FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Malone, JC Liu, SR Vaillant, GE Rentz, DM Waldinger, RJ AF Malone, Johanna C. Liu, Sabrina R. Vaillant, George E. Rentz, Dorene M. Waldinger, Robert J. TI Midlife Eriksonian Psychosocial Development: Setting the Stage for Late-Life Cognitive and Emotional Health SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE Erikson psychosocial development; neuropsychology; executive functioning; late-life depression; longitudinal data ID MINI-MENTAL-STATE; OLDER-ADULTS; GERIATRIC DEPRESSION; MAJOR DEPRESSION; SOCIAL RELATIONSHIPS; EXECUTIVE DYSFUNCTION; ALZHEIMERS-DISEASE; LATE-ONSET; BASE-LINE; IMPAIRMENT AB Erikson's (1950) model of adult psychosocial development outlines the significance of successful involvement within one's relationships, work, and community for healthy aging. He theorized that the consequences of not meeting developmental challenges included stagnation and emotional despair. Drawing on this model, the present study uses prospective longitudinal data to examine how the quality of assessed Eriksonian psychosocial development in midlife relates to late-life cognitive and emotional functioning. In particular we were interested to see whether late-life depression mediated the relationship between Eriksonian development and specific domains of cognitive functioning (i.e., executive functioning and memory). Participants were 159 men from the over-75 year longitudinal Study of Adult Development. The sample was comprised of men from both higher and lower socioeconomic strata. Eriksonian psychosocial development was coded from men's narrative responses to interviews between the ages of 30-47 (Vaillant & Milofsky, 1980). In late life (ages 75-85) men completed a performance-based neuropsychological assessment measuring global cognitive status, executive functioning, and memory. In addition depressive symptomatology was assessed using the Geriatric Depression Scale. Our results indicated that higher midlife Eriksonian psychosocial development was associated with stronger global cognitive functioning and executive functioning, and lower levels of depression 3 to 4 decades later. There was no significant association between Eriksonian development and late-life memory. Late-life depression mediated the relationship between Eriksonian development and both global cognition and executive functioning. All of these results controlled for highest level of education and adolescent intelligence. Findings have important implications for understanding the lasting benefits of psychosocial engagement in mid-adulthood for late-life cognitive and emotional health. In addition, it may be that less successful psychosocial development increases levels of depression making individuals more vulnerable to specific areas of cognitive decline. C1 [Malone, Johanna C.; Vaillant, George E.; Rentz, Dorene M.; Waldinger, Robert J.] Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA USA. [Malone, Johanna C.; Vaillant, George E.; Rentz, Dorene M.; Waldinger, Robert J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Liu, Sabrina R.] Univ Calif Santa Barbara, Dept Psychol, Santa Barbara, CA 93106 USA. RP Malone, JC (reprint author), One Arnold Circle 7, Cambridge, MA 02139 USA. EM johanna.malone@gmail.com FU NIA NIH HHS [R01 AG045230, R01 AG034554] NR 93 TC 1 Z9 1 U1 4 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 EI 1939-0599 J9 DEV PSYCHOL JI Dev. Psychol. PD MAR PY 2016 VL 52 IS 3 BP 496 EP 508 DI 10.1037/a0039875 PG 13 WC Psychology, Developmental SC Psychology GA DE4XL UT WOS:000370633900014 PM 26551530 ER PT J AU Chavarria-Siles, I White, T de Leeuw, C Goudriaan, A Lips, E Ehrlich, S Turner, JA Calhoun, VD Gollub, RL Magnotta, VA Ho, BC Smit, AB Verheijen, MHG Posthuma, D AF Chavarria-Siles, Ivan White, Tonya de Leeuw, Christiaan Goudriaan, Andrea Lips, Esther Ehrlich, Stefan Turner, Jessica A. Calhoun, Vince D. Gollub, Randy L. Magnotta, Vincent A. Ho, Beng-Choon Smit, August B. Verheijen, Mark H. G. Posthuma, Danielle TI Myelination-related genes are associated with decreased white matter integrity in schizophrenia SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DIFFUSION TENSOR; 1ST-EPISODE SCHIZOPHRENIA; BRAIN; ABNORMALITIES; RISK; OLIGODENDROCYTES; ENDOPHENOTYPES; DISORDERS; DEFICITS AB Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity - as measured by fractional anisotropy (FA) - is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA. C1 [Chavarria-Siles, Ivan; de Leeuw, Christiaan; Lips, Esther; Posthuma, Danielle] Vrije Univ Amsterdam, CNCR, Dept Funct Genom, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Chavarria-Siles, Ivan; de Leeuw, Christiaan; Posthuma, Danielle] Vrije Univ Amsterdam, Med Ctr, Dept Complex Trait Genet, De Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. [Chavarria-Siles, Ivan] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [White, Tonya; Posthuma, Danielle] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [White, Tonya] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Goudriaan, Andrea; Smit, August B.; Verheijen, Mark H. G.] Vrije Univ Amsterdam, CNCR, Dept Mol & Cellular Neurobiol, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Ehrlich, Stefan; Gollub, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Ehrlich, Stefan] Tech Univ Dresden, Dept Child & Adolescent Psychiat, Dresden, Germany. [Turner, Jessica A.] Georgia State Univ, Dept Psychiat, Atlanta, GA 30303 USA. [Turner, Jessica A.] Georgia State Univ, Neurosci Inst, Atlanta, GA 30303 USA. [Turner, Jessica A.; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Calhoun, Vince D.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Gollub, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gollub, Randy L.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Magnotta, Vincent A.] Univ Iowa, Dept Radiol, Carver Coll Med, Iowa City, IA 52242 USA. [Ho, Beng-Choon] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. RP Posthuma, D (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Complex Trait Genet, De Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. EM danielle.posthuma@vu.nl FU Netherlands Scientific Organization [NWO 400-08-206, NWO/ZONW 40-00812-98-07-032]; National Institute of Mental Health [K08 MH068540, MH060662]; National Institute on Drug Abuse [P2ODA024196]; National Association for Research in Schizophrenia and Affective Disorders (NARSAD); Netherlands Scientific Organization; Dutch Brain Foundation; VU University Amsterdam FX This study was funded by the Netherlands Scientific Organization Grants NWO 400-08-206 and NWO/ZONW 40-00812-98-07-032 (to Posthuma). The MIND Research Network consortium is supported by the National Institute of Mental Health Grant Numbers K08 MH068540 (to White) and MH060662; the National Institute on Drug Abuse Grant Number P2ODA024196; and the National Association for Research in Schizophrenia and Affective Disorders (NARSAD) (to White). The funding agencies had no role in the design and conduct of the study. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is hosted by SURFsara and supported by the Netherlands Scientific Organization along with the Dutch Brain Foundation and the VU University Amsterdam. NR 37 TC 1 Z9 1 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAR PY 2016 VL 24 IS 3 BP 381 EP 386 DI 10.1038/ejhg.2015.120 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DE2PP UT WOS:000370469500016 PM 26014434 ER PT J AU Karmali, F Chaudhuri, SE Yi, YW Merfeld, DM AF Karmali, Faisal Chaudhuri, Shomesh E. Yi, Yongwoo Merfeld, Daniel M. TI Determining thresholds using adaptive procedures and psychometric fits: evaluating efficiency using theory, simulations, and human experiments SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Psychometric curve; Psychophysics; Efficiency; Precision ID FORCED-CHOICE STAIRCASES; SIGNAL-DETECTION-THEORY; FIXED STEP SIZES; SELF-MOTION; WHOLE-BODY; PERCEPTUAL THRESHOLDS; PSYCHOPHYSICAL PROCEDURES; VERTICAL AXIS; FREQUENCY; DIRECTION AB When measuring thresholds, careful selection of stimulus amplitude can increase efficiency by increasing the precision of psychometric fit parameters (e.g., decreasing the fit parameter error bars). To find efficient adaptive algorithms for psychometric threshold ("sigma") estimation, we combined analytic approaches, Monte Carlo simulations, and human experiments for a one-interval, binary forced-choice, direction-recognition task. To our knowledge, this is the first time analytic results have been combined and compared with either simulation or human results. Human performance was consistent with theory and not significantly different from simulation predictions. Our analytic approach provides a bound on efficiency, which we compared against the efficiency of standard staircase algorithms, a modified staircase algorithm with asymmetric step sizes, and a maximum likelihood estimation (MLE) procedure. Simulation results suggest that optimal efficiency at determining threshold is provided by the MLE procedure targeting a fraction correct level of 0.92, an asymmetric 4-down, 1-up staircase targeting between 0.86 and 0.92 or a standard 6-down, 1-up staircase. Psychometric test efficiency, computed by comparing simulation and analytic results, was between 41 and 58 % for 50 trials for these three algorithms, reaching up to 84 % for 200 trials. These approaches were 13-21 % more efficient than the commonly used 3-down, 1-up symmetric staircase. We also applied recent advances to reduce accuracy errors using a bias-reduced fitting approach. Taken together, the results lend confidence that the assumptions underlying each approach are reasonable and that human threshold forced-choice decision making is modeled well by detection theory models and mimics simulations based on detection theory models. C1 [Karmali, Faisal; Chaudhuri, Shomesh E.; Yi, Yongwoo; Merfeld, Daniel M.] Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, 243 Charles St, Boston, MA 02114 USA. [Karmali, Faisal; Yi, Yongwoo; Merfeld, Daniel M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA USA. [Chaudhuri, Shomesh E.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Karmali, F (reprint author), Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, 243 Charles St, Boston, MA 02114 USA.; Karmali, F (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA USA. EM faisal_karmali@meei.harvard.edu OI Karmali, Faisal/0000-0002-1140-4954 FU National Institute on Deafness and Other Communication Disorders (NIDCD) [R01-DC04158, R56-DC12038, R03-DC013635] FX We appreciate the participation of our anonymous subjects. Marcos Mattana assisted with data collection. We thank Bob Grimes and Wangsong Gong for technical support. Harvard Orchestra provided high-capacity computation for simulations. This research was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) grants R01-DC04158, R56-DC12038 and R03-DC013635. Some of this work was previous described in an academic report of a Harvard School of Engineering and Applied Sciences undergraduate senior design project: Chaudhuri SE (2011) Protocol Design for Characterizing Vestibular Thresholds. The authors declare no competing financial interests. NR 62 TC 2 Z9 2 U1 6 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD MAR PY 2016 VL 234 IS 3 BP 773 EP 789 DI 10.1007/s00221-015-4501-8 PG 17 WC Neurosciences SC Neurosciences & Neurology GA DD9SJ UT WOS:000370265600013 PM 26645306 ER PT J AU Kim, C Smith, KE Castillejos, A Diaz-Aguilar, D Saint-Geniez, M Connor, KM AF Kim, Clifford Smith, Kaylee E. Castillejos, Alexandra Diaz-Aguilar, Daniel Saint-Geniez, Magali Connor, Kip M. TI The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy SO FASEB JOURNAL LA English DT Article DE Cd55; Cd59; factor b; innate immune system; OIR; Vegf ID ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1; OXYGEN-INDUCED RETINOPATHY; PATHOLOGICAL ANGIOGENESIS; 2 PARTS; MOUSE; NEOVASCULARIZATION; PREMATURITY; INHIBITION; IMMUNOLOGY AB Proliferative retinopathic diseases often progress in 2 phases: initial regression of retinal vasculature (phase 1) followed by subsequent neovascularization (NV) (phase 2). The immune system has been shown to aid in vascular pruning in such retinopathies; however, little is known about the role of the alternative complement pathway in the initial vascular regression phase. Using a mouse model of oxygen-induced retinopathy (OIR), we observed that alternative complement pathway-deficient mice (Fb(-/-)) exhibited a mild decrease in vascular loss at postnatal day (P)8 compared with age- and strain-matched controls (P = 0.035). Laser capture microdissection was used to isolate the retinal blood vessels. Expression of the complement inhibitors Cd55 and Cd59 was significantly decreased in blood vessels isolated from hyperoxic retinas compared with those from normoxic control mice. Vegf expression was measured at P8 and found to be significantly lower in OIR mice than in normoxic control mice (P = 0.0048). Further examination of specific Vegf isoform expression revealed a significant decrease in Vegf120 (P = 0.00032) and Vegf188 (P = 0.0092). In conjunction with the major modulating effects of Vegf during early retinal vascular development, our data suggest a modest involvement of the alternative complement pathway in targeting vessels for regression in the initial vaso-obliteration stage of OIR. C1 [Kim, Clifford; Smith, Kaylee E.; Castillejos, Alexandra; Diaz-Aguilar, Daniel; Connor, Kip M.] Massachusetts Eye & Ear Infirm, Angiogenesis Lab, Boston, MA 02114 USA. [Kim, Clifford; Smith, Kaylee E.; Castillejos, Alexandra; Diaz-Aguilar, Daniel; Saint-Geniez, Magali; Connor, Kip M.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Saint-Geniez, Magali] Schepens Eye Res Inst, Boston, MA USA. RP Connor, KM (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Angiogenesis Lab, 243 Cambridge St, Boston, MA 02114 USA. EM kip_connor@meei.harvard.edu OI Connor, Kip/0000-0002-2048-9080 FU U.S. National Institutes of Health/National Eye Institute [R01EY022084/S1, P30EY014104]; Howe Laboratory endowment of the Massachusetts Eye and Ear Infirmary; March of Dimes Foundation [5-FY09-535]; Fight for Sight, Inc. Student Fellowship Award; Research to Prevent Blindness (RPB) Special Research Scholar Award FX This study was supported by U.S. National Institutes of Health/National Eye Institute Grants R01EY022084/S1 (to K.M.C.) and P30EY014104; the Howe Laboratory endowment of the Massachusetts Eye and Ear Infirmary; the March of Dimes Foundation Grant 5-FY09-535; a Fight for Sight, Inc. Student Fellowship Award; and a Research to Prevent Blindness (RPB) Special Research Scholar Award (to K.M.C.). The authors declare no conflicts of interest. NR 27 TC 0 Z9 0 U1 1 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD MAR PY 2016 VL 30 IS 3 BP 1300 EP 1305 DI 10.1096/fj.15-280834 PG 6 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DE1LF UT WOS:000370387800025 PM 26631482 ER PT J AU Park, JJ Wong, DK Wahed, AS Lee, WM Feld, JJ Terrault, N Khalili, M Sterling, RK Kowdley, KV Bzowej, N Lau, DT Kim, WR Smith, C Carithers, RL Torrey, KW Keith, JW Levine, DL Traum, D Ho, S Valiga, ME Johnson, GS Doo, E Lok, ASF Chang, KM AF Park, Jang-June Wong, David K. Wahed, Abdus S. Lee, William M. Feld, Jordan J. Terrault, Norah Khalili, Mandana Sterling, Richard K. Kowdley, Kris V. Bzowej, Natalie Lau, Daryl T. Kim, W. Ray Smith, Coleman Carithers, Robert L. Torrey, Keith W. Keith, James W. Levine, Danielle L. Traum, Daniel Ho, Suzanne Valiga, Mary E. Johnson, Geoffrey S. Doo, Edward Lok, Anna S. F. Chang, Kyong-Mi CA Hepatitis B Res Network TI Hepatitis B Virus-Specific and Global T-Cell Dysfunction in Chronic Hepatitis B SO GASTROENTEROLOGY LA English DT Article DE HBRN; LPS; IFN; IL10 ID IMMUNE-RESPONSE; VIRAL-HEPATITIS; SUSTAINED RESPONSE; PROGRAMMED DEATH-1; HBV INFECTION; E-ANTIGEN; PATHOGENESIS; ETHNICITY; GENOTYPE; THERAPY AB BACKGROUND & AIMS: T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS: We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyteassociated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS: Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg- patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyteassociated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg- patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS: HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation. C1 [Park, Jang-June; Torrey, Keith W.; Keith, James W.; Levine, Danielle L.; Traum, Daniel; Ho, Suzanne; Valiga, Mary E.; Chang, Kyong-Mi] Philadelphia Corporal Michael J Crescenz VA Med C, Philadelphia, PA USA. [Park, Jang-June; Torrey, Keith W.; Keith, James W.; Levine, Danielle L.; Traum, Daniel; Ho, Suzanne; Valiga, Mary E.; Chang, Kyong-Mi] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wong, David K.; Feld, Jordan J.] Univ Toronto, Toronto, ON, Canada. [Wahed, Abdus S.; Johnson, Geoffrey S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Lee, William M.] Univ Texas Southwestern, Dallas, TX USA. [Terrault, Norah; Khalili, Mandana] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sterling, Richard K.] Virginia Commonwealth Univ, Richmond, VA USA. [Kowdley, Kris V.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Bzowej, Natalie] Calif Pacific Med Ctr, San Francisco, CA USA. [Lau, Daryl T.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kim, W. Ray] Mayo Clin, Rochester, MN USA. [Smith, Coleman] Univ Minnesota, Minneapolis, MN USA. [Carithers, Robert L.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Doo, Edward] NIDDK, NIH, Bethesda, MD 20892 USA. [Lok, Anna S. F.