EP 832 DI 10.1152/japplphysiol.00634.2015 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA DJ3KD UT WOS:000374102900002 PM 26823340 ER PT J AU Stary, V Puppala, D Scherrer-Crosbie, M Dillmann, WH Armoundas, AA AF Stary, Victoria Puppala, Dheeraj Scherrer-Crosbie, Marielle Dillmann, Wolfgang H. Armoundas, Antonis A. TI SERCA2a upregulation ameliorates cellular alternans induced by metabolic inhibition SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE electrophysiological; molecular; EC coupling; calcium; mitochondria; cardiac alternans; SERCA; heart failure; arrhythmias ID RAT CARDIAC MYOCYTES; SARCOPLASMIC-RETICULUM; MITOCHONDRIAL CALCIUM; VENTRICULAR-ARRHYTHMIAS; DIABETIC CARDIOMYOPATHY; ELECTRICAL ALTERNANS; ISCHEMIA-REPERFUSION; CA2+ CONCENTRATION; CYTOSOLIC CALCIUM; ATRIAL MYOCYTES AB Cardiac alternans has been associated with the incidence of ventricular tachyarrhythmias and sudden cardiac death. The aim of this study was to investigate the effect of impaired mitochondrial function in the genesis of cellular alternans and to examine whether modulating the sarcoplasmic reticulum (SR) Ca2+ ameliorates the level of alternans. Cardiomyocytes isolated from control and doxycyline-induced sarco( endo) plasmic reticulum Ca2+-ATPase 2a (SERCA2a)-upregulated mice were loaded with two different Ca(2+)indicators to selectively measure mitochondrial and cytosolic Ca(2+)using a custom-made fluorescence photometry system. The degree of alternans was defined as the alternans ratio (AR) [1 - (small Ca2+ intensity)/(large Ca(2+)intensity)]. Blocking of complex I and II, cytochrome-c oxidase, F0F1 synthase,alpha-ketoglutarate dehydrogenase of the electron transport chain, increased alternans in both control and SERCA2a mice (P < 0.01). Changes in AR in SERCA2a-upregulated mice were significantly less pronounced than those observed in control in seven of nine tested conditions (P < 0.04). N-acetyl-L-cysteine (NAC), rescued alternans in myocytes that were previously exposed to an oxidizing agent (P < 0.001). CGP, an antagonist of the mitochondrial Na+-Ca2+ exchanger, had the most severe effect on AR. Exposure to cyclosporin A, a blocker of the mitochondrial permeability transition pore reduced CGP-induced alternans (P < 0.0001). The major findings of this study are that impairment of mitochondrial Ca2+ cycling and energy production leads to a higher amplitude of alternans in both control and SERCA2a-upregulated mice, but changes in SERCA2a-upregulated mice are less severe, indicating that SERCA2a mice are more capable of sustaining electrical stability during stress. This suggests a relationship between sarcoplasmic Ca(2+)content and mitochondrial dysfunction during alternans, which may potentially help to understand changes in Ca2+ signaling in myocytes from diseased hearts, leading to new therapeutic targets. C1 [Stary, Victoria; Puppala, Dheeraj; Scherrer-Crosbie, Marielle; Armoundas, Antonis A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Stary, Victoria] Charite, Dept Cardiol & Pulmonol, Campus Benjamin Franklin, D-13353 Berlin, Germany. [Dillmann, Wolfgang H.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org OI Stary, Victoria/0000-0002-3854-9934 FU American Heart Association (AHA) Scientist Development Grant [0635127N]; AHA [14GRNT20400001]; National Institute of Aging [1R21AG035128]; Stiftung Charite, Deutscher Akademischer Austauschdienst and Arztefinanzzentrum Berlin FX This work was supported by an American Heart Association (AHA) Scientist Development Grant (no. 0635127N), AHA Grant-in-Aid (no. 14GRNT20400001), and by National Institute of Aging Grant 1R21AG035128 to A. A. Armoundas. Support for this work was also provided by Stiftung Charite, Deutscher Akademischer Austauschdienst and Arztefinanzzentrum Berlin to V. Stary. NR 53 TC 0 Z9 0 U1 2 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD APR 15 PY 2016 VL 120 IS 8 BP 865 EP 875 DI 10.1152/japplphysiol.00588.2015 PG 11 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA DJ3KD UT WOS:000374102900006 PM 26846549 ER PT J AU Sun, N Sun, PP Lv, HP Sun, YG Guo, JH Wang, ZR Luo, TT Wang, SY Li, HQ AF Sun, Na Sun, Panpan Lv, Haipeng Sun, Yaogui Guo, Jianhua Wang, Zhirui Luo, Tiantian Wang, Shaoyu Li, Hongquan TI Matrine displayed antiviral activity in porcine alveolar macrophages co-infected by porcine reproductive and respiratory syndrome virus and porcine circovirus type 2 SO SCIENTIFIC REPORTS LA English DT Article ID KAPPA-B ACTIVATION; IN-VITRO; REPLICATION; PCV2; EXPRESSION; INJURY; PIGS; INHIBITION; APOPTOSIS; DISEASE AB The co-infection of porcine reproductive respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) is quite common in clinical settings and no effective treatment to the co-infection is available. In this study, we established the porcine alveolar macrophages (PAM) cells model co-infected with PRRSV/PCV2 with modification in vitro, and investigated the antiviral activity of Matrine on this cell model and further evaluated the effect of Matrine on virus-induced TLR3,4/NF-kappa B/TNF-alpha pathway. The results demonstrated PAM cells inoculated with PRRSV followed by PCV2 2 h later enhanced PRRSV and PCV2 replications. Matrine treatment suppressed both PRRSV and PCV2 infection at 12 h post infection. Furthermore, PRRSV/PCV2 co-infection induced I kappa B alpha degradation and phosphorylation as well as the translocation of NF-kappa B from the cytoplasm to the nucleus indicating that PRRSV/PCV2 co-infection induced NF-kappa B activation. Matrine treatment significantly down-regulated the expression of TLR3, TLR4 and TNF-alpha although it, to some extent, suppressed p-I kappa B alpha expression, suggesting that TLR3,4/NF-kappa B/TNF-alpha pathway play an important role of Matrine in combating PRRSV/PCV2 co-infection. It is concluded that Matrine possesses activity against PRRSV/PCV2 co-infection in vitro and suppression of the TLR3,4/NF-kappa B/TNF-alpha pathway as an important underlying molecular mechanism. These findings warrant Matrine to be further explored for its antiviral activity in clinical settings. C1 [Sun, Na; Sun, Panpan; Lv, Haipeng; Sun, Yaogui; Li, Hongquan] Shanxi Agr Univ, Coll Anim Sci & Vet Med, Taigu 030801, Shanxi, Peoples R China. [Guo, Jianhua] Texas A&M Univ, Coll Vet Med, Dept Pathobiol, College Stn, TX 77843 USA. [Wang, Zhirui] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02114 USA. [Wang, Zhirui] Harvard Univ, Sch Med, Boston, MA USA. [Luo, Tiantian] Shanxi Vet Prevent & Treatment Stn, Taiyuan 030024, Peoples R China. [Wang, Shaoyu] Charles Sturt Univ, Fac Sci, Sch Community Hlth, Orange, NSW, Australia. RP Li, HQ (reprint author), Shanxi Agr Univ, Coll Anim Sci & Vet Med, Taigu 030801, Shanxi, Peoples R China. EM livets@163.com FU Agriculture Science Technology Achievement Transformation Fund [2014GB2A300003]; Graduate Innovation Project of Shanxi Province [20143054]; Key Scientific and Technological Grant from Shanxi Province [20130311026-6] FX This work was supported by Agriculture Science Technology Achievement Transformation Fund (Grant No. 2014GB2A300003) and Graduate Innovation Project of Shanxi Province (Grant No. 20143054) and the Key Scientific and Technological Grant from Shanxi Province (Grant No. 20130311026-6). NR 35 TC 3 Z9 3 U1 7 U2 11 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 APR 15 PY 2016 VL 6 AR 24401 DI 10.1038/srep24401 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ4HL UT WOS:000374165900001 PM 27080155 ER PT J AU Liu, H Rose, ME Culver, S Ma, XC Dixon, CE Graham, SH AF Liu, Hao Rose, Marie E. Culver, Sherman Ma, Xiecheng Dixon, C. Edward Graham, Steven H. TI Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Traumatic brain injury; PPAR gamma; Inflammation; Rosiglitazone; Behavioral; Cell survival ID SPINAL-CORD-INJURY; PPAR-GAMMA; STROKE; AGONIST; DYSFUNCTION; MECHANISMS; THERAPIES; DEFICITS; TARGET; DAMAGE AB Rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been shown to confer neuroprotective effects in stroke and spinal cord injury, but its role in the traumatic brain injury (TBI) is still controversial. Using a controlled cortical impact model in rats, the current study was designed to determine the effects of rosiglitazone treatment (6 mg/kg at 5 min, 6 h and 24 h post injury) upon inflammation and histological outcome at 21 d after TBI. In addition, the effects of rosiglitazone upon inflammatory cytokine transcription, vestibulomotor behavior and spatial memory function were determined at earlier time points (24 h, 1-5 d, 14-20 d post injury, respectively). Compared with the vehicle-treated group, rosiglitazone treatment suppressed production of TNF alpha at 24 h after TBI, attenuated activation of microglia/macrophages and increased survival of CA3 neurons but had no effect on lesion volume at 21 d after TBI. Rosiglitazone-treated animals had improved performance on beam balance testing, but there was no difference in spatial memory function as determined by Morris water maze. In summary, this study indicates that rosiglitazone treatment in the first 24 h after TBI has limited anti-inflammatory and neuroprotective effects in rat traumatic injury. Further study using an alternative dosage paradigm and more sensitive behavioral testing may be warranted. Published by Elsevier Inc. C1 [Liu, Hao; Rose, Marie E.; Culver, Sherman; Ma, Xiecheng; Dixon, C. Edward; Graham, Steven H.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Liu, Hao; Rose, Marie E.; Graham, Steven H.] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15260 USA. [Culver, Sherman; Ma, Xiecheng; Dixon, C. Edward] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA 15216 USA. [Culver, Sherman; Ma, Xiecheng; Dixon, C. Edward] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15216 USA. RP Graham, SH (reprint author), VA Pittsburgh Healthcare Ctr Res, Geriatr Res Educ & Clin Ctr, Off Bldg 30,Mail Code 151, Pittsburgh, PA 15240 USA. EM Steven.Graham@va.gov FU Veteran's Affairs Rehabilitation Research and Development Merit Review Program Award [I01RX000310] FX This work was supported by the Veteran's Affairs Rehabilitation Research and Development Merit Review Program Award I01RX000310 (S.H.G.). NR 26 TC 2 Z9 2 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 15 PY 2016 VL 472 IS 4 BP 648 EP 655 DI 10.1016/j.bbrc.2016.03.003 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DI8LX UT WOS:000373753600013 PM 26947332 ER PT J AU Bryce, SA Wilson, RAM Tiplady, EM Asquith, DL Bromley, SK Luster, AD Graham, GJ Nibbs, RJB AF Bryce, Steven A. Wilson, Ruairi A. M. Tiplady, Eleanor M. Asquith, Darren L. Bromley, Shannon K. Luster, Andrew D. Graham, Gerard J. Nibbs, Robert J. B. TI ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTOR D6; DENDRITIC CELLS; T-CELLS; IN-VIVO; CCX-CKR; LANGERHANS CELLS; ORGAN CHEMOKINE; MIGRATION; EXPRESSION; GRADIENTS AB Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21. CCL21 alone is sufficient for the migration of APCs from skin to LN. CCL19 and CCL21 also bind atypical chemokine receptor (ACKR) 4. ACKR4-mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7(+) APCs into the parenchyma of mouse LN. In this study, we show that ACKR4 also aids APC egress from mouse skin under steady-state and inflammatory conditions. ACKR4 plays a particularly prominent role during cutaneous inflammation when it facilitates Langerhans cell egress from skin and enables the accumulation of dermal dendritic cells in skin-draining LN. Stromal cells in mouse skin, predominantly keratinocytes and a subset of dermal lymphatic endothelial cells, express ACKR4 and are capable of ACKR4-dependent chemokine scavenging in situ. ACKR4-mediated scavenging of dermal-derived CCL19, rather than CCL21, is critical during inflammation, because the aberrant trafficking of skin-derived APCs in Ackr4-deficient mice is completely rescued by genetic deletion of Ccl19. Thus, ACKR4 on stromal cells aids the egress of APCs from mouse skin, and, during inflammation, facilitates CCR7-dependent cell trafficking by scavenging CCL19. C1 [Bryce, Steven A.; Wilson, Ruairi A. M.; Tiplady, Eleanor M.; Asquith, Darren L.; Graham, Gerard J.; Nibbs, Robert J. B.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Glasgow G12 8TA, Lanark, Scotland. [Bromley, Shannon K.; Luster, Andrew D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02114 USA. RP Nibbs, RJB (reprint author), Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Ctr Immunobiol, 120 Univ Pl, Glasgow G12 8TA, Lanark, Scotland. EM robert.nibbs@glasgow.ac.uk OI Nibbs, Robert/0000-0002-8150-0044 FU U.K. Medical Research Council [G0901113]; Biotechnology and Biological Sciences Research Council; National Institutes of Health; Claflin Distinguished Scholar award FX This work was funded by a Programme Grant from the U.K. Medical Research Council (G0901113). E.M.T. is supported by a studentship from the Biotechnology and Biological Sciences Research Council. S.K.B. and A.D.L. are supported by the National Institutes of Health. S.K.B. was supported by a Claflin Distinguished Scholar award. The Cancer Research UK Glasgow Centre (C596/A18076) and the Cancer Research UK Beatson Institute (C596/A17196) provided support for animal facilities. NR 42 TC 1 Z9 1 U1 0 U2 1 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 APR 15 PY 2016 VL 196 IS 8 BP 3341 EP 3353 DI 10.4049/jimmunol.1501542 PG 13 WC Immunology SC Immunology GA DI8AA UT WOS:000373721900013 PM 26976955 ER PT J AU Losoi, H Silverberg, ND Waljas, M Turunen, S Rosti-Otajarvi, E Helminen, M Luoto, TM Julkunen, J Ohman, J Iverson, GL AF Losoi, Heidi Silverberg, Noah D. Waljas, Minna Turunen, Senni Rosti-Otajarvi, Eija Helminen, Mika Luoto, Teemu M. Julkunen, Juhani Ohman, Juha Iverson, Grant L. TI Recovery from Mild Traumatic Brain Injury in Previously Healthy Adults SO JOURNAL OF NEUROTRAUMA LA English DT Article DE outcome; traumatic brain injury; post-concussion syndrome; head injury; cognitive ID QUALITY-OF-LIFE; POST-CONCUSSION SYMPTOMS; BNI FATIGUE SCALE; HEAD-INJURY; POSTCONCUSSION SYNDROME; RELIABILITY; METAANALYSES; IMPAIRMENT; GUIDELINES; VALIDITY AB This prospective longitudinal study reports recovery from mild traumatic brain injury (MTBI) across multiple domains in a carefully selected consecutive sample of 74 previously healthy adults. The patients with MTBI and 40 orthopedic controls (i.e., ankle injuries) completed assessments at 1, 6, and 12 months after injury. Outcome measures included cognition, post-concussion symptoms, depression, traumatic stress, quality of life, satisfaction with life, resilience, and return to work. Patients with MTBI reported more post-concussion symptoms and fatigue than the controls at the beginning of recovery, but by 6 months after injury, did not differ as a group from nonhead injury trauma controls on cognition, fatigue, or mental health, and by 12 months, their level of post-concussion symptoms and quality of life was similar to that of controls. Almost all (96%) patients with MTBI returned to work/normal activities (RTW) within the follow-up of 1 year. A subgroup of those with MTBIs and controls reported mild post-concussion-like symptoms at 1 year. A large percentage of the subgroup who had persistent symptoms had a modifiable psychological risk factor at 1 month (i.e., depression, traumatic stress, and/or low resilience), and at 6 months, they had greater post-concussion symptoms, fatigue, insomnia, traumatic stress, and depression, and worse quality of life. All of the control subjects who had mild post-concussion-like symptoms at 12 months also had a mental health problem (i.e., depression, traumatic stress, or both). This illustrates the importance of providing evidence-supported treatment and rehabilitation services early in the recovery period. C1 [Losoi, Heidi; Waljas, Minna; Turunen, Senni; Rosti-Otajarvi, Eija; Luoto, Teemu M.; Ohman, Juha] Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000, FI-33521 Tampere, Finland. [Losoi, Heidi; Julkunen, Juhani] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Silverberg, Noah D.] Univ British Columbia, GF Strong Rehab Ctr, Div Phys Med & Rehabil, Vancouver, BC V5Z 1M9, Canada. [Helminen, Mika] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Helminen, Mika] Pirkanmaa Hosp Dist, Ctr Sci, Tampere, Finland. [Iverson, Grant L.