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Chang, KM (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA.; Chang, KM (reprint author), Univ Penn, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM kmchang@mail.med.upenn.edu OI Wahed, Abdus/0000-0001-6911-7221; Wong, David/0000-0002-3310-3538 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01, DK 082843, DK082863, DK082864, DK082866, DK082867, DK082871, U01 DK082872, DK082874, DK082919, DK082923, DK082927, DK082943, U01 DK082944]; NIDDK [A-DK-3002-001]; intramural program, NIDDK, National Institutes of Health (NIH); Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases) [P30DK50306]; Immunology Center (NIH Public Health Service Research Grant) [M01-RR00040]; Immunology Center (VA Merit Review) [BX000649, UL1TR000058]; NCATS (National Center for Advancing Translational Sciences, NIH) [UL1TR000058]; CTSA [UL1TR000004, UL1RR024986]; Clinical and Translational Science Award [CTSA] [UL1TR001111]; Gilead Sciences, Inc.; Roche Molecular Systems through the NIDDK; NIH [UO-1DK082866, R01-AI-47519]; Philadelphia VA Medical Research; NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases [P30DK50306]; Molecular Biology and Cell Culture Core Facilities; NIH Public Health Service Research Grant [M01-RR00040]; Office of Research and Development, Department of Veterans Affairs FX The HBRN was funded by a U01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to the following investigators Lewis R. Roberts, MB, ChB, PhD (DK 082843), Anna Suk-Fong Lok, MD (DK082863), Steven H. Belle, PhD, MScHyg (DK082864), Kyong-Mi Chang, MD (DK082866), Michael W. Fried, MD (DK082867), Adrian M. Di Bisceglie, MD (DK082871), William M. Lee, MD (U01 DK082872), Harry L. A. Janssen, MD, PhD (DK082874), Daryl T.-Y. Lau, MD, MPH (DK082919), Richard K. Sterling, MD, MSc (DK082923), Steven-Huy B. Han, MD (DK082927), Robert C. Carithers, MD (DK082943), Norah A. Terrault, MD, MPH (U01 DK082944), an interagency agreement with NIDDK: Lilia M. Ganova-Raeva, PhD (A-DK-3002-001) and support from the intramural program, NIDDK, National Institutes of Health (NIH): Marc G. Ghany, MD. Additional funding to support this study was provided to Kyong-Mi Chang, MD, the Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01-RR00040, VA Merit Review BX000649), Richard K. Sterling, MD, MSc (UL1TR000058, NCATS (National Center for Advancing Translational Sciences, NIH), Norah A. Terrault, MD, MPH (CTSA grant number UL1TR000004), Michael W. Fried, MD (Clinical and Translational Science Award [CTSA] grant number UL1TR001111), and Anna Suk-Fong Lok (CTSA grant number UL1RR024986). Additional support was provided by Gilead Sciences, Inc. and Roche Molecular Systems via a cooperative research and development agreement through the NIDDK. This study was supported by NIH grants UO-1DK082866 and R01-AI-47519; the Philadelphia VA Medical Research; NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306 and its Molecular Biology and Cell Culture Core Facilities; the NIH Public Health Service Research Grant M01-RR00040. This material is based on work supported in part by the Office of Research and Development, Department of Veterans Affairs and with the resources and the use of facilities at the Philadelphia Corporal Michael J. Crescenz VA Medical Center. The contents of this work do not represent the views of the Department of Veterans Affairs or the United States Government. NR 52 TC 6 Z9 9 U1 5 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2016 VL 150 IS 3 BP 684 EP + DI 10.1053/j.gastro.2015.11.050 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE5CH UT WOS:000370648100029 PM 26684441 ER PT J AU Kahi, CJ Boland, CR Dominitz, JA Giardiello, FM Johnson, DA Kaltenbach, T Lieberman, D Levin, TR Robertson, DJ Rex, DK AF Kahi, Charles J. Boland, C. Richard Dominitz, Jason A. Giardiello, Francis M. Johnson, David A. Kaltenbach, Tonya Lieberman, David Levin, Theodore R. Robertson, Douglas J. Rex, Douglas K. TI Colonoscopy Surveillance After Colorectal Cancer Resection: Recommendations of the US Multi-Society Task Force on Colorectal Cancer SO GASTROENTEROLOGY LA English DT Article DE Colonoscopy; Colorectal Neoplasms; Surveillance ID EARLY RECTAL-CANCER; TRANSANAL ENDOSCOPIC MICROSURGERY; COMPUTED TOMOGRAPHIC COLONOGRAPHY; CONTRAST BARIUM ENEMA; FOLLOW-UP STRATEGIES; COLLEGE-OF-RADIOLOGY; CURATIVE RESECTION; CT COLONOGRAPHY; LOCAL EXCISION; RADICAL SURGERY AB The US Multi-Society Task Force has developed updated recommendations to guide health care providers with the surveillance of patients after colorectal cancer (CRC) resection with curative intent. This document is based on a critical review of the literature regarding the role of colonoscopy, flexible sigmoidoscopy, endoscopic ultrasound, fecal testing and CT colonography in this setting. The document addresses the effect of surveillance, with focus on colonoscopy, on patient survival after CRC resection, the appropriate use and timing of colonoscopy for perioperative clearing and for postoperative prevention of metachronous CRC, specific considerations for the detection of local recurrence in the case of rectal cancer, as well as the place of CT colonography and fecal tests in post-CRC surveillance. C1 [Kahi, Charles J.] Richard L Roudebush VA Med Ctr, Indianapolis, IN USA. [Kahi, Charles J.; Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Sch Med, Seattle, WA USA. [Giardiello, Francis M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Johnson, David A.] Eastern VA Med Sch, Norfolk, VA USA. [Kaltenbach, Tonya] Vet Affairs Palo Alto, Palo Alto, CA USA. [Kaltenbach, Tonya] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Lieberman, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Robertson, Douglas J.] VA Med Ctr, White River Jct, VT USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Kahi, CJ (reprint author), Indiana Univ Sch Med, Richard L Roudebush VA Med Ctr, 1481 W 10th St,111G, Indianapolis, IN 46202 USA. EM ckahi2@iu.edu NR 124 TC 8 Z9 8 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2016 VL 150 IS 3 BP 758 EP + DI 10.1053/j.gastro.2016.01.001 PG 22 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE5CH UT WOS:000370648100034 PM 26892199 ER PT J AU Kahi, CJ Boland, CR Dominitz, JA Giardiello, FM Johnson, DA Kaltenbach, T Lieberman, D Levin, TR Robertson, DJ Rex, DK AF Kahi, Charles J. Boland, C. Richard Dominitz, Jason A. Giardiello, Francis M. Johnson, David A. Kaltenbach, Tonya Lieberman, David Levin, Theodore R. Robertson, Douglas J. Rex, Douglas K. TI Colonoscopy surveillance after colorectal cancer resection: recommendations of the US multi-society task force on colorectal cancer SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID EARLY RECTAL-CANCER; TRANSANAL ENDOSCOPIC MICROSURGERY; COMPUTED TOMOGRAPHIC COLONOGRAPHY; CONTRAST BARIUM ENEMA; FOLLOW-UP STRATEGIES; COLLEGE-OF-RADIOLOGY; CURATIVE RESECTION; CT COLONOGRAPHY; LOCAL EXCISION; RADICAL SURGERY AB The US Multi-Society Task Force has developed updated recommendations to guide health care providers with the surveillance of patients after colorectal cancer (CRC) resection with curative intent. This document is based on a critical review of the literature regarding the role of colonoscopy, flexible sigmoidoscopy, endoscopic ultrasound, fecal testing and CT colonography in this setting. The document addresses the effect of surveillance, with focus on colonoscopy, on patient survival after CRC resection, the appropriate use and timing of colonoscopy for perioperative clearing and for postoperative prevention of metachronous CRC, specific considerations for the detection of local recurrence in the case of rectal cancer, as well as the place of CT colonography and fecal tests in post-CRC surveillance. C1 [Kahi, Charles J.] Richard L Roudebush VA Med Ctr, Indianapolis, IN USA. [Kahi, Charles J.; Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Boland, C. Richard] Baylor Univ, Med Ctr Dallas, Dallas, TX USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Sch Med, Seattle, WA USA. [Giardiello, Francis M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Johnson, David A.] Eastern VA Med Sch, Norfolk, VA USA. [Kaltenbach, Tonya] Vet Affairs Palo Alto, Palo Alto, CA USA. [Kaltenbach, Tonya] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Lieberman, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Robertson, Douglas J.] VA Med Ctr, White River Jct, VT USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Kahi, CJ (reprint author), Indiana Univ Sch Med, Richard L Roudebush VA Med Ctr, 1481 W 10th St,111G, Indianapolis, IN 46202 USA. EM ckahi2@iu.edu NR 123 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 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2016 VL 83 IS 3 BP 489 EP U273 DI 10.1016/j.gie.2016.01.020 PG 20 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE1AU UT WOS:000370359000002 PM 26802191 ER PT J AU Cadoni, S Leung, FW AF Cadoni, Sergio Leung, Felix W. TI Discrepancy in the classification of water immersion from water exchange colonoscopy Response SO GASTROINTESTINAL ENDOSCOPY LA English DT Letter ID CONTROLLED-TRIAL; CECAL INTUBATION; INFUSION C1 [Cadoni, Sergio] St Barbara Hosp, Digest Endoscopy Unit, Iglesias, CI, Italy. [Leung, Felix W.] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA USA. [Leung, Felix W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Cadoni, S (reprint author), St Barbara Hosp, Digest Endoscopy Unit, Iglesias, CI, Italy. NR 9 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 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2016 VL 83 IS 3 BP 677 EP 678 DI 10.1016/j.gie.2015.11.012 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE1AU UT WOS:000370359000058 PM 26897057 ER PT J AU Stockdale, SE Tang, LQ Pudilo, E Lucas-Wright, A Chung, BW Horta, M Masongsong, Z Jones, F Belin, TR Sherbourne, C Wells, K AF Stockdale, Susan E. Tang, Lingqi Pudilo, Esmeralda Lucas-Wright, Anna Chung, Bowen Horta, Mariana Masongsong, Zoe Jones, Felica Belin, Thomas R. Sherbourne, Cathy Wells, Kenneth TI Sampling and Recruiting Community-Based Programs Using Community-Partnered Participation Research SO HEALTH PROMOTION PRACTICE LA English DT Article DE CBPR; depression; anxiety ID RANDOMIZED CONTROLLED-TRIAL; QUALITY IMPROVEMENT; PRIMARY-CARE; AFRICAN-AMERICANS; DEPRESSION; INTERVENTION; SERVICES; DISPARITIES; PREVALENCE; ENGAGEMENT AB The inclusion of community partners in participatory leadership roles around statistical design issues like sampling and randomization has raised concerns about scientific integrity. This article presents a case study of a community-partnered, participatory research (CPPR) cluster-randomized, comparative effectiveness trial to examine implications for study validity and community relevance. Using study administrative data, we describe a CPPR-based design and implementation process for agency/ program sampling, recruitment, and randomization for depression interventions. We calculated participation rates and used cross-tabulation to examine balance by intervention status on service sector, location, and program size and assessed differences in potential populations served. We achieved 51.5% agency and 89.6% program participation rates. Programs in different intervention arms were not significantly different on service sector, location, or program size. Participating programs were not significantly different from eligible, nonparticipating programs on community characteristics. We reject claims that including community members in research design decisions compromises scientific integrity. This case study suggests that a CPPR process can improve implementation of a community-grounded, rigorous randomized comparative effectiveness trial. C1 [Stockdale, Susan E.; Chung, Bowen; Belin, Thomas R.; Wells, Kenneth] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Stockdale, Susan E.; Tang, Lingqi] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Tang, Lingqi; Pudilo, Esmeralda; Masongsong, Zoe; Wells, Kenneth] Univ Calif Los Angeles, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Lucas-Wright, Anna; Jones, Felica] Healthy African Amer Families II, Los Angeles, CA USA. [Lucas-Wright, Anna] Charles R Drew Univ Med & Sci, 1621 E 120th St, Los Angeles, CA 90059 USA. [Chung, Bowen; Sherbourne, Cathy; Wells, Kenneth] RAND Corp, Santa Monica, CA USA. [Chung, Bowen] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Horta, Mariana] Princeton Univ, Princeton, NJ 08544 USA. [Belin, Thomas R.; Wells, Kenneth] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Los Angeles, CA USA. RP Stockdale, SE (reprint author), VA Greater Los Angeles Healthcare Syst, 16111 Plummer Ave,Bldg 25,Room A103, Sepulveda, CA 91343 USA. EM susan.stockdale@va.gov NR 35 TC 1 Z9 1 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1524-8399 EI 1552-6372 J9 HEALTH PROMOT PRACT JI Health Promot. Pract. PD MAR PY 2016 VL 17 IS 2 BP 254 EP 264 DI 10.1177/1524839915605059 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DE6WF UT WOS:000370774400012 PM 26384926 ER PT J AU Quinn, AK Ae-Ngibise, KA Jack, DW Boamah, EA Enuameh, Y Mujtaba, MN Chillrud, SN Wylie, BJ Owusu-Agyei, S Kinney, PL Asante, KP AF Quinn, Ashlinn K. Ae-Ngibise, Kenneth Ayuurebobi Jack, Darby W. Boamah, Ellen Abrafi Enuameh, Yeetey Mujtaba, Mohammed Nuhu Chillrud, Steven N. Wylie, Blair J. Owusu-Agyei, Seth Kinney, Patrick L. Asante, Kwaku Poku TI Association of Carbon Monoxide exposure with blood pressure among pregnant women in rural Ghana: Evidence from GRAPHS SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE Household air pollution; Cookstoves; Biomass; Blood pressure; Pregnancy; Cardiovascular disease ID INDOOR AIR-POLLUTION; FINE PARTICULATE MATTER; MICROLIFE WATCHBP HOME; SOLID-FUEL USE; BIOMASS FUELS; CARDIOVASCULAR-DISEASE; HEALTHY-ADULTS; INDIAN WOMEN; COOKING; HYPERTENSION AB Background and objective: The Ghana Randomized Air Pollution and Health Study (GRAPHS) is a community-level randomized-controlled trial of cookstove interventions for pregnant women and their newborns in rural Ghana. Given that household air pollution from biomass burning may be implicated in adverse cardiovascular outcomes, we sought to determine whether exposure to carbon monoxide (CO) from woodsmoke was associated with blood pressure (BP) among 817 adult women. Methods: Multivariate linear regression models were used to evaluate the association between CO exposure, determined with 72 hour personal monitoring at study enrollment, and BP, also measured at study enrollment. At the time of these assessments, women were in the first or second trimester of pregnancy. Results: A significant positive association was found between CO exposure and diastolic blood pressure (DBP): on average, each 1 ppm increase in exposure to CO was associated with 0.43 mmHg higher DBP [0.01, 0.86]. A non-significant positive trend was also observed for systolic blood pressure (SBP). Conclusion: This study is one of very few to have examined the relationship between household air pollution and blood pressure among pregnant women, who are at particular risk for hypertensive complications. The results of this cross-sectional study suggest that household air pollution from wood-burning fires is associated with higher blood pressure, particularly DBP, in pregnant women at early to mid gestation. The clinical implications of the observed association toward the eventual development of chronic hypertension and/or hypertensive complications of pregnancy remain uncertain, as few of the women were overtly hypertensive at this point in their pregnancies. (C) 2015 Elsevier GmbH. All rights reserved. C1 [Quinn, Ashlinn K.; Jack, Darby W.; Kinney, Patrick L.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Ae-Ngibise, Kenneth Ayuurebobi; Boamah, Ellen Abrafi; Enuameh, Yeetey; Mujtaba, Mohammed Nuhu; Owusu-Agyei, Seth; Asante, Kwaku Poku] Kintampo Hlth Res Ctr, Ghana Hlth Serv, Kintampo, Brong Ahafo Reg, Ghana. [Chillrud, Steven N.] Columbia Univ, Lamont Doherty Earth Observ, Palisades, NY USA. [Wylie, Blair J.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02114 USA. [Wylie, Blair J.] Harvard Univ, Sch Med, Boston, MA USA. RP Quinn, AK (reprint author), Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. EM aquinn@columbia.edu FU Interdisciplinary Training Grant in Climate and Health [T32 ES023770]; United States National Institute of Environmental Health Sciences [NIH 1R01ES019547, P30 ES009089]; Global Alliance for Clean Cookstoves; Thrasher Research Fund; Ghana Ministry of Health FX Funding for AQ provided by the Interdisciplinary Training Grant in Climate and Health (T32 ES023770). Funding for GRAPHS is provided through the United States National Institute of Environmental Health Sciences (NIH 1R01ES019547; P30 ES009089), The Global Alliance for Clean Cookstoves, the Thrasher Research Fund, and the Ghana Ministry of Health. NR 53 TC 0 Z9 0 U1 10 U2 21 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4639 EI 1618-131X J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD MAR PY 2016 VL 219 IS 2 BP 176 EP 183 DI 10.1016/j.ijheh.2015.10.004 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DE6VG UT WOS:000370771100003 PM 26614250 ER PT J AU Wolpin, SE Parks, J Galligan, M Russell, KJ Berry, DL AF Wolpin, Seth E. Parks, Jason Galligan, Mary Russell, Kenneth J. Berry, Donna L. TI Information Needs of Men with Localized Prostate Cancer During Radiation Therapy SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Prostate cancer; Patient reported outcomes; Information priorities; Tailored teaching ID QUALITY-OF-LIFE; FUNCTIONAL