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Charlestown Navy Yard, Charlestown, MA USA. [Iverson, Grant L.] Spaulding Rehabil Hosp, Boston, MA USA. [Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Losoi, H (reprint author), Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000, FI-33521 Tampere, Finland. EM heidi.losoi@gmail.com OI Ohman, Juha/0000-0002-6592-1367 NR 54 TC 5 Z9 5 U1 15 U2 32 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 APR 15 PY 2016 VL 33 IS 8 BP 766 EP 776 DI 10.1089/neu.2015.4070 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DJ0ZM UT WOS:000373932900007 PM 26437675 ER PT J AU Solsnes, AE Sripada, K Yendiki, A Bjuland, KJ Ostgard, HF Aanes, S Grunewaldt, KH Lohaugen, GC Eikenes, L Haberg, AK Rimol, LM Skranes, J AF Solsnes, Anne Elisabeth Sripada, Kam Yendiki, Anastasia Bjuland, Knut Jorgen Ostgard, Heidi Furre Aanes, Synne Grunewaldt, Kristine Hermansen Lohaugen, Gro C. Eikenes, Live Haberg, Asta K. Rimol, Lars M. Skranes, Jon TI Limited microstructural and connectivity deficits despite subcortical volume reductions in school-aged children born preterm with very low birth weight SO NEUROIMAGE LA English DT Article DE DTI; Cohort study; Connectivity; Tractography; Premature; Development ID YOUNG-ADULTS BORN; HUMAN CEREBRAL-CORTEX; WHITE-MATTER MICROSTRUCTURE; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; FOR-GESTATIONAL-AGE; CORTICAL SURFACE; COGNITIVE FUNCTION; BRAIN-INJURY; PERIVENTRICULAR LEUKOMALACIA AB Preterm birth and very low birth weight (VLBW, <= 1500 g) are worldwide problems that burden survivors with lifelong cognitive, psychological, and physical challenges. In this multimodal structural magnetic resonance imaging (MRI) and diffusion MRI (dMRI) study, we investigated differences in subcortical brain volumes and white matter tract properties in children born preterm with VLBW compared to term-born controls (mean age = 8 years). Subcortical brain structure volumes and cortical thickness estimates were obtained, and fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were generated for 18 white matter tracts. We also assessed structural relationships between white matter tracts and cortical thickness of the tract endpoints. Compared to controls, the VLBW group had reduced volumes of thalamus, globus pallidus, corpus callosum, cerebral white matter, ventral diencephalon, and brain stem, while the ventricular system was larger in VLBW subjects, after controlling for age, sex, IQ, and estimated total intracranial volume. For the dMRI parameters, group differences were not significant at the whole-tract level, though pointwise analysis found shorter segments affected in forceps minor and left superior longitudinal fasciculus - temporal bundle. IQ did not correlate with subcortical volumes or dMRI measures in the VLBW group. While the deviations in subcortical volumes were substantial, there were fewdifferences in dMRI measures between the two groups, which may reflect the influence of advances in perinatal care on white matter development. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Solsnes, Anne Elisabeth; Sripada, Kam; Bjuland, Knut Jorgen; Ostgard, Heidi Furre; Aanes, Synne; Grunewaldt, Kristine Hermansen; Lohaugen, Gro C.; Rimol, Lars M.; Skranes, Jon] Norwegian Univ Sci & Technol, Dept Lab Med, Childrens & Womens Hlth, N-7489 Trondheim, Norway. [Yendiki, Anastasia] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Yendiki, Anastasia] Harvard Univ, Sch Med, Boston, MA USA. [Grunewaldt, Kristine Hermansen] St Olavs Hosp, Dept Pediat, Trondheim, Norway. [Lohaugen, Gro C.; Skranes, Jon] Sorlandet Hosp, Dept Pediat, Arendal, Norway. [Eikenes, Live; Haberg, Asta K.] Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, N-7489 Trondheim, Norway. [Haberg, Asta K.] Norwegian Univ Sci & Technol, Dept Neurosci, N-7489 Trondheim, Norway. [Haberg, Asta K.] St Olavs Hosp, Dept Med Imaging, Trondheim, Norway. RP Sripada, K (reprint author), Norwegian Univ Sci & Technol, Fac Med, Dept Lab Med, Childrens & Womens Hlth, N-7489 Trondheim, Norway. EM kam.sripada@ntnu.no OI Bjuland, Knut Jorgen/0000-0001-7573-4728 FU Research Council of Norway's FRIMED program [204935/F20]; Central Norway Regional Health Authority [46056907]; Norwegian University of Science and Technology [46056907] FX We are grateful for the continued participation and cooperation of the families in our study. We thank radiologist Jana Rydland for evaluating the MRI scans clinically, radiographer Bjarte Dagfinn Snekvik for coordinating the imaging, and research assistants Iren Aina Bastholm and Elisabeth Mellemstrand Stavnes. We appreciate the collaboration with Profs. Kristine B. Walhovd and Anders M. Fjell of the Lifespan Changes in Brain and Cognition group, Department of Psychology, University of Oslo, Norway. The Abel Cluster, owned by the University of Oslo and the Norwegian Metacenter for Computational Science and operated by the Department for Research Computing at the University of Oslo Center for Information Technology (http://www.hpc.uio.no), was used for image processing. This project was supported by the Research Council of Norway's FRIMED program (project number 204935/F20) and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (project number 46056907). NR 103 TC 1 Z9 1 U1 1 U2 4 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 APR 15 PY 2016 VL 130 BP 24 EP 34 DI 10.1016/j.neuroimage.2015.12.029 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DH4HG UT WOS:000372745600003 PM 26712340 ER PT J AU Bernardoni, F King, JA Geisler, D Stein, E Jaite, C Natsch, D Tam, FI Boehm, I Seidel, M Roessner, V Ehrlich, S AF Bernardoni, Fabio King, Joseph A. Geisler, Daniel Stein, Elisa Jaite, Charlotte Naetsch, Dagmar Tam, Friederike I. Boehm, Ilka Seidel, Maria Roessner, Veit Ehrlich, Stefan TI Weight restoration therapy rapidly reverses cortical thinning in anorexia nervosa: A longitudinal study SO NEUROIMAGE LA English DT Article DE Anorexia nervosa; Cerebral cortex; Cortical thickness; FreeSurfer; Structural MRI; Subcortical structures; Longitudinal ID HUMAN CEREBRAL-CORTEX; HIPPOCAMPAL PYRAMIDAL CELLS; SURFACE-BASED ANALYSIS; BODY-MASS INDEX; EATING-DISORDERS; TISSUE VOLUME; COMPUTED-TOMOGRAPHY; BRAIN ABNORMALITIES; COORDINATE SYSTEM; CINGULATE CORTEX AB Structural magnetic resonance imaging studies have documented reduced gray matter in acutely ill patients with anorexia nervosa to be at least partially reversible following weight restoration. However, few longitudinal studies exist and the underlying mechanisms of these structural changes are elusive. In particular, the relative speed and completeness of brain structure normalization during realimentation remain unknown. Here we report from a structural neuroimaging study including a sample of adolescent/young adult female patients with acute anorexia nervosa (n=47), long-term recovered patients (n=34), and healthy controls (n=75). The majority of acutely ill patients were scanned longitudinally (n=35): at the beginning of standardized weight restoration therapy and again after partial weight normalization (> 10% body mass index increase). High-resolution structural images were processed and analyzed with the longitudinal stream of FreeSurfer software to test for changes in cortical thickness and volumes of select subcortical regions of interest. We found globally reduced cortical thickness in acutely ill patients to increase rapidly (0.06mm/month) during brief weight restoration therapy (approximate to 3 months). This significant increase was predicted by weight restoration alone and could not be ascribed to potentially mediating factors such as duration of illness, hydration status, or symptom improvements. By comparing cortical thickness in partially weight-restored patients with that measured in healthy controls, we confirmed that cortical thickness had normalized already at follow-up. This pattern of thinning in illness and rapid normalization during weight rehabilitation was largely mirrored in subcortical volumes. Together, our findings indicate that structural brain insults inflicted by starvation in anorexia nervosa may be reversed at a rate much faster than previously thought if interventions are successful before the disorder becomes chronic. This provides evidence drawing previously speculated mechanisms such as (de-) hydration and neurogenesis into question and suggests that neuronal and/or glial remodeling including changes in macromolecular content may underlie the gray matter alterations observed in anorexia nervosa. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bernardoni, Fabio; King, Joseph A.; Geisler, Daniel; Stein, Elisa; Naetsch, Dagmar; Tam, Friederike I.; Boehm, Ilka; Seidel, Maria; Roessner, Veit; Ehrlich, Stefan] Tech Univ Dresden, Eating Disorder Serv & Researech Ctr, Dept Child & Adolescent Psychiat, Fac Med, D-01307 Dresden, Germany. [Jaite, Charlotte] Charite, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-13353 Berlin, Germany. [Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ehrlich, Stefan] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ehrlich, S (reprint author), Tech Univ Dresden, Translat Dev Neurosci Sect, Dept Child & Adolescent Psychiat, Fac Med,Univ Hosp CG Carus, Fetscherstr 74, D-01307 Dresden, Germany. EM transden.lab@uniklinikum.de FU Deutsche Forschungsgemeinschaft [EH 367/5-1, SFB 940]; Swiss Anorexia Nervosa Foundation [20-12] FX This work was supported by the Deutsche Forschungsgemeinschaft (EH 367/5-1 and SFB 940) and the Swiss Anorexia Nervosa Foundation (project no. 20-12). NR 81 TC 3 Z9 3 U1 4 U2 13 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 APR 15 PY 2016 VL 130 BP 214 EP 222 DI 10.1016/j.neuroimage.2016.02.003 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DH4HG UT WOS:000372745600019 PM 26876474 ER PT J AU Liu, SJ Nowakowski, TJ Pollen, AA Lui, JH Horlbeck, MA Attenello, FJ He, D Weissman, JS Kriegstein, AR Diaz, AA Lim, DA AF Liu, Siyuan John Nowakowski, Tomasz J. Pollen, Alex A. Lui, Jan H. Horlbeck, Max A. Attenello, Frank J. He, Daniel Weissman, Jonathan S. Kriegstein, Arnold R. Diaz, Aaron A. Lim, Daniel A. TI Single-cell analysis of long non-coding RNAs in the developing human neocortex SO GENOME BIOLOGY LA English DT Article DE lncRNA; Single-cell RNA-seq; Developing brain; CRISPRi ID EMBRYONIC STEM-CELLS; GENOME-WIDE ANALYSIS; CEREBRAL-CORTEX; MOUSE-BRAIN; IN-VIVO; REVEALS; GENE; EXPRESSION; SEQ; TRANSCRIPTOME AB Background: Long non-coding RNAs (lncRNAs) comprise a diverse class of transcripts that can regulate molecular and cellular processes in brain development and disease. LncRNAs exhibit cell type-and tissue-specific expression, but little is known about the expression and function of lncRNAs in the developing human brain. Furthermore, it has been unclear whether lncRNAs are highly expressed in subsets of cells within tissues, despite appearing lowly expressed in bulk populations. Results: We use strand-specific RNA-seq to deeply profile lncRNAs from polyadenylated and total RNA obtained from human neocortex at different stages of development, and we apply this reference to analyze the transcriptomes of single cells. While lncRNAs are generally detected at low levels in bulk tissues, single-cell transcriptomics of hundreds of neocortex cells reveal that many lncRNAs are abundantly expressed in individual cells and are cell type-specific. Notably, LOC646329 is a lncRNA enriched in single radial glia cells but is detected at low abundance in tissues. CRISPRi knockdown of LOC646329 indicates that this lncRNA regulates cell proliferation. Conclusion: The discrete and abundant expression of lncRNAs among individual cells has important implications for both their biological function and utility for distinguishing neural cell types. C1 [Liu, Siyuan John; Attenello, Frank J.; He, Daniel; Diaz, Aaron A.; Lim, Daniel A.] Univ Calif San Francisco, Dept Neurol Surg, Ray & Dagmar Dolby Regenerat Med Bldg, San Francisco, CA 94143 USA. [Liu, Siyuan John; Nowakowski, Tomasz J.; Pollen, Alex A.; Lui, Jan H.; Attenello, Frank J.; He, Daniel; Kriegstein, Arnold R.; Diaz, Aaron A.; Lim, Daniel A.] Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Nowakowski, Tomasz J.; Pollen, Alex A.; Lui, Jan H.; Kriegstein, Arnold R.] Dept Neurol, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Weissman, Jonathan S.] Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Weissman, Jonathan S.] Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Weissman, Jonathan S.] Calif Inst Quantitat Biomed Res, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Weissman, Jonathan S.] Ctr RNA Syst Biol, San Francisco, CA 94143 USA. [Liu, Siyuan John; Nowakowski, Tomasz J.; Pollen, Alex A.; Lui, Jan H.; Horlbeck, Max A.; Attenello, Frank J.; He, Daniel; Weissman, Jonathan S.; Kriegstein, Arnold R.; Diaz, Aaron A.; Lim, Daniel A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lim, Daniel A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Lui, Jan H.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Lui, Jan H.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Diaz, AA; Lim, DA (reprint author), Univ Calif San Francisco, Dept Neurol Surg, Ray & Dagmar Dolby Regenerat Med Bldg, San Francisco, CA 94143 USA. EM Aaron.Diaz@ucsf.edu; Daniel.Lim@ucsf.edu FU VA [5I01 BX000252-06]; NIH [1R01NS091544-01A1, U01 MH105989, F30 NS092319-01]; NIH SPORE DRP; Shurl and Kay Curci Foundation; Hana Jabsheh Initiative; UCSF-CTSI [UL1 TR000004]; Damon Runyon Cancer Research Foundation [DRG-2166-13] FX This project was supported by VA 5I01 BX000252-06, NIH 1R01NS091544-01A1, NIH SPORE DRP, the Shurl and Kay Curci Foundation, and the Hana Jabsheh Initiative (to DAL), UCSF-CTSI UL1 TR000004 (to AAD), and NIH U01 MH105989 to ARK. SJL is supported by NIH F30 NS092319-01. AAP is supported by a Damon Runyon Cancer Research Foundation postdoctoral fellowship (DRG-2166-13). NR 59 TC 16 Z9 16 U1 13 U2 47 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD APR 14 PY 2016 VL 17 AR 67 DI 10.1186/s13059-016-0932-1 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DJ5WK UT WOS:000374281300001 PM 27081004 ER PT J AU Platz, E Lewis, EF Uno, H Peck, J Pivetta, E Merz, AA Hempel, D Wilson, C Frasure, SE Jhund, PS Cheng, S Solomon, SD AF Platz, Elke Lewis, Eldrin F. Uno, Hajime Peck, Julie Pivetta, Emanuele Merz, Allison A. Hempel, Dorothea Wilson, Christina Frasure, Sarah E. Jhund, Pardeep S. Cheng, Susan Solomon, Scott D. TI Detection and prognostic value of pulmonary congestion by lung ultrasound in ambulatory heart failure patients SO EUROPEAN HEART JOURNAL LA English DT Article DE Heart failure; Pulmonary congestion; Lung ultrasound; Prognosis ID INTEGRATED DISCRIMINATION; DYSPNEA; RECLASSIFICATION; ASSOCIATION; STATEMENT; DIAGNOSIS; IMPACT; EDEMA AB Aims Pulmonary congestion is a common and important finding in heart failure (HF). While clinical examination and chest radiography are insensitive, lung ultrasound (LUS) is a novel technique that may detect and quantify subclinical pulmonary congestion. We sought to independently relate LUS and clinical findings to 6-month HF hospitalizations and all-cause mortality (composite primary outcome). Methods We used LUS to examine 195 NYHA class II-IV HF patients (median age 66, 61% men, 74% white, ejection fraction 34%) during routine cardiology outpatient visits. Lung ultrasound was performed in eight chest zones with a pocket ultrasound device (median exam duration 2 min) and analysed offline. Results In 185 patients with adequate LUS images in all zones, the sum of B-lines (vertical lines on LUS) ranged from 0 to 13. B-lines, analysed by tertiles, were associated with clinical and laboratory markers of congestion. Thirty-two per cent of patients demonstrated >= 3 B-lines on LUS, yet 81% of these patients had no findings on auscultation. During the follow-up period, 50 patients (27%) were hospitalized for HF or died. Patients in the third tertile (>= 3 B-lines) had a four-fold higher risk of the primary outcome (adjusted HR 4.08, 95% confidence interval, CI 1.95, 8.54; P < 0.001) compared with those in the first tertile and spent a significantly lower number of days alive and out of the hospital (125 days vs. 165 days; adjusted P < 0.001). Conclusions Pulmonary congestion assessed by ultrasound is prevalent in ambulatory patients with chronic HF, is associated with other features of clinical congestion, and identifies those who have worse prognosis. C1 [Platz, Elke; Merz, Allison A.; Frasure, Sarah E.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Platz, Elke; Lewis, Eldrin F.; Uno, Hajime; Frasure, Sarah E.; Cheng, Susan; Solomon, Scott D.] Harvard Univ, Sch Med, Boston, MA USA. [Lewis, Eldrin F.; Merz, Allison A.; Cheng, Susan; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Uno, Hajime] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Peck, Julie] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Pivetta, Emanuele] AOU Citta Salute & Sci Torino, Div Emergency Med, Dept Med Sci, Turin, Italy. [Pivetta, Emanuele] AOU Citta Salute & Sci Torino, Dept Med Sci, High Dependency Unit, Canc Epidemiol Unit, Turin, Italy. [Pivetta, Emanuele] Univ Turin, Turin, Italy. [Hempel, Dorothea] Univ Med Ctr Mainz, Dept Cardiol Angiol & Intens Care, Mainz, Germany. [Wilson, Christina] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Jhund, Pardeep S.] Univ Glasgow, Inst Cardiovasc & Med Sci, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. RP Platz, E (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA.; Platz, E (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM eplatz@bwh.harvard.edu FU Eleanor and Miles Shore Fellowship; American Heart Association [13CRP14330000]; National Heart, Lung and Blood Institute [1K23HL123533-01A1] FX This work was supported by grants from the Eleanor and Miles Shore Fellowship (E.P.) and the American Heart Association (grant number 13CRP14330000) (E.P.). The writing of this manuscript was supported by a grant from the National Heart, Lung and Blood Institute (grant number 1K23HL123533-01A1) (E.P.). NR 23 TC 8 Z9 8 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD APR 14 PY 2016 VL 37 IS 15 BP 1244 EP 1251 DI 10.1093/eurheartj/ehv745 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DJ1TC UT WOS:000373985800017 PM 26819225 ER PT J AU Aras, MA Teerlink, JR AF Aras, Mandar A. Teerlink, John R. TI Lung ultrasound: a 'B-line' to the prediction of decompensated heart failure SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID PULMONARY CONGESTION; REHOSPITALIZATION C1 [Aras, Mandar A.; Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Teerlink, John R.] San Francisco VA Med Ctr, Sect Cardiol, 111C Bldg 203,Room 2A-49,4150 Clement St, San Francisco, CA 94121 USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Sect Cardiol, 111C Bldg 203,Room 2A-49,4150 Clement St, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu NR 11 TC 4 Z9 4 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD APR 14 PY 2016 VL 37 IS 15 BP 1252 EP 1254 DI 10.1093/eurheartj/ehw094 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DJ1TC UT WOS:000373985800018 PM 27080198 ER PT J AU Kaur, A Webster, MR Marchbank, K Behera, R Ndoye, A Kugel, CH Dang, VM Appleton, J O'Connell, MP Cheng, P Valiga, AA Morissette, R McDonnell, NB Ferrucci, L Kossenkov, AV Meeth, K Tang, HY Yin, XF Wood, WH Lehrmann, E Becker, KG Flaherty, KT Frederick, DT Wargo, JA Cooper, ZA Tetzlaff, MT Hudgens, C Aird, KM Zhang, RG Xu, XW Liu, Q Bartlett, E Karakousis, G Eroglu, Z Lo, RS Chan, M Menzies, AM Long, GV Johnson, DB Sosman, J Schilling, B Schadendorf, D Speicher, DW Bosenberg, M Ribas, A Weeraratna, AT AF Kaur, Amanpreet Webster, Marie R. Marchbank, Katie Behera, Reeti Ndoye, Abibatou Kugel, Curtis H., III Dang, Vanessa M. Appleton, Jessica O'Connell, Michael P. Cheng, Phil Valiga, Alexander A. Morissette, Rachel McDonnell, Nazli B. Ferrucci, Luigi Kossenkov, Andrew V. Meeth, Katrina Tang, Hsin-Yao Yin, Xiangfan Wood, William H., III Lehrmann, Elin Becker, Kevin G. Flaherty, Keith T. Frederick, Dennie T. Wargo, Jennifer A. Cooper, Zachary A. Tetzlaff, Michael T. Hudgens, Courtney Aird, Katherine M. Zhang, Rugang Xu, Xiaowei Liu, Qin Bartlett, Edmund Karakousis, Giorgos Eroglu, Zeynep Lo, Roger S. Chan, Matthew Menzies, Alexander M. Long, Georgina V. Johnson, Douglas B. Sosman, Jeffrey Schilling, Bastian Schadendorf, Dirk Speicher, David W. Bosenberg, Marcus Ribas, Antoni Weeraratna, Ashani T. TI sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance SO NATURE LA English DT Article ID BETA-CATENIN; OXIDATIVE STRESS; CELLS; TUMOR; GROWTH; PROGRESSION; PHENOTYPE; CANCER; MITF AB Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression(1-4), we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in beta-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly. C1 [Kaur, Amanpreet; Webster, Marie R.; Marchbank, Katie; Behera, Reeti; Ndoye, Abibatou; Kugel, Curtis H., III; Dang, Vanessa M.; Appleton, Jessica; O'Connell, Michael P.; Valiga, Alexander A.; Kossenkov, Andrew V.; Tang, Hsin-Yao; Yin, Xiangfan; Aird, Katherine M.; Zhang, Rugang; Liu, Qin; Speicher, David W.; Weeraratna, Ashani T.] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. [Kaur, Amanpreet] Univ Sci, Philadelphia, PA 19104 USA. [Cheng, Phil] Univ Zurich, Dept Dermatol, CH-8006 Zurich, Switzerland. [Morissette, Rachel; McDonnell, Nazli B.; Ferrucci, Luigi; Wood, William H., III; Lehrmann, Elin; Becker, Kevin G.] NIA, NIH, Baltimore, MD 21224 USA. [Meeth, Katrina; Bosenberg, Marcus] Yale Univ, Dept Dermatol & Pathol, New Haven, CT 06511 USA. [Flaherty, Keith T.; Frederick, Dennie T.] Massachusetts Gen Hosp, Ctr Canc, Dev Therapeut, Boston, MA 02114 USA. [Wargo, Jennifer A.; Cooper, Zachary A.; Tetzlaff, Michael T.; Hudgens, Courtney] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Xu, Xiaowei; Bartlett, Edmund; Karakousis, Giorgos] Univ Penn, Dept Surg, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Xu, Xiaowei; Bartlett, Edmund; Karakousis, Giorgos] Univ Penn, Dept Pathol, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Eroglu, Zeynep] City Hope Med Ctr, Dept Med Oncol, Duarte, CA 91010 USA. [Lo, Roger S.; Ribas, Antoni] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Chan, Matthew] Westmead Hosp, Crown Princess Mary Canc Ctr, Westmead, NSW 2145, Australia. [Menzies, Alexander M.; Long, Georgina V.] Melanoma Inst Australia, Sydney, NSW 2000, Australia. [Menzies, Alexander M.; Long, Georgina V.] Univ Sydney, Sydney, NSW 2000, Australia. [Johnson, Douglas B.; Sosman, Jeffrey] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Schilling, Bastian; Schadendorf, Dirk] Univ Duesburg Essen, Dept Dermatol, Univ Hosp, West German Canc Ctr, Essen, Germany. [Schilling, Bastian; Schadendorf, Dirk] German Canc Consortium DKTK, D-45127 Heidelberg, Germany. RP Weeraratna, AT (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM aweeraratna@wistar.org OI Bartlett, Edmund/0000-0002-0923-153X; Cooper, Zachary/0000-0003-1059-0940 FU National Institute on Aging, Baltimore, Maryland; Harry J. Lloyd Foundation; ACS-IRG; Melanoma Research Foundation; Cancer Center Support Grant [P30 CA010815]; [P01 CA 114046-06]; [T32 CA 9171-36]; [RO1 CA174746-01] FX We thank D. Altieri, R. Marais, Z. Ronai, M. McMahon, and B. Vogelstein for comments on the manuscript. We thank R. Somasundaram for advice on immune analyses, M. Herlyn for the WM cell lines, and G. Bollag for PLX4720. We also thank R. Delgiacco, D. Gourevitch, F. Keeney, and D. Schultz. We thank A. Dias-Wanigasekera, E. Gaddy, and M. Ha for technical assistance, and R. Locke for editing the manuscript. This work was supported in part by funds from the Intramural Program of the National Institute on Aging, Baltimore, Maryland (N.M., K.G.B., R. M., W.H.W., L.F.), The Harry J. Lloyd Foundation (K.M., A.T.W.), P01 CA 114046-06 (A.T.W., Q.L.), T32 CA 9171-36 (M.R.W., C.H.K.), an ACS-IRG award (A.T.W.), the Melanoma Research Foundation (A.T.W.), and RO1 CA174746-01 (A.T.W., A.K.). Core facilities at the Wistar are supported by Cancer Center Support Grant P30 CA010815. NR 29 TC 20 Z9 20 U1 9 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD APR 14 PY 2016 VL 532 IS 7598 BP 250 EP + DI 10.1038/nature17392 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7TJ UT WOS:000374415100043 PM 27042933 ER PT J AU Ghogawala, Z Dziura, J Butler, WE Dai, F Terrin, N Magge, SN Coumans, JVCE Harrington, JF Amin-Hanjani, S Schwartz, JS Sonntag, VKH Barker, FG Benzel, EC AF Ghogawala, Zoher Dziura, James Butler, William E. Dai, Feng Terrin, Norma Magge, Subu N. Coumans, Jean-Valery C. E. Harrington, J. Fred Amin-Hanjani, Sepideh Schwartz, J. Sanford Sonntag, Volker K. H. Barker, Fred G., II Benzel, Edward C. TI Laminectomy plus Fusion versus Laminectomy Alone for Lumbar Spondylolisthesis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OUTCOMES RESEARCH TRIAL; LOW-BACK-PAIN; DEGENERATIVE SPONDYLOLISTHESIS; SPINAL STENOSIS; REOPERATION RATES; GUIDELINE UPDATE; COST-UTILITY; DECOMPRESSION; PERFORMANCE; RATIONALE AB BACKGROUND The comparative effectiveness of performing instrumented (rigid pedicle screws affixed to titanium alloy rods) lumbar spinal fusion in addition to decompressive laminectomy in patients with symptomatic lumbar grade I degenerative spondylolisthesis with spinal stenosis is unknown. METHODS In this randomized, controlled trial, we assigned patients, 50 to 80 years of age, who had stable degenerative spondylolisthesis (degree of spondylolisthesis, 3 to 14 mm) and symptomatic lumbar spinal stenosis to undergo either decompressive laminectomy alone (decompression-alone group) or laminectomy with posterolateral instrumented fusion (fusion group). The primary outcome measure was the change in the physical-component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36; range, 0 to 100, with higher scores indicating better quality of life) 2 years after surgery. The secondary outcome measure was the score on the Oswestry Disability Index (range, 0 to 100, with higher scores indicating more disability related to back pain). Patients were followed for 4 years. RESULTS A total of 66 patients (mean age, 67 years; 80% women) underwent randomization. The rate of follow-up was 89% at 1 year, 86% at 2 years, and 68% at 4 years. The fusion group had a greater increase in SF-36 physical-component summary scores at 2 years after surgery than did the decompression-alone group (15.2 vs. 9.5, for a difference of 5.7; 95% confidence interval, 0.1 to 11.3; P = 0.046). The increases in the SF-36 physical-component summary scores in the fusion group remained greater than those in the decompression-alone group at 3 years and at 4 years (P = 0.02 for both years). With respect to reductions in disability related to back pain, the changes in the Oswestry Disability Index scores at 2 years after surgery did not differ significantly between the study groups (-17.9 in the decompression-alone group and -26.3 in the fusion group, P = 0.06). More blood loss and longer hospital stays occurred in the fusion group than in the decompression-alone group (P< 0.001 for both comparisons). The cumulative rate of reoperation was 14% in the fusion group and 34% in the decompression-alone group (P = 0.05). CONCLUSIONS Among patients with degenerative grade I spondylolisthesis, the addition of lumbar spinal fusion to laminectomy was associated with slightly greater but clinically meaningful improvement in overall physical health-related quality of life than laminectomy alone. C1 [Ghogawala, Zoher; Magge, Subu