STATUS; SATISFACTION; COMPUTER; IMPACT AB The purpose of this study was to describe how patient information needs change over the course of receiving radiation therapy for prostate cancer. Convenience sampling was utilized to recruit men with stage I-III prostate cancer. A longitudinal repeated measures design was implemented for this pilot study. Patients were presented with 36 paired comparisons, each asking the participant to choose the most important information topic(s) for today. Following completion of the survey instruments, the clinic nurse delivered the four top-ranked information topic handouts to each patient with brief instruction on how to use the handouts. Over the course of 6 months, we were able to recruit 35 men. The four highest priority topics across all four sessions were prognosis, stage of disease, treatment options, and side effects. Our results suggest trends in the information priorities that men hold over the course of radiation treatment. The information priorities do appear to shift over time, notably prognosis concerns and risk for family members continued to rise over time, while side effect information declined. These findings will extend an already strong foundation of evidence for preparatory information in radiation therapy. Furthermore, these findings will strengthen current evidence that computerized assessment of patient self-report information is feasible and an important adjunct to clinical practice. C1 [Wolpin, Seth E.; Parks, Jason] Univ Washington, Sch Nursing, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Galligan, Mary] Seattle Canc Care Alliance, Dept Hematol Oncol, Seattle, WA USA. [Russell, Kenneth J.] Univ Washington, Dept Radiat Oncol, Sch Med, Seattle, WA USA. [Berry, Donna L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, 44 Binney St, Boston, MA 02115 USA. RP Wolpin, SE (reprint author), Univ Washington, Sch Nursing, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. EM swolpin@uw.edu FU Oncology Nursing Society Foundation FX The Oncology Nursing Society Foundation provided funding for our study. We would like to acknowledge the staff of the Seattle Cancer Care Alliance Radiation Oncology Clinic and all the men who participated in this study. NR 23 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2016 VL 31 IS 1 BP 142 EP 146 DI 10.1007/s13187-015-0804-5 PG 5 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA DD9US UT WOS:000370271800021 PM 25833286 ER PT J AU Reinshagen, C Redjal, N Sajed, DP Nahed, BV Walcott, BP AF Reinshagen, Clemens Redjal, Navid Sajed, Dipti P. Nahed, Brian V. Walcott, Brian P. TI Intracranial dural based chondroma SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Brain tumor; Chondroma; Histopathology; Surgery ID OF-THE-LITERATURE; OLLIERS-DISEASE; SOLITARY CHONDROMA; MAFFUCCIS-SYNDROME; GIANT CHONDROMA; ENCHONDROMA; CONVEXITY; MUTATIONS; PATIENT; ORIGIN AB Intracranial chondromas are benign, slow-growing, cartilaginous tumors, which comprise only about 0.2% of all intracranial tumors. The majority of these lesions occur at the base of the skull, where they are thought to arise from residual embryonic chondrogenic cells along the basal synchondrosis. Very rarely, they may also originate from the convexity dura, falx cerebri, or the brain parenchyma. We present a patient with a dural based chondroma to highlight the technical considerations of surgical resection. The recent literature on intracranial chondromas regarding incidence, pathophysiologic origin, clinical symptoms, imaging, histopathology and prognosis is reviewed. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Reinshagen, Clemens] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA USA. [Reinshagen, Clemens] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Redjal, Navid; Nahed, Brian V.; Walcott, Brian P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg Room 502, Boston, MA 02114 USA. [Sajed, Dipti P.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Walcott, BP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg Room 502, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu OI Reinshagen, Clemens/0000-0002-8524-4578 NR 29 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 MAR PY 2016 VL 25 BP 161 EP 163 DI 10.1016/j.jocn.2015.05.052 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DE0HA UT WOS:000370304500039 PM 26602798 ER PT J AU Osborn, KE Shytle, RD Frontera, AT Soble, JR Schoenberg, MR AF Osborn, Katie E. Shytle, R. Douglas Frontera, Alfred T. Soble, Jason R. Schoenberg, Mike R. TI Addressing Potential Role of Magnesium Dyshomeostasis to Improve Treatment Efficacy for Epilepsy: A Reexamination of the Literature SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Review DE magnesium; seizure; epilepsy; epileptogenesis; metal ion; electrolyte imbalance; ketogenic diet ID ASPARTATE-INDUCED SEIZURES; SECONDARY HYPOCALCEMIA; KETOGENIC DIET; FAMILIAL HYPOMAGNESEMIA; ANTIEPILEPTIC DRUGS; REFRACTORY EPILEPSY; CHILDHOOD EPILEPSY; AMERICAN-ACADEMY; DOUBLE-BLIND; DEFICIENCY AB Magnesium (Mg2+) is an abundant mineral in the body serving many biochemical functions. Magnesium supplementation has been shown to raise seizure threshold in animal and human studies, but the etiological contribution of magnesium deficiency to the onset and maintenance of epilepsy, as well as the degree to which it impacts antiepileptic drug efficacy, remains poorly understood. This may be due, at least in part, to the inherent limitations of commonly used serum levels as a measure of functional magnesium status, as well as insufficient data regarding relative bioavailabilities of various magnesium salts and chelates for use with humans. To date, I randomized clinical trial has been conducted assessing Mg2+ supplementation in epilepsy, and findings yielded promising results. Yet a notable dearth in the literature remains, and more studies are needed. To better understand the potential role of magnesium deficiency as a causal factor in epilepsy, more convenient and accurate measurement methods should to be developed and employed in randomized, controlled trials of oral magnesium supplementation in epilepsy. Findings from such studies have the potential to facilitate far-reaching clinical and economic improvements in epilepsy treatment standards. C1 [Osborn, Katie E.; Schoenberg, Mike R.] Univ S Florida, Morsani Coll Med, Dept Psychiat & Behav Neurosci, Tampa, FL USA. [Osborn, Katie E.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Shytle, R. Douglas; Schoenberg, Mike R.] Univ S Florida, Morsani Coll Med, Dept Neurosurg & Brain Repair, Ctr Excellence Aging & Brain Repair, Tampa, FL USA. [Frontera, Alfred T.; Schoenberg, Mike R.] Univ S Florida, Dept Neurol, Morsani Coll Med, Tampa, FL 33620 USA. [Soble, Jason R.] South Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. RP Schoenberg, MR (reprint author), USF Morsani Coll Med, Dept Psychiat & Behav Neurosci, 3515 E Fletcher Ave, Tampa, FL 33613 USA.; Schoenberg, MR (reprint author), USF Morsani Coll Med, Dept Neurol, 3515 E Fletcher Ave, Tampa, FL 33613 USA.; Schoenberg, MR (reprint author), USF Morsani Coll Med, Dept Neurosurg, 3515 E Fletcher Ave, Tampa, FL 33613 USA. EM mschoenb@health.usf.edu NR 66 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD MAR PY 2016 VL 56 IS 3 BP 260 EP 265 DI 10.1002/jcph.626 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DD8GB UT WOS:000370162700002 PM 26313363 ER PT J AU Neel, VA Todorova, K Wang, J Kwon, E Kang, M Liu, QS Gray, N Lee, SW Mandinova, A AF Neel, Victor A. Todorova, Kristina Wang, Jun Kwon, Eunjeong Kang, Minjeong Liu, Qingsong Gray, Nathanael Lee, Sam W. Mandinova, Anna TI Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial Tumor SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PIK3CA MUTATIONS; ONCOGENIC PIK3CA; FGFR3 MUTATIONS; EPIDERMAL NEVI; SKIN-CANCER; INHIBITOR; LOCALIZATION; ACTIVATION; APOPTOSIS; KINASES AB Seborrheic keratoses (SKs) are common benign skin tumors that share many morphological features with their malignant counterpart, squamous cell carcinoma. SKs frequently have acquired oncogenic mutations in the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt signaling cascade. We developed a reliable culture system to study SKs in vitro and screened these cells using a library of selective kinase inhibitors to evaluate effects on cell survival. These benign tumors are sensitive to inhibition by ATP-competitive Akt inhibitors, including A-443654 and GSK690693. RNA interference-mediated Akt suppression mimicked the effects of enzyme inhibition in cultured cells. Akt inhibition suppressed phosphorylation of downstream targets of Akt kinase that are critical for cell survival, including MDM2 and FOXO3a, and induced apoptosis. Cell death was also dependent on p53, mutations in which, although common in cutaneous squamous cell carcinoma, have not been identified in SKs. Intact explants of SKs were also sensitive to Akt inhibition. In addition to the obvious therapeutic implications of these findings, identifying the signaling characteristics that differentiate benign and malignant tumors may inform our understanding of the malignant state. C1 [Neel, Victor A.