N.] Lahey Hosp & Med Ctr, Dept Neurosurg, Alan L & Jacqueline B Stuart Spine Res Ctr, Burlington, MA 01805 USA. [Butler, William E.; Coumans, Jean-Valery C. E.; Barker, Fred G., II] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Terrin, Norma] Tufts Univ, Sch Med, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Ghogawala, Zoher] Greenwich Hosp, Wallace Trials Ctr, Greenwich, CT USA. [Dziura, James; Dai, Feng] Yale Univ, Sch Publ Hlth, Yale Ctr Analyt Sci, New Haven, CT USA. [Harrington, J. Fred] Univ New Mexico, Dept Neurosurg, Albuquerque, NM 87131 USA. [Amin-Hanjani, Sepideh] Univ Illinois, Dept Neurosurg, Chicago, IL USA. [Schwartz, J. Sanford] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Schwartz, J. Sanford] Univ Penn, Wharton Sch Business, Philadelphia, PA 19104 USA. [Schwartz, J. Sanford] Univ Penn, Leonard Davis Inst, Philadelphia, PA 19104 USA. [Sonntag, Volker K. H.] Barrow Neurol Inst, Barrow Neurosurg Associates, Phoenix, AZ 85013 USA. [Benzel, Edward C.] Cleveland Clin Fdn, Ctr Spine Hlth, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Benzel, Edward C.] Cleveland Clin Fdn, Dept Neurosurg, 9500 Euclid Ave, Cleveland, OH 44195 USA. RP Ghogawala, Z (reprint author), Lahey Hosp & Med Ctr, Dept Neurosurg, 41 Mall Rd, Burlington, MA 01805 USA. EM zoher.ghogawala@lahey.org FU Jean and David Wallace Foundation [GH 382]; Greenwich Lumbar Stenosis SLIP Study Fund [GH 384]; Stephanie and Lawrence Flinn, Jr. Charitable Trust FX Supported by research grants from the Jean and David Wallace Foundation (GH 382) and the Greenwich Lumbar Stenosis SLIP Study Fund (GH 384), which was established by Lucinda B. Watson with support from the Stephanie and Lawrence Flinn, Jr. Charitable Trust and James and Elizabeth Li, and by Alan and Jacqueline Stuart, who provided funds to create a Spine Outcomes Research Center at Lahey Hospital and Medical Center to complete the analysis of the SLIP trial results. NR 30 TC 18 Z9 18 U1 5 U2 8 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 APR 14 PY 2016 VL 374 IS 15 BP 1424 EP 1434 DI 10.1056/NEJMoa1508788 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3TD UT WOS:000374128400006 PM 27074067 ER PT J AU Schwartz, KR El Saleeby, CM Nimkin, K Friedmann, AM Moon, A Zukerberg, LR AF Schwartz, Kevin R. El Saleeby, Chadi M. Nimkin, Katherine Friedmann, Alison M. Moon, Aeri Zukerberg, Lawrence R. TI Case 11-2016: A 12-Year-Old Boy with Malaise, Fevers, Abdominal Pain, and Pallor SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HODGKINS-DISEASE; LYMPHOMA; CHILDREN; CHEMOTHERAPY; ADOLESCENTS; ANEMIA; RISK C1 [Schwartz, Kevin R.; El Saleeby, Chadi M.; Friedmann, Alison M.; Moon, Aeri] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Nimkin, Katherine] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Schwartz, Kevin R.; El Saleeby, Chadi M.; Friedmann, Alison M.; Moon, Aeri] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Nimkin, Katherine] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Schwartz, KR (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA.; Schwartz, KR (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. NR 19 TC 0 Z9 0 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 14 PY 2016 VL 374 IS 15 BP 1466 EP 1476 DI 10.1056/NEJMcpc1512458 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3TD UT WOS:000374128400011 PM 27074070 ER PT J AU Graff, RE Meisner, A Ahearn, TU Fiorentino, M Loda, M Giovannucci, EL Mucci, LA Pettersson, A AF Graff, Rebecca E. Meisner, Allison Ahearn, Thomas U. Fiorentino, Michelangelo Loda, Massimo Giovannucci, Edward L. Mucci, Lorelei A. Pettersson, Andreas CA Transdisciplinary Prostate Canc TI Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by ERG tumour protein expression SO BRITISH JOURNAL OF CANCER LA English DT Article DE circulating sex hormones; prostate cancer; TMPRSS2:ERG; ERG expression ID ANDROGEN RECEPTOR GENE; CAG REPEAT LENGTH; MECHANISMS; FUSIONS; REARRANGEMENTS; POLYMORPHISM; METAANALYSIS AB Background: Experimental studies have shown androgen receptor stimulation to facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase risk of developing TMPRSS2: ERG-positive prostate cancer specifically. Methods: We conducted a nested case-control study of 200 prostate cancer cases and 1057 controls from the Physicians' Health Study and Health Professionals Follow-up Study. We examined associations between pre-diagnostic circulating levels of total testosterone, free testosterone, DHT, androstanediol glucuronide, estradiol, and SHBG and risk of prostate cancer by TMPRSS2: ERG status. TMPRSS2: ERG was estimated by ERG immunohistochemistry. We used multivariable unconditional polytomous logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ERG-positive (n = 94) and, separately, ERG-negative (n = 106) disease. Results: Free testosterone was significantly associated with the risk of ERG-positive prostate cancer (OR: 1.37, 95% CI: 1.05-1.77), but not ERG-negative prostate cancer (OR: 1.09, 95% CI: 0.86-1.38) (P-diff = 0.17). None of the remaining hormones evaluated showed clear differential associations with ERG-positive vs ERG-negative disease. Conclusions: These findings provide some suggestive evidence that higher pre-diagnostic free testosterone levels are associated with an increased risk of developing TMPRSS2: ERG-positive prostate cancer. C1 [Graff, Rebecca E.; Ahearn, Thomas U.; Fiorentino, Michelangelo; Giovannucci, Edward L.; Mucci, Lorelei A.; Pettersson, Andreas] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. [Graff, Rebecca E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, 1450 3rd St, San Francisco, CA 94158 USA. [Meisner, Allison] Univ Washington, Dept Biostat, 1959 NE Pacific St, Seattle, WA 98195 USA. [Fiorentino, Michelangelo; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, 450 Brookline Ave, Boston, MA 02115 USA. [Fiorentino, Michelangelo] St Orsola Marcello Malpighi Hosp, Addarii Inst, Pathol Unit, Via Pietro Albertoni 15, I-40138 Bologna, Italy. [Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Giovannucci, Edward L.; Mucci, Lorelei A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. [Pettersson, Andreas] Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, SE-17177 Stockholm, Sweden. RP Graff, RE (reprint author), Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA.; Graff, RE (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 1450 3rd St, San Francisco, CA 94158 USA. EM Rebecca.Graff@ucsf.edu FU Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence (SPORE) in Prostate Cancer [P50 CA090381]; National Cancer Institute at the National Institutes of Health [R25 CA112355, T32 CA09001, CA136578, CA141298, PO1 CA055075, UM1CA167552, U01CA098233]; American Cancer Society-Ellison Foundation [PF-14-140-01-CCE]; National Institutes of Health [CA097193, CA34944, CA40360, HL26490, HL34595] FX We would like to thank the participants and staff of the PHS and HPFS for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of these data. We would like to acknowledge Dr Nadir Rifai at Children's Hospital, Boston whose laboratory measured the circulating biomarkers, and Dr Howard D. Sesso for his valuable contributions to the PHS. The TMAs were constructed by the Tissue Microarray Core Facility at the Dana-Farber/Harvard Cancer Center. This work was supported by the Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence (SPORE) in Prostate Cancer (P50 CA090381); the National Cancer Institute at the National Institutes of Health (R25 CA112355 to REG, T32 CA09001 to TUA, CA136578, CA141298, PO1 CA055075, UM1CA167552, U01CA098233); and the American Cancer Society-Ellison Foundation Postdoctoral Fellowship (PF-14-140-01-CCE to TUA). The Physicians' Health Study was supported by the National Institutes of Health (CA097193, CA34944, CA40360, HL26490, HL34595). LAM is a Prostate Cancer Foundation Young Investigator. NR 29 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD APR 13 PY 2016 VL 114 IS 8 BP 939 EP 944 DI 10.1038/bjc.2016.61 PG 6 WC Oncology SC Oncology GA DJ3TJ UT WOS:000374129200011 PM 26986253 ER PT J AU Saunders, EJ Dadaev, T Leongamornlert, DA Al Olama, AA Benlloch, S Giles, GG Wiklund, F Groenberg, H Haiman, CA Schleutker, J Nordestgaard, BG Travis, RC Neal, D Pasayan, N Khaw, KT Stanford, JL Blot, WJ Thibodeau, SN Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Brenner, H Park, JY Kaneva, R Batra, J Teixeira, MR Pandha, H Govindasami, K Muir, K Easton, DF Eeles, RA Kote-Jarai, Z AF Saunders, Edward J. Dadaev, Tokhir Leongamornlert, Daniel A. Al Olama, Ali Amin Benlloch, Sara Giles, Graham G. Wiklund, Fredrik Groenberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Borge G. Travis, Ruth C. Neal, David Pasayan, Nora Khaw, Kay-Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen N. Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Y. Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Govindasami, Koveela Muir, Ken Easton, Douglas F. Eeles, Rosalind A. Kote-Jarai, Zsofia CA UK Genetic Prostate Canc Study Col UK ProtecT Study Collaborators PRACTICAL Consortium TI Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array SO BRITISH JOURNAL OF CANCER LA English DT Article DE DNA repair; prostate cancer; genome-wide association study; GWAS; iCOGS ID LUNG-CANCER; ASSOCIATION ANALYSIS; COMMON VARIANTS; SEQUENCING DATA; RARE VARIANTS; RISK; MUTATIONS; DISEASE; LOCI; DAMAGE AB Background: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of similar to 100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. Methods: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Results: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. Conclusions: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers. C1 [Saunders, Edward J.; Dadaev, Tokhir; Leongamornlert, Daniel A.; Govindasami, Koveela; Eeles, Rosalind A.; Kote-Jarai, Zsofia] Inst Canc Res & Royal Marsden NHS Fdn Trust, 123 Old Brompton Rd, London SW7 3RP, England. [Al Olama, Ali Amin; Benlloch, Sara; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Worts Causeway, Cambridge CB1 8RN, England. [Giles, Graham G.] Canc Epidemiol Ctr, Canc Council Victoria, 1 Rathdowne St, Carlton, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3053, Australia. [Wiklund, Fredrik; Groenberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Haiman, Christopher A.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Haiman, Christopher A.] Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Schleutker, Johanna] Univ Tampere, Inst Biomed Technol & BioMediTech, Tampere 33520, Finland. [Schleutker, Johanna] FimLab Labs, Tampere 33520, Finland. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev & Gentofte Hosp, Herlev Ringvej 75, DK-2730 Herlev, Denmark. [Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England. [Neal, David] Univ Cambridge, Addenbrookes Hosp, Surg Oncol Urooncol S4, Cambridge CB2 2QQ, England. [Neal, David] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 2QQ, England. [Pasayan, Nora] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Forvie Site,Robinson Way, Cambridge CB2 0SR, England. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Blot, William J.] Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA. [Thibodeau, Stephen N.] Mayo Clin, Rochester, MN 55905 USA. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, D-89075 Ulm, Germany. Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, 45 Francis St,ASB 2-3, Boston, MA 02245 USA. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, PL-70115 Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT 84132 USA. [Cannon-Albright, Lisa] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT 84132 USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Park, Jong Y.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Kaneva, Radka] Med Univ Sofia, Mol Med Ctr, 2 Zdrave St, Sofia 1431, Bulgaria. [Kaneva, Radka] Med Univ Sofia, Dept Med Chem & Biochem, 2 Zdrave St, Sofia 1431, Bulgaria. [Batra, Jyotsna] Queensland Univ Technol, Australian Prostate Canc Res Centre Qld, Inst Hlth & Biomed Innovat, Brisbane, Qld 4102, Australia. [Batra, Jyotsna] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4102, Australia. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal. [Pandha, Hardev] Univ Surrey, Guildford GU2 7XH, Surrey, England. [Muir, Ken] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. RP Kote-Jarai, Z (reprint author), Inst Canc Res & Royal Marsden NHS Fdn Trust, 123 Old Brompton Rd, London SW7 3RP, England. EM zsofia.kote-jarai@icr.ac.uk RI Batra, Jyotsna/B-4130-2011; Brenner, Hermann/B-4627-2017; OI Brenner, Hermann/0000-0002-6129-1572; albright, lisa/0000-0003-2602-3668; Giles, Graham/0000-0003-4946-9099 FU Canadian Institutes of Health Research; Cancer Research UK [C5047/A10692, 14136, C12292/A11174, C1281/A12014, C1287/A 10710, C1287/A10118, C16913/A6135, C490/A10124, C5047/A15007, C5047/A3354, C5047/A7357, C5047/A8384, C522/A8649, C8197/A16565]; Department of Health; Medical Research Council [1000143, C8197/A10123, C8197/A10865, G0401527, G0500966, G0500966/75466, MR/M009092/1, MR/M012190/1]; NCI NIH HHS [1U19 CA148112, 1U19 CA148537, CA098758, CA128978, CA54281, CA63464, P30 CA68485, R01 CA092447, R01CA056678, R01CA082664, R01CA092579, R01CA128813, R01CA72818, U01 CA164973] NR 42 TC 1 Z9 1 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD APR 13 PY 2016 VL 114 IS 8 BP 945 EP 952 DI 10.1038/bjc.2016.50 PG 8 WC Oncology SC Oncology GA DJ3TJ UT WOS:000374129200012 PM 26964030 ER PT J AU Wu, JW Turcotte, R Alt, C Runnels, JM Tsao, H Lin, CP AF Wu, Juwell W. Turcotte, Raphael Alt, Clemens Runnels, Judith M. Tsao, Hensin Lin, Charles P. TI Defining Clonal Color in Fluorescent Multi-Clonal Tracking SO SCIENTIFIC REPORTS LA English DT Article ID STEM-CELLS; DROSOPHILA-MELANOGASTER; BIOLOGICAL APPLICATIONS; RGB MARKING; PROTEINS; MOUSE; BRAINBOW; IDENTIFICATION; HOMEOSTASIS; EXPRESSION AB Clonal heterogeneity and selection underpin many biological processes including development and tumor progression. Combinatorial fluorescent protein expression in germline cells has proven its utility for tracking the formation and regeneration of different organ systems. Such cell populations encoded by combinatorial fluorescent proteins are also attractive tools for understanding clonal expansion and clonal competition in cancer. However, the assignment of clonal identity requires an analytical framework in which clonal markings can be parameterized and validated. Here we present a systematic and quantitative method for RGB analysis of fluorescent melanoma cancer clones. We then demonstrate refined clonal trackability of melanoma cells using this scheme. C1 [Wu, Juwell W.; Turcotte, Raphael; Alt, Clemens; Runnels, Judith M.; Lin, Charles P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wu, Juwell W.; Turcotte, Raphael; Alt, Clemens; Runnels, Judith M.; Lin, Charles P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Tsao, Hensin] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Harvard Univ, Wellman Ctr Photomed, Sch Med, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Melanoma & Pigmented Les Ctr, Boston, MA 02114 USA. [Lin, Charles P.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Lin, CP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Lin, CP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.; Tsao, H (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA.; Tsao, H (reprint author), Harvard Univ, Wellman Ctr Photomed, Sch Med, Boston, MA 02114 USA.; Tsao, H (reprint author), Massachusetts Gen Hosp, Melanoma & Pigmented Les Ctr, Boston, MA 02114 USA.; Lin, CP (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM htsao@mgh.harvard.edu; charles_lin@mgh.harvard.edu FU NIH [2P50 CA86355, K24CA149202] FX We thank Dr Kristoffer Riecken (ne Weber) and Dr Boris Fehse for kindly providing the LeGO vectors and Dr Sarah Coffey for the VSV-G plasmids. We also thank Dr Tzu-Ming Liu, Jenny Njauw, Dr. Joel Spencer, Dr. Alicia Carlson, and the Wellman Center Photopathology Core for technical assistance. This work is supported by NIH 2P50 CA86355 and K24CA149202. NR 47 TC 1 Z9 1 U1 5 U2 13 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 APR 13 PY 2016 VL 6 AR 24303 DI 10.1038/srep24303 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ1LX UT WOS:000373965400001 PM 27073117 ER PT J AU Zhang, W Okimura, T Xu, L Zhang, LJ Oda, T Kwak, M Yu, Q Jin, JO AF Zhang, Wei Okimura, Takasi Xu, Li Zhang, Lijun Oda, Tatsuya Kwak, Minseok Yu, Qing Jin, Jun-O TI Ascophyllan functions as an adjuvant to promote anti-cancer effect by dendritic cell activation SO ONCOTARGET LA English DT Article DE ascophyllan; adjuvant; dendritic cell maturation; cytotoxic lymphocyte activation; anti-cancer; Immunology and Microbiology Section; Immune response; Immunity ID REGULATORY T-CELLS; IN-VIVO; POLYSACCHARIDE ASCOPHYLLAN; SULFATED POLYSACCHARIDE; CROSS-PRESENTATION; IMMUNE-RESPONSES; TUMOR-IMMUNITY; ANTIGEN; CANCER; NODOSUM AB Our previous study demonstrated that ascophyllan, a sulfated polysaccharide purified from brown alga, has immune-activating effects. In this study, we evaluated ascophyllan as an adjuvant for its therapeutic and preventive effect on tumor in a mouse melanoma model. Ascophyllan induced migration of DCs to spleen and tumor-draining lymph node (drLN) in a mouse B16 melanoma model. Moreover, ascophyllan induced activation of dendritic cells (DCs), and promoted IFN-gamma- and TNF-alpha-producing Th1 immune responses in tumor-bearing mice. In addition, treatment with a combination of ascophyllan and ovalbumin (OVA) in the tumor-bearing mice promoted proliferation of OVA-specific CD4 and CD8 T cells and migration of those cells into the tumor, consequently inhibiting the tumor growth. Immunization with the combination of ascophyllan and OVA caused enhanced OVA-specific antibody production and memory T cell responses compared to OVA immunization alone, and almost completely prevented B16-OVA tumor growth upon subsequent tumor challenge. Finally, the combination of ascophyllan and OVA prevented B16-OVA tumor invasion and metastasis into the liver. Thus, these results demonstrate that ascophyllan can function as an adjuvant to induce DC activation, antigen specific CTL activation, Th1 immune response and antibody production, and hence may be useful as a therapeutic and preventive tumor vaccine. C1 [Zhang, Wei; Xu, Li; Zhang, Lijun; Jin, Jun-O] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. [Okimura, Takasi] Hayashikane Sangyo Co Ltd, Div Res & Dev, Yamaguchi, Japan. [Oda, Tatsuya] Nagasaki Univ, Grad Sch Sci & Technol, Nagasaki 852, Japan. [Kwak, Minseok] Pukyong Natl Univ, Dept Chem, Busan, South Korea. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Yu, Qing] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 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 Research fund for International Young Scientists from National Natural Science Foundation of China [81550110507]; Major New Drug Discovery Science and Technology [2012ZX0930313]; National Basic Research Program of China (937 Program) [2011CB910702]; Nagasaki University Major Research Project (Research Initiative for Adaptation to Future Ocean Change); National Research Foundation of Korea Grant - Korean Government [NRF-2014R1A1A2059063] FX This study was supported by Research fund for International Young Scientists from National Natural Science Foundation of China (81550110507). Lijun Zhang was supported by the Major New Drug Discovery Science and Technology (2012ZX0930313) and the National Basic Research Program of China (937 Program) (2011CB910702). Tatsuya Oda was supported by a fund from Nagasaki University Major Research Project (Research Initiative for Adaptation to Future Ocean Change). Minseok Kwak was supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2014R1A1A2059063). NR 32 TC 2 Z9 2 U1 3 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 19284 EP 19298 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000018 PM 27008707 ER PT J AU Tokunaga, R Imamura, Y Nakamura, K Ishimoto, T Nakagawa, S Miyake, K Nakaji, Y Tsuda, Y Iwatsuki, M Baba, Y Sakamoto, Y Miyamoto, Y Saeki, H Yoshida, N Oki, E Watanabe, M Oda, Y Bass, AJ Maehara, Y Baba, H AF Tokunaga, Ryuma Imamura, Yu Nakamura, Kenichi Ishimoto, Takatsugu Nakagawa, Shigeki Miyake, Keisuke Nakaji, Yu Tsuda, Yasuo Iwatsuki, Masaaki Baba, Yoshifumi Sakamoto, Yasuo Miyamoto, Yuji Saeki, Hiroshi Yoshida, Naoya Oki, Eiji Watanabe, Masayuki Oda, Yoshinao Bass, Adam J. Maehara, Yoshihiko Baba, Hideo TI Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma SO ONCOTARGET LA English DT Article DE Esophagogastric junction adenocarcinoma; Esophageal adenocarcinoma; FGFR2; Targeting therapy; Amplification ID GASTRIC CARDIA ADENOCARCINOMA; TIME QUANTITATIVE PCR; ESOPHAGEAL ADENOCARCINOMA; COPY NUMBER; BARRETTS-ESOPHAGUS; CLINICOPATHOLOGICAL FEATURES; PHASE-3 TRIAL; CANCER; FGFR2; GENOME AB Background: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. Patients and methods: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Results: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. Conclusion: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma. C1 [Tokunaga, Ryuma; Imamura, Yu; Nakamura, Kenichi; Ishimoto, Takatsugu; Nakagawa, Shigeki; Miyake, Keisuke; Iwatsuki, Masaaki; Baba, Yoshifumi; Sakamoto, Yasuo; Miyamoto, Yuji; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto, Japan. [Imamura, Yu; Nakaji, Yu; Tsuda, Yasuo; Saeki, Hiroshi; Oki, Eiji; Watanabe, Masayuki; Maehara, Yoshihiko] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 812, Japan. [Nakaji, Yu; Oda, Yoshinao] Kyushu Univ, Grad Sch Med Sci, Dept Anat Pathol, Pathol Sci, Fukuoka 812, Japan. [Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bass, Adam J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Bass, Adam J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Bass, Adam J.] Harvard Univ, Sch Med, Boston, MA USA. RP Baba, H (reprint author), Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto, Japan. EM hdobaba@kumamoto-u.ac.jp FU YOKOYAMA Foundation for Clinical Pharmacology [YRY1310]; Uehara Memorial Foundation FX This work was supported by the YOKOYAMA Foundation for Clinical Pharmacology (YRY1310), and the Uehara Memorial Foundation. NR 40 TC 0 Z9 0 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 19748 EP 19761 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000051 PM 26933914 ER PT J AU Song, JH Padi, SKR Luevano, LA Minden, MD DeAngelo, DJ Hardiman, G Ball, LE Warfel, NA Kraft, AS AF Song, Jin H. Padi, Sathish K. R. Luevano, Libia A. Minden, Mark D. DeAngelo, Daniel J. Hardiman, Gary Ball, Lauren E. Warfel, Noel A. Kraft, Andrew S. TI Insulin receptor substrate 1 is a substrate of the Pim protein kinases SO ONCOTARGET LA English DT Article DE insulin; IGF1; IRS1; Pim kinase; Pim kinase inhibitor ID E-MU-MYC; CELL-GROWTH; PHOSPHORYLATION NETWORKS; TRANSGENIC MICE; PHORBOL ESTERS; INHIBITOR; AKT; ACTIVATION; LEUKEMIA; SURVIVAL AB The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy. C1 [Song, Jin H.; Warfel, Noel A.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85724 USA. [Song, Jin H.; Padi, Sathish K. R.; Luevano, Libia A.; Warfel, Noel A.; Kraft, Andrew S.] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Minden, Mark D.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [DeAngelo, Daniel J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Hardiman, Gary] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Hardiman, Gary] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Hardiman, Gary] Med Univ S Carolina, Ctr Genom Med, Charleston, SC 29425 USA. [Ball, Lauren E.] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. RP Song, JH (reprint author), Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85724 USA.; Song, JH; Kraft, AS (reprint author), Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. EM jinsong@email.arizona.edu; akraft@uacc.arizona.edu FU University of Arizona Cancer Center Support Grant [P30CA023074]; NIH [R01CA173200]; DOD [W81XWH-12-1-0560] FX This project was supported by University of Arizona Cancer Center Support Grant P30CA023074, and NIH R01CA173200, DOD W81XWH-12-1-0560 to ASK. NR 46 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 20152 EP 20165 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000080 PM 26956053 ER PT J AU He, BK Nohara, K Park, N Park, YS Guillory, B Zhao, ZY Garcia, JM Koike, N Lee, CC Takahashi, JS Yoo, SH Chen, Z AF He, Baokun Nohara, Kazunari Park, Noheon Park, Yong-Sung Guillory, Bobby Zhao, Zhaoyang Garcia, Jose M. Koike, Nobuya Lee, Cheng Chi Takahashi, Joseph S. Yoo, Seung-Hee Chen, Zheng TI The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome SO CELL METABOLISM LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; REV-ERB-ALPHA; HIGH-FAT DIET; INSULIN-RESISTANCE; ROR-ALPHA; CITRUS FLAVONOIDS; LIPID-METABOLISM; GENE-EXPRESSION; T-CELLS; CLOCK AB Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network. C1 [He, Baokun; Nohara, Kazunari; Park, Yong-Sung; Zhao, Zhaoyang; Lee, Cheng Chi; Yoo, Seung-Hee; Chen, Zheng] Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, 6431 Fannin St, Houston, TX 77030 USA. [Park, Noheon; Takahashi, Joseph S.] Univ Texas SW Med Ctr Dallas, Dept Neurosci, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Guillory, Bobby; Garcia, Jose M.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Ctr Translat Res Inflammatory Dis, MCL,Div Endocrinol Diabet & Metab, Houston, TX 77030 USA. [Guillory, Bobby; Garcia, Jose M.] Baylor Coll Med, Huffington Ctr Aging, Dan L Duncan Canc Ctr, Dept Med & Mol & Cell Biol, Houston, TX 77030 USA. [Koike, Nobuya] Kyoto Prefectural Univ Med, Dept Physiol & Syst Biosci, Kyoto 6028566, Japan. [Takahashi, Joseph S.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Garcia, Jose M.] Univ Washington, VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, 1660 South Columbian Way S-182-GRECC, Seattle, WA 98108 USA. RP Chen, Z (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, 6431 Fannin St, Houston, TX 77030 USA. EM zheng.chen.1@uth.tmc.edu OI Takahashi, Joseph/0000-0003-0384-8878 FU Welch Foundation [AU-1731]; American Heart Association [11SDG7600045]; NIH/National Institute on Aging [R01AG045828]; NIH/National Institute of General Medical Sciences [R01 GM114424]; Texas Medical Center Digestive Disease Center P/F Awards (National Institute of Diabetes and Digestive and Kidney Diseases) [P30-DK056338]; U.S.A. Department of Veterans Affairs [BX000507, CX000174]; NIH [AG040583, T32AG000183, NIH/DP1 OD000895]; JSPS [26293048]; Uehara Memorial Foundation FX We thank C. Lee for reagent; C. Stephan, E. Song, C. Ayoub, and T.M. Tran for technical support; and S. McKnight, C. Green, M. Bogdanov, G. Lee, D. Marshak, C. Wu, P. Griffin, R. Garcia-Ordonez, and G. Gloston for helpful advice and/or critical reading of the manuscript. This work is supported in part by The Welch Foundation (AU-1731), the American Heart Association (11SDG7600045), and the NIH/National Institute on Aging (R01AG045828) to Z.C., NIH/National Institute of General Medical Sciences (R01 GM114424) to S.-H.Y., Texas Medical Center Digestive Disease Center P/F Awards (National Institute of Diabetes and Digestive and Kidney Diseases Center Grant P30-DK056338) to S.-H.Y. and Z.C., U.S.A. Department of Veterans Affairs, BX000507 and CX000174; and NIH AG040583 to J.M.G., T32AG000183 to B.G., NIH/DP1 OD000895 to C.C.L., and JSPS KAKENHI (26293048) and the Uehara Memorial Foundation to N.K. J.S.T. is an Investigator in the Howard Hughes Medical Institute. NR 85 TC 13 Z9 13 U1 9 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD APR 12 PY 2016 VL 23 IS 4 BP 610 EP 621 DI 10.1016/j.cmet.2016.03.007 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DJ3RL UT WOS:000374123200010 PM 27076076 ER PT J AU Lee, BC Kim, MS Pae, M Yamamoto, Y Eberle, D Shimada, T Kamei, N Park, HS Sasorith, S Woo, JR You, J Mosher, W Brady, HJM Shoelson, SE Lee, J AF Lee, Byung-Cheol Kim, Myung-Sunny Pae, Munkyong Yamamoto, Yasuhiko Eberle, Delphine Shimada, Takeshi Kamei, Nozomu Park, Hee-Sook Sasorith, Souphatta Woo, Ju Rang You, Jia Mosher, William Brady, Hugh J. M. Shoelson, Steven E. Lee, Jongsoon TI Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity SO CELL METABOLISM LA English DT Article ID NECROSIS-FACTOR-ALPHA; T-CELLS; NK CELLS; IMMUNE-RESPONSE; INFLAMMATION; SUBSETS; E4BP4; ACCUMULATION; HOMEOSTASIS; ACTIVATION AB Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNF alpha, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4(+/-) mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4(-/-) mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNF alpha, and thereby contribute to the development of obesity-induced insulin resistance. C1 [Lee, Byung-Cheol; Kim, Myung-Sunny; Pae, Munkyong; Yamamoto, Yasuhiko; Eberle, Delphine; Shimada, Takeshi; Kamei, Nozomu; Sasorith, Souphatta; Woo, Ju Rang; You, Jia; Mosher, William; Shoelson, Steven E.; Lee, Jongsoon] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Lee, Byung-Cheol; Kim, Myung-Sunny; Pae, Munkyong; Yamamoto, Yasuhiko; Eberle, Delphine; Shimada, Takeshi; Kamei, Nozomu; Sasorith, Souphatta; Woo, Ju Rang; You, Jia; Mosher, William; Shoelson, Steven E.; Lee, Jongsoon] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Lee, Byung-Cheol] Kyung Hee Univ, Coll Korean Med, Dept Internal Med, Seoul 130701, South Korea. [Kim, Myung-Sunny; Park, Hee-Sook] Korea Food Res Inst, Songnam 463746, South Korea. [Kim, Myung-Sunny; Park, Hee-Sook] UST, Songnam 463746, South Korea. [Brady, Hugh J. M.