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Neel, Victor A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Todorova, Kristina; Wang, Jun; Kwon, Eunjeong; Kang, Minjeong; Lee, Sam W.; Mandinova, Anna] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Todorova, Kristina; Wang, Jun; Kwon, Eunjeong; Kang, Minjeong; Lee, Sam W.; Mandinova, Anna] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Gray, Nathanael] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol,Dept Biol Chem & Mol Pharmacol, 44 Binney St, Boston, MA 02115 USA. [Lee, Sam W.; Mandinova, Anna] Broad Inst Harvard & MIT, Cambridge, MA USA. [Mandinova, Anna] Harvard Stem Cell Inst, Cambridge, MA USA. RP Neel, VA (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA.; Neel, VA (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA.; Mandinova, A (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA.; Mandinova, A (reprint author), Harvard Univ, Sch Med, Charlestown, MA 02129 USA. EM VNEEL@partners.org; amandinova@mgh.harvard.edu FU NIH [CA140615, CA195534]; Department of Dermatology, Division of Dermatologic Surgery, Massachusetts General Hospital, Boston FX This work was supported by NIH Grants CA140615, CA195534 and intra-departmental funds from the Department of Dermatology, Division of Dermatologic Surgery, Massachusetts General Hospital, Boston. The work was approved by the MGH IRB. The work was done in Charlestown and Boston, Massachusetts, USA NR 34 TC 3 Z9 3 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2016 VL 136 IS 3 BP 696 EP 705 DI 10.1016/j.jid.2015.12.023 PG 10 WC Dermatology SC Dermatology GA DE4TL UT WOS:000370623100025 PM 26739095 ER PT J AU Hayakawa, K Wang, XH Lo, EH AF Hayakawa, Kazuhide Wang, Xiaohua Lo, Eng H. TI CD200 increases alternatively activated macrophages through cAMP-response element binding protein - C/EBP-beta signaling SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE alternatively activated M phi; C; EBP-beta; CD200-Fc; CREB; NF-kappa B ID STROKE; MECHANISMS; CREB; TRANSCRIPTION; EXPRESSION; REPAIR; MICE AB The concept of macrophage polarization toward different phenotypes after CNS injury has been increasingly discussed. Here, we propose that CD200 treatment may help shift pro-inflammatory macrophages to an arginase 1 (Arg1)-, transglutaminase 2 (TGM2)-, and transforming growth factor beta 1 (TGF-)-positive phenotype. Rat macrophages were stimulated by interferon and lipopolysaccharide (LPS) to induce pro-inflammatory phenotypes. Treatment with human CD200-Fc up-regulated expression levels of alternatively activated M2-like markers such as Arg1 and TGM2 but suppressed pro-inflammatory M1-like markers such as toll-like receptor 4, interleukin 1 beta (IL-1), IL-6, and GM-CSF. Concomitantly, CD200-Fc enhanced (CCAAT/enhancer-binding protein) C/EBP-beta promoter activity, whereas NF-B activity was suppressed. Treatment with CD200-Fc also up-regulated potentially beneficial TGF- expression in macrophages. When C/EBP-beta signaling was suppressed with siRNA, the effect of CD200-Fc on Arg1, TGM2 and TGF- up-regulation was canceled. Taken together, these data provide proof-of-principle that targeting CD200 signaling may be a novel therapeutic approach to shift macrophages toward M2-like polarization via modulating cAMP-response element binding protein-C/EBP-beta transcriptional activity. C1 Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA USA. Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Hayakawa, K; Lo, EH (reprint author), Harvard Univ, Sch Med, Neuroprotect Res Lab, Massachusetts Gen Hosp East 149 2401, Charlestown, MA 02129 USA. EM Khayakawa1@mgh.harvard.edu; Lo@helix.mgh.harvard.edu FU National Institute of Health FX This research was supported by the National Institute of Health. NR 21 TC 4 Z9 5 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2016 VL 136 IS 5 BP 900 EP 906 DI 10.1111/jnc.13492 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DE5BT UT WOS:000370646500002 PM 26670206 ER PT J AU Qin, LM Bouchard, R Pugazhenthi, S AF Qin, LiMei Bouchard, Ron Pugazhenthi, Subbiah TI Regulation of cyclic AMP response element-binding protein during neuroglial interactions SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; CREB; human neuroprogenitor cells; microglia; neuroinflammation; signal transduction ID MEDIATED DOWN-REGULATION; NECROSIS-FACTOR-ALPHA; HIPPOCAMPAL NEUROGENESIS; DIFFERENTIAL REGULATION; MICROGLIAL ACTIVATION; ALZHEIMERS-DISEASE; TRANSGENIC MICE; BCL-2 PROMOTER; CELLS; TRANSCRIPTION AB Communications between neurons and glial cells play an important role in regulating homeostasis in the central nervous system. cAMP response element-binding protein (CREB), a transcription factor, is down-regulated by neurotoxins, which are known to be released by activated glial cells. To determine the role of CREB signaling in neuroglial interactions, we used three neuroglial coculture models consisting of human neuroprogenitor cell (NPC)-derived neurons and human microglia. Conditioned medium from the Abeta (A)-activated microglia decreased CREB phosphorylation and brain-derived neurotrophic factor promoter activity (47%), whereas the same medium induced (p<0.01) the promoter of CXCL10, a chemokine, in NPC-derived neuron-rich cultures. These effects were reversed when microglia were exposed to A in the presence of minocycline, an anti-inflammatory agent. The expression of CREB targets, including brain-derived neurotrophic factor, synapsin-1, and BIRC3 decreased by 50-65% (p<0.01) in neurons isolated by laser capture microdissection in close proximity of microglia in neuroglial mixed cultures. Neuronal survival actively modulated microglial behavior when neurons and microglia were cocultured side-by-side on semicircles of ACLAR membrane. Neuronal injury, caused by the over-expression of dominant negative form of CREB, exacerbated A-mediated microglial activation, whereas CREB over-expression resulted in decreased microglial activation. Decreases in the levels of neuronal markers were observed when NPCs were differentiated in the presence of proinflammatory cytokines IL-1, tumor necrosis factor , or IL-6. Instead, the NPCs differentiated into a glial phenotype, and these effects were more pronounced in the presence of tumor necrosis factor . Our findings suggest that CREB down-regulation is an important component of defective neuroglial communications in the brain during neuroinflammation. C1 [Qin, LiMei; Bouchard, Ron; Pugazhenthi, Subbiah] Vet Affairs Med Ctr, Endocrinol Sect, Denver, CO USA. [Bouchard, Ron; Pugazhenthi, Subbiah] Univ Colorado Denver, Dept Med, Aurora, CO USA. RP Pugazhenthi, S (reprint author), Univ Colorado, Denver VA Med Ctr, Anschutz Med Campus,Mail Stop 8106, Aurora, CO 80045 USA.; Pugazhenthi, S (reprint author), Univ Colorado, Dept Med, Anschutz Med Campus,Mail Stop 8106, Aurora, CO 80045 USA. EM subbiah.pugazhenthi@ucdenver.edu FU Veterans Administration [NEUD-004-07F] FX This work was carried out with the use of resources and facilities at the Denver VA Medical Center. This study was supported by Merit Review grant NEUD-004-07F from the Veterans Administration (to S.P.). RT-PCR analysis was performed at the University of Colorado Cancer Center Core Facility. Digital deconvolution microscopy was carried out at the VA Microscopy Core Facility. Authors declare that there is no conflict of interest associated with this manuscript. NR 42 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2016 VL 136 IS 5 BP 918 EP 930 DI 10.1111/jnc.13497 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DE5BT UT WOS:000370646500004 PM 26677139 ER PT J AU Samantaray, S Das, A Matzelle, DC Yu, SP Wei, L Varma, A Ray, SK Banik, NL AF Samantaray, Supriti Das, Arabinda Matzelle, Denise C. Yu, Shan P. Wei, Ling Varma, Abhay Ray, Swapan K. Banik, Naren L. TI Administration of low dose estrogen attenuates gliosis and protects neurons in acute spinal cord injury in rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE acute spinal cord injury; calpain; estrogen; estrogen receptors; gliosis; neuroprotection ID APOPTOTIC CELL-DEATH; TRAUMATIC BRAIN-INJURY; CEREBRAL BLOOD-VESSELS; RECEPTOR-ALPHA; UP-REGULATION; NEUROPROTECTIVE AGENT; FUNCTIONAL RECOVERY; SIGNAL-TRANSDUCTION; CALPAIN INHIBITORS; CORTICAL-NEURONS AB Spinal cord injury (SCI) is a debilitating condition with neurological deficits and loss of motor function that, depending on the severity, may lead to paralysis. The only treatment currently available