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, South Kensington Campus, London SW7 2AZ, England. [Pae, Munkyong] Chungbuk Natl Univ, Dept Food & Nutr, Cheongju 361763, South Korea. [Eberle, Delphine] Univ Lille, CHRU Lille, EA Environm Perinatal & Sante 4489, F-59000 Lille, France. RP Lee, J (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA.; Lee, J (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM jongsoon.lee@joslin.harvard.edu OI Brady, Hugh/0000-0002-3152-067X FU Korea Food Research Institute [E0150302-01, E0080202-08]; Helen and Morton Adler Chair; NIH [R21 DK80380, R01 DK95327, P30 DK36836]; American Diabetes Association [RA 1-10-BS-97, 1-15-BS-111] FX We thank Drs. Diane Mathis (Harvard Medical School) and Lydia Lynch (Brigham and Women's Hospital/Harvard Medical School) for helpful discussions. We also thank Drs. E. Leadbetter, M.B. Brenner, M.A. Exley, and S. Balk (Harvard Medical School) for providing the Ja18 and Cd1d knockout mice. We thank J. LaVecchio and G. Buruzula at Joslin Diabetes Research Center Flow Cytometry Core. This work was supported by grants from the Korea Food Research Institute E0150302-01 and E0080202-08 (M.-S.K.); the Helen and Morton Adler Chair (S.E.S.); NIH grants R21 DK80380 (J.L.), R01 DK95327 (S.E.S.), and P30 DK36836 (Joslin Diabetes Research Center); and the American Diabetes Association grants RA 1-10-BS-97 and 1-15-BS-111 (J.L.). NR 45 TC 11 Z9 11 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD APR 12 PY 2016 VL 23 IS 4 BP 685 EP 698 DI 10.1016/j.cmet.2016.03.002 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DJ3RL UT WOS:000374123200016 PM 27050305 ER PT J AU Dake, MD Ansel, GM Jaff, MR Ohki, T Saxon, RR Smouse, HB Machan, LS Snyder, SA O'Leary, EE Ragheb, AO Zeller, T AF Dake, Michael D. Ansel, Gary M. Jaff, Michael R. Ohki, Takao Saxon, Richard R. Smouse, H. Bob Machan, Lindsay S. Snyder, Scott A. O'Leary, Erin E. Ragheb, Anthony O. Zeller, Thomas CA Zilver PTX Investigators TI Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery 5-Year Results of the Zilver PTX Randomized Trial SO CIRCULATION LA English DT Article DE angioplasty; drug-eluting stents; paclitaxel; peripheral artery disease; stents ID SUPERFICIAL FEMORAL-ARTERY; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; BARE NITINOL STENT; QUALITY-OF-LIFE; BALLOON ANGIOPLASTY; POPLITEAL ARTERIES; FOLLOW-UP; OCCLUSIVE DISEASE; COATED BALLOON; LESIONS AB Background - This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent [BMS]), and provisional DES versus provisional BMS. Methods and Results - Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS. Conclusions - The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments. C1 [Dake, Michael D.] Stanford Univ, Med Ctr, Dept Cardiovasc Surg, Stanford, CA 94305 USA. [Ansel, Gary M.] Riverside Methodist Hosp, Ohio Hlth, Dept Med, Columbus, OH USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. [Ohki, Takao] Jikei Univ Hosp, Dept Surg, Tokyo, Japan. [Saxon, Richard R.] Tri City Med Ctr, Dept Diagnost Imaging & Intervent Radiol, Oceanside, CA USA. [Smouse, H. Bob] OSF St Francis Med Ctr, Dept Radiol, Peoria, IL USA. [Machan, Lindsay S.] Univ British Columbia, Dept Radiol, Vancouver, BC, Canada. [Snyder, Scott A.; O'Leary, Erin E.; Ragheb, Anthony O.] Cook Res Inc, W Lafayette, IN USA. [Zeller, Thomas] Herz Zentrum, Dept Angiol, Bad Krozingen, Germany. RP Dake, MD (reprint author), Stanford Univ, Sch Med, Dept Cardiovasc Surg, Falk Cardiovasc Res Ctr, 300 Pasteur Dr, Stanford, CA 94305 USA. EM mddake@stanford.edu FU Cook Medical FX This study was sponsored by Cook Medical. NR 34 TC 15 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD APR 12 PY 2016 VL 133 IS 15 BP 1472 EP 1483 DI 10.1161/CIRCULATIONAHA.115.016900 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DJ0ZR UT WOS:000373933400006 PM 26969758 ER PT J AU Patton, KK Ellinor, PT Ezekowitz, M Kowey, P Lubitz, SA Perez, M Piccini, J Turakhia, M Wang, P Viskin, S AF Patton, Kristen K. Ellinor, Patrick T. Ezekowitz, Michael Kowey, Peter Lubitz, Steven A. Perez, Marco Piccini, Jonathan Turakhia, Mintu Wang, Paul Viskin, Sami CA Amer Heart Assoc Electrocardiograp Council Clinical Cardiology Council Functional Genomics Transl TI Electrocardiographic Early Repolarization A Scientific Statement From the American Heart Association SO CIRCULATION LA English DT Editorial Material DE AHA Scientific Statements; cardiac conduction defect; risk assessment ID IDIOPATHIC VENTRICULAR-FIBRILLATION; J-WAVE-SYNDROMES; J-POINT ELEVATION; SHORT QT SYNDROME; ACUTE MYOCARDIAL-INFARCTION; SUDDEN CARDIAC DEATH; BRUGADA-SYNDROME; NATURAL-HISTORY; BIRACIAL COHORT; ST-SEGMENT C1 [Patton, Kristen K.] Univ Washington, Seattle, WA 98195 USA. [Ellinor, Patrick T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Ezekowitz, Michael] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA USA. [Kowey, Peter] Lankenau Cardiol, Philadelphia, PA USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Perez, Marco] Stanford Univ, Stanford, CA 94305 USA. [Piccini, Jonathan] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Turakhia, Mintu] Stanford Univ, Sch Med, VA Palo Alto Hlth Care Syst, Stanford, CA 94305 USA. [Viskin, Sami] Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. [Wang, Paul] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Patton, KK (reprint author), Univ Washington, Seattle, WA 98195 USA. OI Patton, Kristen K./0000-0002-9034-6966 NR 73 TC 3 Z9 3 U1 0 U2 2 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 APR 12 PY 2016 VL 133 IS 15 BP 1520 EP 1529 DI 10.1161/CIR.0000000000000388 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DJ0ZR UT WOS:000373933400012 PM 27067089 ER PT J AU Cavazza, A Miccio, A Romano, O Petiti, L Tagliazucchi, GM Peano, C Severgnini, M Rizzi, E De Bellis, G Bicciato, S Mavilio, F AF Cavazza, Alessia Miccio, Annarita Romano, Oriana Petiti, Luca Tagliazucchi, Guidantonio Malagoli Peano, Clelia Severgnini, Marco Rizzi, Ermanno De Bellis, Gianluca Bicciato, Silvio Mavilio, Fulvio TI Dynamic Transcriptional and Epigenetic Regulation of Human Epidermal Keratinocyte Differentiation SO STEM CELL REPORTS LA English DT Article ID LEUKEMIA-VIRUS INTEGRATION; GENOME-WIDE ANALYSIS; HUMAN CELL-TYPES; STEM-CELLS; RETROVIRAL INTEGRATION; CHROMATIN REGULATORS; GENE-EXPRESSION; SUPER-ENHANCERS; CLONAL ANALYSIS; START SITES AB Human skin is maintained by the differentiation and maturation of interfollicular stem and progenitors cells. We used DeepCAGE, genome-wide profiling of histone modifications and retroviral integration analysis, to map transcripts, promoters, enhancers, and super-enhancers (SEs) in prospectively isolated keratinocytes and transit-amplifying progenitors, and retrospectively defined keratinocyte stem cells. We show that >95% of the active promoters are in common and differentially regulated in progenitors and differentiated keratinocytes, while approximately half of the enhancers and SEs are stage specific and account for most of the epigenetic changes occurring during differentiation. Transcription factor (TF) motif identification and correlation with TF binding site maps allowed the identification of TF circuitries acting on enhancers and SEs during differentiation. Overall, our study provides a broad, genome-wide description of chromatin dynamics and differential enhancer and promoter usage during epithelial differentiation, and describes a novel approach to identify active regulatory elements in rare stem cell populations. C1 [Cavazza, Alessia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Miccio, Annarita] Imagine Inst, F-75015 Paris, France. [Romano, Oriana; Tagliazucchi, Guidantonio Malagoli; Bicciato, Silvio; Mavilio, Fulvio] Univ Modena & Reggio Emilia, Dept Life Sci, I-41125 Modena, Italy. [Petiti, Luca; Peano, Clelia; Severgnini, Marco; Rizzi, Ermanno; De Bellis, Gianluca] CNR, Inst Biomed Technol, I-20132 Milan, Italy. [Mavilio, Fulvio] Genethon, 1Bis Rue Int, F-91002 Evry, France. RP Mavilio, F (reprint author), Univ Modena & Reggio Emilia, Dept Life Sci, I-41125 Modena, Italy.; Mavilio, F (reprint author), Genethon, 1Bis Rue Int, F-91002 Evry, France. EM fmavilio@genethon.fr OI Severgnini, Marco/0000-0001-8655-1206; rizzi, ermanno/0000-0002-9898-2326 FU European Research Council (ERC-AdG, GT-SKIN); Italian Ministry of Education, University and Research (EPIGEN Epigenomics Flagship Project) FX This work was supported by grants from the European Research Council (ERC-2010-AdG, GT-SKIN) and the Italian Ministry of Education, University and Research (EPIGEN Epigenomics Flagship Project). NR 40 TC 3 Z9 3 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD APR 12 PY 2016 VL 6 IS 4 BP 618 EP 632 DI 10.1016/j.stemcr.2016.03.003 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DI8ZW UT WOS:000373792100016 PM 27050947 ER PT J AU Garrido, MM AF Garrido, Melissa M. TI Covariate Adjustment and Propensity Score SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Garrido, Melissa M.] James J Peters VA Med Ctr, 130 W Kingsbridge Rd,4A-17J, Bronx, NY USA. RP Garrido, MM (reprint author), James J Peters VA Med Ctr, 130 W Kingsbridge Rd,4A-17J, Bronx, NY USA. EM melissa.garrido@mssm.edu NR 3 TC 0 Z9 0 U1 3 U2 5 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 APR 12 PY 2016 VL 315 IS 14 BP 1521 EP 1522 DI 10.1001/jama.2015.19081 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DJ0EE UT WOS:000373873800026 PM 27115275 ER PT J AU Inohara, T Kohsaka, S Miyata, H Ueda, I Maekawa, Y Fukuda, K Cohen, DJ Kennedy, KF Rumsfeld, JS Spertus, JA AF Inohara, Taku Kohsaka, Shun Miyata, Hiroaki Ueda, Ikuko Maekawa, Yuichiro Fukuda, Keiichi Cohen, David J. Kennedy, Kevin F. Rumsfeld, John S. Spertus, John A. TI Performance and Validation of the US NCDR Acute Kidney Injury Prediction Model in Japan SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE external validation; percutaneous coronary intervention; risk model; serum creatinine ID PERCUTANEOUS CORONARY INTERVENTION; CONTRAST-INDUCED NEPHROPATHY; RENAL-FAILURE; APPROPRIATENESS; DATABASE; OUTCOMES; REGISTRY AB BACKGROUND Stratifying patient risk for acute kidney injury (AKI) prior to percutaneous coronary intervention (PCI) can enable clinicians to tailor their approach to minimize AKI. The National Cardiovascular Data Registry (NCDR) CathPCI Registry recently developed 2 prediction models: for AKI and AKI requiring dialysis (AKI-D). OBJECTIVES This study sought to externally validate the NCDR AKI and AKI-D models in a Japanese population. Determining the generalizability of the U.S. model could support quality improvement efforts in Japan. METHODS The NCDR prediction models were applied to 11,041 consecutive patients in the Japanese multicenter PCI registry. AKI was defined as an absolute increase >= 0.3 mg/dL or a relative increase of 50% in serum creatinine, in accordance with the definition of AKI Network criteria; AKI-D was defined as initiation of dialysis after PCI. Discrimination and calibration of the NCDR models were tested in the Japanese cohort. If the model was perfectly calibrated, the slope and intercept would equal 1.0 and 0.0, respectively. RESULTS In the Japanese PCI cohort, AKI and AKI-D occurred in 10.5% and 1.5% of patients, respectively. The NCDR AKI prediction model showed good discrimination (c-statistic = 0.76) and calibration (slope = 0.93 and intercept = -0.10) in both acute and nonacute PCI. The AKI-D prediction model had good discrimination (c-statistic = 0.92), but while the calibration slope was good (1.04), the intercept was significantly underestimated (0.96). However, this was corrected with recalibration (slope = 1.04 and intercept = -0.087). CONCLUSIONS In a Japanese population, the NCDR AKI models validly predict post-procedural AKI and, with recalibration, AKI-D. Prospective use of these models to inform clinical decision making should be tested as a means of reducing AKI after PCI in Japan. (C) 2016 by the American College of Cardiology Foundation. C1 [Inohara, Taku; Kohsaka, Shun; Ueda, Ikuko; Maekawa, Yuichiro; Fukuda, Keiichi] Keio Univ, Sch Med, Dept Cardiol, Tokyo 1608582, Japan. [Inohara, Taku] Hiratsuka City Hosp, Dept Cardiol, Hiratsuka, Kanagawa, Japan. [Miyata, Hiroaki] Keio Univ, Sch Med, Dept Hlth Policy & Management, Tokyo 1608582, Japan. [Cohen, David J.; Kennedy, Kevin F.; Spertus, John A.] Univ Missouri, Sch Med, St Lukes Mid Amer Heart Inst, Kansas City, MO 64108 USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. RP Kohsaka, S (reprint author), Keio Univ, Sch Med, Dept Cardiol, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. EM kohsaka@cpnet.med.keio.ac.jp OI Kohsaka, Shun/0000-0003-3779-2972 FU Japan Society for the Promotion of Science [25460630, 80571398]; Pfizer Health Research Foundation; Pfizer Japan, Inc.; Bayer Pharmaceutical Co., Ltd. FX The present study was funded by the Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (Grant Nos. 25460630, 80571398) and Pfizer Health Research Foundation. The funders had no role in the conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation or approval of the manuscript. Dr. Kohsaka has received unrestricted research grants for the Department of Cardiology, Keio University School of Medicine, from Pfizer Japan, Inc. and Bayer Pharmaceutical Co., Ltd. Dr. Rumsfeld is the Chief Science Officer of the National Cardiovascular Data Registry. Dr. Spertus is the principal investigator of a contract from the American College of Cardiology Foundation to analyze the National Cardiovascular Data Registry data; and has an equity interest in Health Outcomes Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Peter A. McCullough, MD, served as Guest Editor for this paper. NR 26 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 12 PY 2016 VL 67 IS 14 BP 1715 EP 1722 DI 10.1016/j.jacc.2016.01.049 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI3LP UT WOS:000373400500009 PM 27056778 ER PT J AU Kulkarni, A Rao, P Natarajan, S Goldman, A Sabbisetti, VS Khater, Y Korimerla, N Chandrasekar, V Mashelkar, RA Sengupta, S AF Kulkarni, Ashish Rao, Poornima Natarajan, Siva Goldman, Aaron Sabbisetti, Venkata S. Khater, Yashika Korimerla, Navya Chandrasekar, Vineethkrishna Mashelkar, Raghunath A. Sengupta, Shiladitya TI Reporter nanoparticle that monitors its anticancer efficacy in real time SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nanoparticle; immunotherapy; monitoring; chemotherapy; reporter ID POSITRON-EMISSION-TOMOGRAPHY; IMMUNE-RELATED RESPONSE; IN-VIVO; ANTITUMOR EFFICACY; CANCER-THERAPY; TUMOR HETEROGENEITY; FLUORESCENT PEPTIDE; COLORECTAL-CANCER; CASPASE ACTIVITY; GENE DELIVERY AB The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo. C1 [Kulkarni, Ashish; Rao, Poornima; Natarajan, Siva; Goldman, Aaron; Khater, Yashika; Korimerla, Navya; Chandrasekar, Vineethkrishna; Sengupta, Shiladitya] Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol,Lab Nanomed, Boston, MA 02115 USA. [Kulkarni, Ashish; Rao, Poornima; Natarajan, Siva; Goldman, Aaron; Khater, Yashika; Korimerla, Navya; Chandrasekar, Vineethkrishna; Sengupta, Shiladitya] Harvard Univ, Sch Med, Div Biomed Engn, Boston, MA 02115 USA. [Sabbisetti, Venkata S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Renal Kidney Med,Dept Med, Boston, MA 02115 USA. [Mashelkar, Raghunath A.] Natl Chem Lab, Pune 411008, Maharashtra, India. [Sengupta, Shiladitya] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kulkarni, A; Sengupta, S (reprint author), Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol,Lab Nanomed, Boston, MA 02115 USA.; Kulkarni, A; Sengupta, S (reprint author), Harvard Univ, Sch Med, Div Biomed Engn, Boston, MA 02115 USA.; Mashelkar, RA (reprint author), Natl Chem Lab, Pune 411008, Maharashtra, India.; Sengupta, S (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ashishk@mit.edu; ram@ncl.res.in; shiladit@mit.edu OI Natarajan, Siva Kumar /0000-0002-9663-079X FU Department of Defense (DoD) Breast Cancer Research Program Collaborative Innovator Grant [W81XWH-09-1-0700]; National Institutes of Health [1R01CA135242]; DoD Breakthrough Award [BC132168]; American Lung Association Innovation Award [LCD-259932-N]; American Cancer Society Postdoctoral Fellowship [122854-PF-12-226-01-CDD] FX S.S. is supported by a Department of Defense (DoD) Breast Cancer Research Program Collaborative Innovator Grant (W81XWH-09-1-0700), National Institutes of Health Grant R01 (1R01CA135242), a DoD Breakthrough Award (BC132168), and an American Lung Association Innovation Award (LCD-259932-N). A.G. is supported by an American Cancer Society Postdoctoral Fellowship (122854-PF-12-226-01-CDD). NR 74 TC 3 Z9 3 U1 15 U2 42 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 APR 12 PY 2016 VL 113 IS 15 BP E2104 EP E2113 DI 10.1073/pnas.1603455113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI8PG UT WOS:000373762400005 PM 27036008 ER PT J AU Haerter, F Eikermann, M AF Haerter, Friederike Eikermann, Matthias TI Reversing neuromuscular blockade: inhibitors of the acetylcholinesterase versus the encapsulating agents sugammadex and calabadion SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE encapsulation; Respiratory complications; reversal; neuromuscular transmission block ID POSTOPERATIVE RESIDUAL CURARIZATION; NEGATIVE PHARYNGEAL PRESSURE; GENIOGLOSSUS MUSCLE-ACTIVITY; BLOCKING-AGENTS; RENAL-FAILURE; NEOSTIGMINE REVERSAL; RESPIRATORY COMPLICATIONS; AIRWAY COLLAPSIBILITY; CLINICAL-IMPLICATIONS; TRACHEAL INTUBATION AB Introduction: Acetylcholinesterase inhibitors (neostigmine, edrophonium) and encapsulating agents (sugammadex and calabadion) can be used to reverse residual neuromuscular blockade (NMB). Areas covered: This review provides information about efficacy, effectiveness, and side effects of drugs (acetylcholinesterase inhibitors and encapsulating agents) used to reverse neuromuscular blocking agents (NMBAs). Expert opinion: The therapeutic range of acetylcholinesterase-inhibitors is narrow and effectiveness studies demonstrate clinicians don't use these unspecific reversal agents effectively to increase postoperative respiratory safety. The encapsulating drugs sugammadex and calabadion reverse all levels of NMB, and complete recovery of muscle strength can be achieved almost immediately after administration. For this reason encapsulating agents can be used as a solution for "cannot intubate cannot ventilate"- situations. Poor binding selectivity of encapsulating agents carries the risk of displacement of the NMBA by a competitively binding drug, which may lead to recurarization. In order to avoid side-effects, related to unspecific binding of endogenous proteins and drugs administered perioperatively it is prudent to titrate the dose of reversal agents to the minimal effective dose, depending on the depth of neuromuscular transmission block identified by neuromuscular transmission monitoring. Calabadions provide a diversified (increased binding selectivity) and expanded (reversal of benzylisoquinolines) spectrum of possible indications. C1 [Haerter, Friederike; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Haerter, Friederike; Eikermann, Matthias] Harvard Univ, Sch Med, Boston, MA USA. [Eikermann, Matthias] Univ Duisburg Essen, Univ Hosp Essen, Dept Anesthesia & Crit Care Med, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org NR 131 TC 3 Z9 3 U1 5 U2 15 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD APR 12 PY 2016 VL 17 IS 6 BP 819 EP 833 DI 10.1517/14656566.2016.1145667 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH7SS UT WOS:000372994700004 PM 26799963 ER PT J AU Maughan-Brown, B Lloyd, N Bor, J Venkataramani, AS AF Maughan-Brown, Brendan Lloyd, Neil Bor, Jacob Venkataramani, Atheendar S. TI Changes in self-reported HIV testing during South Africa's 2010/2011 national testing campaign: gains and shortfalls SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE HIV/AIDS; testing; HCT; southern Africa; socio-economic determinants; disparities ID SOCIOECONOMIC DETERMINANTS; NATURAL EXPERIMENT; RISK; COUNTRIES; INFECTION; HOME; PREVENTION; DIAGNOSIS; EDUCATION; TOWNSHIP AB Objectives: HIV counselling and testing is critical to HIV prevention and treatment efforts. Mass campaigns may be an effective strategy to increase HIV testing in countries with generalized HIV epidemics. We assessed the self-reported uptake of HIV testing among individuals who had never previously tested for HIV, particularly those in high-risk populations, during the period of a national, multisector testing campaign in South Africa (April 2010 and June 2011). Design: This study was a prospective cohort study. Methods: We analyzed data from two waves (2010/2011, n = 16,893; 2012, n = 18,707) of the National Income Dynamics Study, a nationally representative cohort that enabled prospective identification of first-time testers. We quantified the number of adults (15 years and older) testing for the first time nationally. To assess whether the campaign reached previously underserved populations, we examined changes in HIV testing coverage by age, gender, race and province sub-groups. We also estimated multivariable logistic regression models to identify socio-economic and demographic predictors of first-time testing. Results: Overall, the proportion of adults ever tested for HIV increased from 43.7% (95% confidence interval (CI): 41.48, 45.96) to 65.2% (95% CI: 63.28, 67.10) over the study period, with approximately 7.6 million (95% CI: 6,387,910; 8,782,986) first-time testers. Among black South Africans, the country's highest HIV prevalence sub-group, HIV testing coverage improved among poorer and healthier individuals, thus reducing gradients in testing by wealth and health. In contrast, HIV testing coverage remained lower for men, younger individuals and the less educated, indicating persistent if not widening disparities by gender, age and education. Large geographic disparities in coverage also remained as of 2012. Conclusions: Mass provision of HIV testing services can be effective in increasing population coverage of HIV testing. The geographic and socio-economic disparities in programme impacts can help guide best practices for future efforts. These efforts should focus on hard-to-reach populations, including men and less-educated individuals. C1 [Maughan-Brown, Brendan; Lloyd, Neil; Bor, Jacob; Venkataramani, Atheendar S.] Univ Cape Town, Southern Africa Labour & Dev Res Unit, ZA-7925 Cape Town, South Africa. [Bor, Jacob] Boston Univ, Sch Publ Hlth, Dept Global Hlth, Boston, MA USA. [Venkataramani, Atheendar S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Internal Med, Boston, MA USA. [Venkataramani, Atheendar S.] Harvard Univ, Ctr Populat & Dev Studies, Cambridge, MA 02138 USA. RP Venkataramani, AS (reprint author), Div Gen Internal Med, 50 Staniford St,9th Floor 954-1, Boston, MA 02445 USA. EM avenkataramani@partners.org FU National Research Foundation, South Africa through the Research Career Advancement Fellowship; European Union; US National Institutes of Health [K23MH106362] FX Financial support for the study was provided by the Programme to Support Pro-Poor Policy Development II, a partnership between the Presidency, Republic of South Africa, and the European Union. The contents of this paper are the sole responsibility of the authors and can in no way be taken to reflect the views of the Presidency, Republic of South Africa, and the European Union. Brendan Maughan-Brown also acknowledges support from the National Research Foundation, South Africa, through the Research Career Advancement Fellowship. Atheendar S. Venkataramani acknowledges salary support from the US National Institutes of Health (K23MH106362). NR 55 TC 0 Z9 0 U1 1 U2 1 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD APR 11 PY 2016 VL 19 AR 20658 DI 10.7448/IAS.19.1.20658 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DM2KB UT WOS:000376174400001 PM 27072532 ER PT J AU Townsend, EC Murakami, MA Christodoulou, A Christie, AL Koster, J DeSouza, TA Morgan, EA Kallgren, SP Liu, HY Wu, SC Plana, O Montero, J Stevenson, KE Rao, P Vadhi, R Andreeff, M Armand, P Ballen, KK Barzaghi-Rinaudo, P Cahill, S Clark, RA Cooke, VG Davids, MS DeAngelo, DJ Dorfman, DM Eaton, H Ebert, BL Etchin, J Firestone, B Fisher, DC Freedman, AS Galinsky, IA Gao, H Garcia, JS Garnache-Ottou, F Graubert, TA Gutierrez, A Halilovic, E Harris, MH Herbert, ZT Horwitz, SM Inghirami, G Intlekoffer, AM Ito, M Izraeli, S Jacobsen, ED Jacobson, CA Jeay, S Jeremias, I Kelliher, MA Koch, R Konopleva, M Kopp, N Kornblau, SM Kung, AL Kupper, TS LaBoeuf, N LaCasce, AS Lees, E Li, LS Look, AT Murakami, M Muschen, M Neuberg, D Ng, SY Odejide, OO Orkin, SH Paquette, RR Place, AE Roderick, JE Ryan, JA Sallan, SE Shoji, B Silverman, LB Soiffer, RJ Steensma, DP Stegmaier, K Stone, RM Tamburini, J Thorner, AR van Hummelen, P Wadleigh, M Wiesmann, M Weng, AP Wuerthner, JU Williams, DA Wollison, BM Lane, AA Letai, A Bertagnolli, MM Ritz, J Brown, M Long, H Aster, JC Shipp, MA Griffin, JD Weinstock, DM AF Townsend, Elizabeth C. Murakami, Mark A. Christodoulou, Alexandra Christie, Amanda L. Koester, Johannes DeSouza, Tiffany A. Morgan, Elizabeth A. Kallgren, Scott P. Liu, Huiyun Wu, Shuo-Chieh Plana, Olivia Montero, Joan Stevenson, Kristen E. Rao, Prakash Vadhi, Raga Andreeff, Michael Armand, Philippe Ballen, Karen K. Barzaghi-Rinaudo, Patrizia Cahill, Sarah Clark, Rachael A. Cooke, Vesselina G. Davids, Matthew S. DeAngelo, Daniel J. Dorfman, David M. Eaton, Hilary Ebert, Benjamin L. Etchin, Julia Firestone, Brant Fisher, David C. Freedman, Arnold S. Galinsky, Ilene A. Gao, Hui Garcia, Jacqueline S. Garnache-Ottou, Francine Graubert, Timothy A. Gutierrez, Alejandro Halilovic, Ensar Harris, Marian H. Herbert, Zachary T. Horwitz, Steven M. Inghirami, Giorgio Intlekoffer, Andrew M. Ito, Moriko Izraeli, Shai Jacobsen, Eric D. Jacobson, Caron A. Jeay, Sebastien Jeremias, Irmela Kelliher, Michelle A. Koch, Raphael Konopleva, Marina Kopp, Nadja Kornblau, Steven M. Kung, Andrew L. Kupper, Thomas S. LaBoeuf, Nicole LaCasce, Ann S. Lees, Emma Li, Loretta S. Look, A. Thomas Murakami, Masato Muschen, Markus Neuberg, Donna Ng, Samuel Y. Odejide, Oreofe O. Orkin, Stuart H. Paquette, Rachel R. Place, Andrew E. Roderick, Justine E. Ryan, Jeremy A. Sallan, Stephen E. Shoji, Brent Silverman, Lewis B. Soiffer, Robert J. Steensma, David P. Stegmaier, Kimberly Stone, Richard M. Tamburini, Jerome Thorner, Aaron R. van Hummelen, Paul Wadleigh, Martha Wiesmann, Marion Weng, Andrew P. Wuerthner, Jens U. Williams, David A. Wollison, Bruce M. Lane, Andrew A. Letai, Anthony Bertagnolli, Monica M. Ritz, Jerome Brown, Myles Long, Henry Aster, Jon C. Shipp, Margaret A. Griffin, James D. Weinstock, David M. TI The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice SO CANCER CELL LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CANCER XENOGRAFTS; TUMOR XENOGRAFTS; GENE-EXPRESSION; CLINICAL-TRIAL; MODELS; HETEROGENEITY; INHIBITION; RESISTANCE; MECHANISMS AB More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease. C1 [Townsend, Elizabeth C.; Murakami, Mark A.; Christodoulou, Alexandra; Christie, Amanda L.; Koester, Johannes; DeSouza, Tiffany A.; Liu, Huiyun; Wu, Shuo-Chieh; Plana, Olivia; Montero, Joan; Armand, Philippe; Cahill, Sarah; Davids, Matthew S.; DeAngelo, Daniel J.; Fisher, David C.; Freedman, Arnold S.; Galinsky, Ilene A.; Garcia, Jacqueline S.; Jacobsen, Eric D.; Jacobson, Caron A.; Koch, Raphael; Kopp, Nadja; LaCasce, Ann S.; Ng, Samuel Y.; Odejide, Oreofe O.; Ryan, Jeremy A.; Soiffer, Robert J.; Steensma, David P.; Stone, Richard M.; Wadleigh, Martha; Lane, Andrew A.; Letai, Anthony; Ritz, Jerome; Brown, Myles; Long, Henry; Shipp, Margaret A.; Griffin, James D.; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Koester, Johannes; Rao, Prakash; Vadhi, Raga; Brown, Myles; Long, Henry] Dana Farber Canc Inst, Ctr Funct Canc Epigen, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Morgan, Elizabeth A.; Dorfman, David M.; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Kallgren, Scott P.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Stevenson, Kristen E.; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Ballen, Karen K.; Graubert, Timothy A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Clark, Rachael A.; Kupper, Thomas S.; LaBoeuf, Nicole] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Barzaghi-Rinaudo, Patrizia; Cooke, Vesselina G.; Firestone, Brant; Gao, Hui; Halilovic, Ensar; Ito, Moriko; Jeay, Sebastien; Lees, Emma; Murakami, Masato; Wiesmann, Marion; Wuerthner, Jens U.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Barzaghi-Rinaudo, Patrizia; Cooke, Vesselina G.; Firestone, Brant; Gao, Hui; Halilovic, Ensar; Ito, Moriko; Jeay, Sebastien; Lees, Emma; Murakami, Masato; Wiesmann, Marion; Wuerthner, Jens U.] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland. [Eaton, Hilary] Dana Farber Canc Inst, Off Res & Technol Ventures, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Ebert, Benjamin L.] Brigham & Womens Hosp, Dept Hematol, 75 Francis St, Boston, MA 02115 USA. [Garnache-Ottou, Francine] INSERM UMR1098, EFS Bourgogne Franche Comte, F-25020 Besancon, France. [Gutierrez, Alejandro] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. [Herbert, Zachary T.] Dana Farber Canc Inst, Mol Biol Core Facil, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Horwitz, Steven M.; Intlekoffer, Andrew M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Inghirami, Giorgio] Weill Cornell Med Coll, Dept Pathol, New York, NY 10065 USA. [Izraeli, Shai] Tel Hashomer & Tel Aviv Univ, Sheba Med Ctr, Funct Genom & Leukemia Res, Ramat Gan, Israel. [Jeremias, Irmela] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Dept Gene Vectors, Marchioninistr 25, D-81377 Munich, Germany. [Jeremias, Irmela] Univ Munich, Dr Von Hauner Childrens Hosp, Dept Pediat, Lindwurmstr 4, D-80337 Munich, Germany. [Kelliher, Michelle A.; Roderick, Justine E.] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01655 USA. [Andreeff, Michael; Konopleva, Marina; Kornblau, Steven M.] Univ Texas Houston, MD Anderson Canc Ctr, Leukemia Div, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Kung, Andrew L.; Williams, David A.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. [Etchin, Julia; Gutierrez, Alejandro; Li, Loretta S.; Look, A. Thomas; Orkin, Stuart H.; Place, Andrew E.; Sallan, Stephen E.; Silverman, Lewis B.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Muschen, Markus; Bertagnolli, Monica M.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Shoji, Brent] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Tamburini, Jerome] Univ Paris 05, Sorbonne Paris Cite, Fac Med, F-75005 Paris, France. [Paquette, Rachel R.; Thorner, Aaron R.; van Hummelen, Paul; Wollison, Bruce M.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. [Weng, Andrew P.] British Columbia Canc Res Ctr, Dept Pathol, Vancouver, BC V5Z 1H8, Canada. [Harris, Marian H.] Boston Childrens Hosp, Dept Pathol, Boston, MA 02215 USA. [Weinstock, David M.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Weinstock, DM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA.; Weinstock, DM (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM dweinstock@partners.org OI Morgan, Elizabeth/0000-0001-5880-9337; Kung, Andrew/0000-0002-9091-488X FU Damon Runyon Cancer Research Foundation; Gabrielle's Angel Foundation for Cancer Research; Novartis FX These studies were made possible through the generosity of a large number of anonymous donors, as well as the patients who provided their samples for research. We thank Kevin Shannon for thoughtful comments. A.G. is supported by the Damon Runyon Cancer Research Foundation and Gabrielle's Angel Foundation for Cancer Research. D.M.W. is a Leukemia and Lymphoma Society Scholar. B.F., E.H., M.I., S.J., E.L., M. Murakami, M. Wiesmann, and J.U.W. are employees of Novartis. M.B., J.D.G., and D.M.W. receive research funding from and are consultants for Novartis. P.R. is a consultant to Selecta Biosciences. NR 37 TC 9 Z9 9 U1 5 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD APR 11 PY 2016 VL 29 IS 4 BP 574 EP 586 DI 10.1016/j.ccell.2016.03.008 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DI9WY UT WOS:000373854600019 PM 27070704 ER PT J AU Hoover, AJ Lazari, M Ren, H Narayanam, MK Murphy, JM van Dam, RM Hooker, JM Ritter, T AF Hoover, Andrew J. Lazari, Mark Ren, Hong Narayanam, Maruthi Kumar Murphy, Jennifer M. van Dam, R. Michael Hooker, Jacob M. Ritter, Tobias TI A Transmetalation Reaction Enables the Synthesis of [F-18]5-Fluorouracil from [F-18]Fluoride for Human PET Imaging SO ORGANOMETALLICS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; STABLE NICKEL PRECATALYST; HETEROAROMATIC IODONIUM SALTS; CROSS-COUPLING REACTION; ARYLBORONIC ACIDS; COLORECTAL-CARCINOMA; LIVER METASTASES; F-18-LABELED 5-FLUOROURACIL; OXIDATIVE FLUORINATION; REDUCTIVE ELIMINATION AB Translation of new F-18-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for F-18-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful F-18-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [F-18]fluoride of human doses of [F-18]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel 6-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [F-18]5-fluorouracil precursor. Routine production of >10 mCi doses of [F-18]5-fluorouracil was accomplished with a new instrument for azeotrope-free [F-18]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated F-18-fluorination. C1 [Hoover, Andrew J.; Ren, Hong; Ritter, Tobias] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Ren, Hong; Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ren, Hong; Hooker, Jacob M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ren, Hong; Hooker, Jacob M.; Ritter, Tobias] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Lazari, Mark; Narayanam, Maruthi Kumar; Murphy, Jennifer M.; van Dam, R. Michael] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, 570 Westwood Plaza, Los Angeles, CA 90095 USA. [Lazari, Mark; Narayanam, Maruthi Kumar; Murphy, Jennifer M.; van Dam, R. Michael] Univ Calif Los Angeles, David Geffen Sch Med, Crump Inst Mol Imaging, 570 Westwood Plaza, Los Angeles, CA 90095 USA. [Ritter, Tobias] Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany. RP Ritter, T (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.; Ritter, T (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA.; Ritter, T (reprint author), Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany. EM ritter@chemistry.harvard.edu FU NIH-NIGMS [GM088237]; NIH-NIBIB [EB013042]; Blavatnik Biomedical Accelerator; DOE BER [DE-SC0001249]; Harvard/MGH Nuclear Medicine Training Program from the Department of Energy [DE-SC0008430]; National Center for Research Resources [1S10RR017208-01A1]; DOE SCGF FX Funding provided by NIH-NIGMS (GM088237), NIH-NIBIB (EB013042), the Blavatnik Biomedical Accelerator, DOE BER (DE-SC0001249), the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy (DE-SC0008430, in support of H.R.), National Center for Research Resources (1S10RR017208-01A1), and the DOE SCGF (graduate fellowship to AJ.H.) is gratefully acknowledged. Acknowledgment is given to Dr. Shao-Liang Zheng, Dr. Michael Campbell, and Heejun Lee (Harvard University) for assistance with X-ray crystallographic analysis, Judit Sore, Kari Phan, and Garima Gautham (Massachusetts General Hospital) for assistance with cGMP validation, Dr. Nickeisha Stephenson (Vasdev Lab, Harvard Medical School and Massachusetts General Hospital) for the aryl bromide precursor to 3i, and Martin G. Strebl for attempted synthesis of a nickel complex by oxidative addition. NR 84 TC 7 Z9 7 U1 11 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0276-7333 EI 1520-6041 J9 ORGANOMETALLICS JI Organometallics PD APR 11 PY 2016 VL 35 IS 7 BP 1008 EP 1014 DI 10.1021/acs.organomet.6b00059 PG 7 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA DJ3AN UT WOS:000374077200014 PM 27087736 ER PT J AU Jaff, MR AF Jaff, Michael R. TI Wait-The Inferior Vena Cava Is Thrombosed? Now What? SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE inferior vena cava filters; stent(s); thrombolytic therapy; vena cava thrombosis ID PERIPHERAL ARTERY-DISEASE; VENOUS THROMBOEMBOLISM; RANDOMIZED-TRIAL; VEIN-THROMBOSIS; ANGIOPLASTY; MANAGEMENT; BALLOON C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jaff, Michael R.] Harvard Univ, Sch Med, Boston, MA USA. RP Jaff, MR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,Warren 905, Boston, MA 02114 USA. EM mjaff@partners.org NR 13 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD APR 11 PY 2016 VL 9 IS 7 BP 644 EP 645 DI 10.1016/j.jcin.2016.01.018 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI5VX UT WOS:000373569700006 PM 26952910 ER PT J AU Shahid, M Javed, AA Chandra, D Ramsey, HE Shah, D Khan, MF Zhao, LP Wu, MX AF Shahid, Mohd Javed, Ammar A. Chandra, David Ramsey, Haley E. Shah, Dilip Khan, Mohammed F. Zhao, Liping Wu, Mei X. TI IEX-1 deficiency induces browning of white adipose tissue and resists diet-induced obesity SO SCIENTIFIC REPORTS LA English DT Article ID INDUCED INSULIN-RESISTANCE; INDUCED GENE IEX-1; KAPPA-B; MACROPHAGE POLARIZATION; CELL-DEATH; BEIGE FAT; MICE; INFLAMMATION; APOPTOSIS; MUSCLE AB Chronic inflammation plays a crucial role in the pathogenesis of obesity and insulin resistance. However, the primary mediators that affect energy homeostasis remain ill defined. Here, we report an unexpected role for immediate early response gene X-1 (IEX-1), a downstream target of NF-kappa B, in energy metabolism. We found that IEX-1 expression was highly induced in white adipose tissue (WAT) in both epidydmal and subcutaneous depots but not in interscapular brown adipose tissue (BAT) in mice fed a high fat diet (HFD). Null mutation of IEX-1 protected mice against HFD-induced adipose and hepatic inflammation, hepatic steatosis, and insulin resistance. Unexpectedly, IEX-1 knockout (IEX-1(-/-)) mice gained markedly less weight on HFD for 20 weeks as compared to wild-type (WT) littermates (37 +/- 3 versus 48 +/- 2 gm) due to increased energy expenditure. Mechanistically, we showed that IEX-1 deficiency induced browning and activated thermogenic genes program in WAT but not in BAT by promoting alternative activation of adipose macrophages. Consequently, IEX-1(-/-) mice exhibited enhanced thermogenesis (24 +/- 0.1 versus 22 +/- 0.1 kcal/hour/kg in WT mice) explaining increased energy expenditure and lean phenotype in these mice. In conclusion, the present study suggests that IEX-1 is a novel physiological regulator of energy homeostasis via its action in WAT. C1 [Shahid, Mohd; Javed, Ammar A.; Chandra, David; Ramsey, Haley E.; Shah, Dilip; Wu, Mei X.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Shahid, Mohd; Javed, Ammar A.; Chandra, David; Ramsey, Haley E.; Shah, Dilip; Wu, Mei X.] Harvard Univ, Dept Dermatol, Sch Med, Boston, MA 02114 USA. [Khan, Mohammed F.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Shriners Hosp Children, Boston, MA 02114 USA. [Khan, Mohammed F.; Zhao, Liping] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Zhao, Liping] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Wu, Mei X.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA USA. RP Shahid, M (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Shahid, M (reprint author), Harvard Univ, Dept Dermatol, Sch Med, Boston, MA 02114 USA. EM mshahid.mgh@gmail.com FU National Institutes of Health [DK103955, AI050822, AI070785]; American Heart Association; BADERC grant [P30 DK057521] FX We thank Dr. Jenny Zhao and Danian Cao for their help with immunohistochemistry, histology, and FACS analysis. This work is supported by National Institutes of Health grants DK103955 (MS), AI050822 and AI070785 and a Grant-in-Aid (0855762D) from the American Heart Association (M.X.W.) and a BADERC grant P30 DK057521 (LZ). NR 39 TC 1 Z9 1 U1 0 U2 4 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 APR 11 PY 2016 VL 6 AR 24135 DI 10.1038/srep24135 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9XV UT WOS:000373856900001 PM 27063893 ER PT J AU Sagara, Y Freedman, RA Vaz-Luis, I Mallory, MA Wong, SM Aydogan, F DeSantis, S Barry, WT Golshan, M AF Sagara, Yasuaki Freedman, Rachel A. Vaz-Luis, Ines Mallory, Melissa Anne Wong, Stephanie M. Aydogan, Fatih DeSantis, Stephen Barry, William T. Golshan, Mehra TI Patient Prognostic Score and Associations With Survival Improvement Offered by Radiotherapy After Breast-Conserving Surgery for Ductal Carcinoma In Situ: A Population-Based Longitudinal Cohort Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADIATION-THERAPY; PROPENSITY SCORE; RECURRENCE RISK; WIDE EXCISION; CANCER; WOMEN; INDEX; DCIS; OVERDIAGNOSIS; CONSERVATION AB Purpose Radiotherapy (RT) after breast-conserving surgery (BCS) is a standard treatment option for the management of ductal carcinoma in situ (DCIS). We sought to determine the survival benefit of RT after BCS on the basis of risk factors for local recurrence. Patients and Methods A retrospective longitudinal cohort study was performed to identify patients with DCIS diagnosed between 1988 and 2007 and treated with BCS by using SEER data. Patients were divided into the following two groups: BCS+RT (RT group) and BCS alone (non-RT group). We used a patient prognostic scoring model to stratify patients on the basis of risk of local recurrence. We performed a Cox proportional hazards model with propensity score weighting to evaluate breast cancer mortality between the two groups. Results We identified 32,144 eligible patients with DCIS, 20,329 (63%) in the RT group and 11,815 (37%) in the non-RT group. Overall, 304 breast cancer-specific deaths occurred over a median follow-up of 96 months, with a cumulative incidence of breast cancer mortality at 10 years in the weighted cohorts of 1.8% (RT group) and 2.1% (non-RT group; hazard ratio, 0.73; 95% CI, 0.62 to 0.88). Significant improvements in survival in the RT group compared with the non-RT group were only observed in patients with higher nuclear grade, younger age, and larger tumor size. The magnitude of the survival difference with RT was significantly correlated with prognostic score (P < .001). Conclusion In this population-based study, the patient prognostic score for DCIS is associated with the magnitude of improvement in survival offered by RT after BCS, suggesting that decisions for RT could be tailored on the basis of patient factors, tumor biology, and the prognostic score. (C) 2016 by American Society of Clinical Oncology C1 [Sagara, Yasuaki; Mallory, Melissa Anne; Aydogan, Fatih; Golshan, Mehra] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Sagara, Yasuaki] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02215 USA. [Freedman, Rachel A.; Vaz-Luis, Ines; DeSantis, Stephen; Barry, William T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wong, Stephanie M.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Aydogan, Fatih] Istanbul Univ, Cerrahpasa Med Sch, Istanbul, Turkey. RP Sagara, Y (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Brigham & Womens Hosp, 450 Brookline Ave,Yawkey 1444, Boston, MA 02215 USA. EM yasuaki@sagara.or.jp FU National Institutes of Health [R25CA089017] FX Supported by the National Institutes of Health Grant No. R25CA089017. NR 43 TC 8 Z9 8 U1 4 U2 4 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 APR 10 PY 2016 VL 34 IS 11 BP 1190 EP + DI 10.1200/JCO.2015.65.1869 PG 11 WC Oncology SC Oncology GA DJ6PG UT WOS:000374334800009 PM 26834064 ER EF