is methylprednisolone, which is widely used and renders limited efficacy in SCI. Therefore, other therapeutic agents must be developed. The neuroprotective efficacy of estrogen in SCI was studied with a pre-clinical and pro-translational perspective. Acute SCI was induced in rats that were treated with low doses of estrogen (1, 5, 10, or 100g/kg) and compared with vehicle-treated injured rats or laminectomy control (sham) rats at 48h post-SCI. Changes in gliosis and other pro-inflammatory responses, expression and activity of proteolytic enzymes (e.g., calpain, caspase-3), apoptosis of neurons in SCI, and cell death were monitored via Western blotting and immunohistochemistry. Negligible pro-inflammatory responses or proteolytic events and very low levels of neuronal death were found in sham rats. In contrast, vehicle-treated SCI rats showed profound pro-inflammatory responses with reactive gliosis, elevated expression and activity of calpain and caspase-3, elevated Bax:Bcl-2 ratio, and high levels of neuronal death in lesion and caudal regions of the injured spinal cord. Estrogen treatment at each dose reduced pro-inflammatory and proteolytic activities and protected neurons in the caudal penumbra in acute SCI. Estrogen treatment at 10g was found to be as effective as 100g in ameliorating the above parameters in injured animals. Results from this investigation indicated that estrogen at a low dose could be a promising therapeutic agent for treating acute SCI. C1 [Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C.; Varma, Abhay; Banik, Naren L.] Med Univ S Carolina, Dept Neurol & Neurosurg, 96 Jonathan Lucas St,Suite 309 CSB,MSC 606, Charleston, SC 29425 USA. [Yu, Shan P.; Wei, Ling] Emory Univ, Sch Med, Dept Anesthesia, Atlanta, GA USA. [Ray, Swapan K.] Univ S Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC USA. [Banik, Naren L.] Ralph H Johnson Vet Adm, Med Ctr, Charleston, SC USA. RP Banik, NL (reprint author), Med Univ S Carolina, Dept Neurol & Neurosurg, 96 Jonathan Lucas St,Suite 309 CSB,MSC 606, Charleston, SC 29425 USA. EM baniknl@musc.edu FU NIH [R01-NS31622, R01 NS45967]; Veterans Administration [1IOBX00126 and 1IOBX002349]; South Carolina State Spinal Cord Research Fund [SCIRF-2015-P-01, SCIRF-2015-P-04, SCIRF-2015-I-01]; Department of Neurosurgery, MUSC; MUSC-CTSA program FX This work was supported in part by funding from NIH (R01-NS31622 and R01 NS45967); Veterans Administration (1IOBX00126 and 1IOBX002349); South Carolina State Spinal Cord Research Fund (SCIRF-2015-P-01, SCIRF-2015-P-04, and SCIRF-2015-I-01); Department of Neurosurgery, MUSC; and MUSC-CTSA program. We also thank Dr. Kelly Guyton for her valuable contribution to this work. Authors declare no conflict of interests. NR 73 TC 1 Z9 1 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2016 VL 136 IS 5 BP 1064 EP 1073 DI 10.1111/jnc.13464 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DE5BT UT WOS:000370646500016 PM 26662641 ER PT J AU Cillo, JE Basi, D Peacock, Z Aghaloo, T Bouloux, G Dodson, T Edwards, SP Kademani, D AF Cillo, Joseph E., Jr. Basi, David Peacock, Zachary Aghaloo, Tara Bouloux, Gary Dodson, Thomas Edwards, Sean P. Kademani, Deepak TI Proceedings of the American Association of Oral and Maxillofacial Surgeons 2015 Research Summit SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID GIANT-CELL GRANULOMA; MCCUNE-ALBRIGHT SYNDROME; LIQUID-NITROGEN CRYOTHERAPY; CALCITONIN NASAL SPRAY; ORTHOGNATHIC SURGERY; SURGICAL-TREATMENT; FIBROUS DYSPLASIA; METHYLENE-BLUE; NEVUS SYNDROME; RECONSTRUCTION AB The Fifth Biennial Research Summit of the American Association of Oral and Maxillofacial Surgeons and its Committee on Research Planning and Technology Assessment was held in Rosemont, Illinois on May 6 and 7, 2015. The goal of the symposium is to provide a forum for the most recent clinical and scientific advances to be brought to the specialty. The proceedings of the events of that summit are presented in this report. (C) 2016 American Association of Oral and Maxillofacial Surgeons C1 [Cillo, Joseph E., Jr.] Allegheny Gen Hosp, Div Oral & Maxillofacial Surg, Pittsburgh, PA 15212 USA. [Peacock, Zachary] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Aghaloo, Tara] Univ Calif Los Angeles, Sch Dent, Clin Res, Los Angeles, CA 90024 USA. [Aghaloo, Tara] Univ Calif Los Angeles, Sch Dent, Sect Oral & Maxillofacial Surg, Div Diagnost & Surg Sci, Los Angeles, CA 90024 USA. [Bouloux, Gary] Emory Univ, Dept Oral & Maxillofacial Surg, Atlanta, GA 30322 USA. [Dodson, Thomas] Univ Washington, Dept Oral & Maxillofacial Surg, Seattle, WA 98195 USA. [Edwards, Sean P.] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Edwards, Sean P.] Univ Michigan, Sch Dent, Residency Program, Ann Arbor, MI 48109 USA. [Edwards, Sean P.] Univ Michigan, Sch Dent, Pediat Oral & Maxillofacial Surg, Ann Arbor, MI 48109 USA. [Kademani, Deepak] North Mem & Hubert Humphrey Canc Ctr, Dept Oral & Maxillofacial Surg, Minneapolis, MN USA. [Kademani, Deepak] North Mem & Hubert Humphrey Canc Ctr, Oral Head & Neck Oncol & Reconstruct Surg, Minneapolis, MN USA. RP Cillo, JE (reprint author), Allegheny Gen Hosp, Div Oral & Maxillofacial Surg, Allegheny Hlth Network, 320 East North Ave,Suite 0107, Pittsburgh, PA 15212 USA. EM jecdna@aol.com NR 66 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAR PY 2016 VL 74 IS 3 BP 429 EP 437 DI 10.1016/j.joms.2015.11.029 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DE1FX UT WOS:000370373300006 PM 26707430 ER PT J AU Inverso, G Dodson, TB Gonzalez, ML Chuang, SK AF Inverso, Gino Dodson, Thomas B. Gonzalez, Martin L. Chuang, Sung-Kiang TI Complications of Moderate Sedation Versus Deep Sedation/General Anesthesia for Adolescent Patients Undergoing Third Molar Extraction SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID AMBULATORY ANESTHESIA; SURGERY; OUTCOMES; ANXIETY; CHOICE AB Purpose: To examine the complications resulting from moderate sedation versus deep sedation/general anesthesia for adolescent patients undergoing third molar extraction and determine whether any differences in complication risks exist between the 2 levels of sedation. Materials and Methods: We performed a prospective study of the Oral and Maxillofacial Surgery Outcomes System from January 2001 to December 2010. The primary predictor variable was the level of sedation, divided into 2 groups: moderate sedation versus deep sedation/general anesthesia. The primary outcome was the incidence of adverse complications resulting from the sedation level. Differences in the cohort characteristics were analyzed using the independent samples t test, chi(2) test, and analysis of variance, as appropriate. Multivariable logistic regression was used to measure the effect the level of sedation had on the adverse complication rate. Results: Patients in the moderate sedation group had a complication rate of 0.5%, and patients in the deep sedation/general anesthesia group had a complication rate of 0.9%. Compared with moderate sedation, deep sedation/general anesthesia did not pose a significantly increased risk of adverse anesthesia complications (adjusted odds ratio 1.63, 95% confidence interval 0.95 to 2.81; P = .077). Conclusions: The results of our study have shown that the risk of adverse anesthesia complications is not increased when choosing between moderate and deep sedation/general anesthesia for adolescent patients undergoing third molar extraction. (C) 2016 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 74: 474-479, 2016 C1 [Inverso, Gino] Hosp Univ Penn, Dept Oral & Maxillofacial Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. [Dodson, Thomas B.] Univ Washington, Sch Dent, Dept Oral & Maxillofacial Surg, Seattle, WA 98195 USA. [Dodson, Thomas B.] Univ Washington, Sch Dent, Hosp Affairs, Seattle, WA 98195 USA. [Gonzalez, Martin L.] Amer Assoc Oral & Maxillofacial Surg, Rosemont, IL USA. [Chuang, Sung-Kiang] Harvard Univ, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. [Chuang, Sung-Kiang] Massachusetts Gen Hosp, Ctr Appl Clin Invest, Boston, MA 02114 USA. RP Inverso, G (reprint author), Univ Penn, Dept Oral & Maxillofacial Surg, Perelman Ctr Adv Med, 4 South Pavil,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM gino.inverso@uphs.upenn.edu NR 14 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAR PY 2016 VL 74 IS 3 BP 474 EP 479 DI 10.1016/j.joms.2015.10.009 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DE1FX UT WOS:000370373300011 PM 26546845 ER PT J AU Panchal, N Zide, M AF Panchal, Neeraj Zide, Michael TI The Parkland 12-Minute Checklist Tracheotomy SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article AB Purpose: To validate the surgical time and propose a new checklist or algorithm to execute a tracheotomy within 12 minutes with optimal outcomes. Materials and Methods: The authors designed and implemented a checklist method for tracheotomy based on 6 consecutive patients with respiratory failure and prolonged intubation in a medical intensive care unit. The primary outcome variable was surgical time for a tracheotomy performed by a fifth-or sixth-year resident under the supervision of the senior author (M.Z.). Results: Six consecutive patients undergoing tracheotomy (mean, 48 yr; range, 24 to 55 yr; 4 men and 2 women) were included in the study. The average time recorded from the incision to correct insertion of the tracheotomy tube and confirmation of carbon dioxide return by the anesthesiologist was 10.66 minutes (range, 8 to 12 minutes). Conclusion: This checklist facilitates the execution of a time-efficient and safe tracheotomy in less than 12 minutes. (C) 2016 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 74: 556-561, 2016 C1 [Panchal, Neeraj] Univ Texas Southwestern, Parkland Mem Hosp, Dallas, TX USA. [Panchal, Neeraj] Univ Penn, Dept Oral & Maxillofacial Surg, Philadelphia, PA 19104 USA. [Panchal, Neeraj] Philadelphia Vet Affairs Med Ctr, Dept Oral & Maxillofacial Surg, Philadelphia, PA USA. [Zide, Michael] Univ Texas SW Med Ctr Dallas, Div Oral & Maxillofacial Surg, Parkland Mem Hosp, Dallas, TX 75390 USA. RP Panchal, N (reprint author), 3400 Spruce St,5 White Bldg, Philadelphia, PA 19104 USA. EM neeraj.panchal@uphs.upenn.edu NR 7 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAR PY 2016 VL 74 IS 3 BP 556 EP 561 DI 10.1016/j.joms.2015.10.022 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DE1FX UT WOS:000370373300023 PM 26657394 ER PT J AU Liu, GZ Jawitz, OK Zheng, D Gusberg, RJ Kim, AW AF Liu, Geoffrey Z. Jawitz, Oliver K. Zheng, Daniel Gusberg, Richard J. Kim, Anthony W. TI Reflective Writing for Medical Students on the Surgical Clerkship: Oxymoron or Antidote? SO JOURNAL OF SURGICAL EDUCATION LA English DT Article DE empathy; narrative medicine; reflective writing ID PHYSICIAN EMPATHY; GENERAL-SURGERY; SPECIALTY; SCHOOL; CAREER AB OBJECTIVES: Reflective writing has emerged as a solution to declining empathy during clinical training. However, the role for reflective writing has not been studied in a surgical setting. The aim of this proof-of-concept study was to assess receptivity to a reflective-writing intervention among third year medical students on their surgical clerkship. STUDY DESIGN: The reflective-writing intervention was a 1-hour, peer-facilitated writing workshop. This study employed a pre post-intervention design. Subjects were surveyed on their experience 4 weeks before participation in the intervention and immediately afterwards. Surveys assessed student receptivity to reflective writing as well as self-perceived empathy, writing habits, and communication behaviors using a Likert-response scale. Quantitative responses were analyzed using paired t tests and linear regression. Qualitative responses were analyzed using an iterative consensus model. SETTING: Yale-New Haven hospital, a tertiary care academic center. PARTICIPANTS: All medical students of Yale School of Medicine, rotating on their surgical clerkship during a 9-month period (74 in total) were eligible. In all, 25 students completed this study. RESULTS: The proportion of students desiring more opportunities for reflective writing increased from 32%-64%. The proportion of students receptive to a mandatory writing workshop increased from 16%-40%. These differences were both significant (p = 0.003 and p = 0.001). In all, 88% of students also reported new insight as a result of the workshop. In total, 39% of students reported a more positive impression of the surgical profession after participation. CONCLUSION: Overall, the workshop was well-received by students and improved student attitudes toward reflective writing and the surgical profession. Larger studies are required to validate the effect of this workshop on objective empathy measures. This study demonstrates how reflective writing can be incorporated into a presurgical curriculum. (C) 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved. C1 [Liu, Geoffrey Z.; Jawitz, Oliver K.; Zheng, Daniel; Gusberg, Richard J.; Kim, Anthony W.] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. RP Liu, GZ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM gzliu@partners.org NR 22 TC 0 Z9 0 U1 3 U2 6 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 MAR-APR PY 2016 VL 73 IS 2 BP 296 EP 304 DI 10.1016/j.jsurg.2015.11.002 PG 9 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA DE2ON UT WOS:000370466700019 PM 26794901 ER PT J AU Soura, E Eliades, PJ Shannon, K Stratigos, AJ Tsao, H AF Soura, Efthymia Eliades, Philip J. Shannon, Kristen Stratigos, Alexander J. Tsao, Hensin TI Hereditary melanoma: Update on syndromes and management Genetics of familial atypical multiple mole melanoma syndrome SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE CDK4; CDKN2A; familial melanoma syndromes; FAMMM; melanoma genetics; mixed cancer syndromes ID CUTANEOUS MALIGNANT-MELANOMA; TOTAL-BODY PHOTOGRAPHY; PANCREATIC-CARCINOMA SYNDROME; GERM-LINE MUTATIONS; PRONE FAMILIES; FAMMM SYNDROME; HIGH-RISK; SUSCEPTIBILITY GENES; CDKN2A MUTATIONS; EARLY-DIAGNOSIS AB Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis. C1 [Soura, Efthymia; Stratigos, Alexander J.] Andreas Sygros Hosp, Univ Clin, Dept Dermatol 1, Athens, Greece. [Eliades, Philip J.; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Eliades, Philip J.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Shannon, Kristen; Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Melanoma Genet Program, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Edwards 211,50 Blossom St, Boston, MA 02114 USA.; Tsao, H (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Edwards 211,50 Blossom St, Boston, MA 02114 USA. EM htsao@partners.org OI Soura, Efthymia/0000-0003-0324-5647 FU National Institutes of Health [K24 CA149202] FX Supported by National Institutes of Health grant K24 CA149202 (Dr Tsao) and by the generous donors to Massachusetts General Hospital on behalf of melanoma research. NR 71 TC 6 Z9 6 U1 3 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 MAR PY 2016 VL 74 IS 3 BP 395 EP 407 DI 10.1016/j.jaad.2015.08.038 PG 13 WC Dermatology SC Dermatology GA DE1FO UT WOS:000370372300005 PM 26892650 ER PT J AU Soura, E Eliades, PJ Shannon, K Stratigos, AJ Tsao, H AF Soura, Efthymia Eliades, Philip J. Shannon, Kristen Stratigos, Alexander J. Tsao, Hensin TI Hereditary melanoma: Update on syndromes and management Emerging melanoma cancer complexes and genetic counseling SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE BAP1; familial melanoma syndrome; melanoma genetics; MITF; mixed cancer syndromes; PTEN; TERT ID TERT PROMOTER MUTATIONS; HAMARTOMA TUMOR SYNDROME; GERMLINE BAP1 MUTATIONS; CUTANEOUS MELANOMA; UVEAL MELANOMA; TELOMERE LENGTH; MALIGNANT MESOTHELIOMA; TRANSCRIPTION FACTOR; SPORADIC MELANOMA; MITF AB Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal. C1 [Soura, Efthymia; Stratigos, Alexander J.] Andreas Sygros Hosp, Univ Clin, Dept Dermatol 1, Athens, Greece. [Eliades, Philip J.; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Eliades, Philip J.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Shannon, Kristen; Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Melanoma Genet Program, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Edwards 211,50 Blossom St, Boston, MA 02114 USA.; Tsao, H (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Edwards 211,50 Blossom St, Boston, MA 02114 USA. EM htsao@partners.org FU National Institutes of Health [K24 CA149202] FX Supported by National Institutes of Health grant K24 CA149202 (Dr Tsao) and by the generous donors to Massachusetts General Hospital on behalf of melanoma research. NR 52 TC 5 Z9 5 U1 2 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 MAR PY 2016 VL 74 IS 3 BP 411 EP 420 DI 10.1016/j.jaad.2015.08.037 PG 10 WC Dermatology SC Dermatology GA DE1FO UT WOS:000370372300006 PM 26892651 ER PT J AU Shimada, YJ Tsugawa, Y Brown, DFM Hasegawa, K AF Shimada, Yuichi J. Tsugawa, Yusuke Brown, David F. M. Hasegawa, Kohei TI Bariatric Surgery and Emergency Department Visits and Hospitalizations for Heart Failure Exacerbation Population-Based, Self-Controlled Series SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE confounder; epidemic; heart failure; obesity ID MORBIDLY OBESE-PATIENTS; BODY-MASS INDEX; RANDOMIZED CONTROLLED-TRIALS; NATIONAL DIABETES REGISTRY; NATRIURETIC PEPTIDE LEVELS; SURGICAL OUTCOMES; UNITED-STATES; WEIGHT-LOSS; MORTALITY; IMPACT AB BACKGROUND The United States is battling obesity and heart failure (HF) epidemics. Although studies have suggested relationships between obesity and HF morbidity, little is known regarding the effects of substantial weight reduction in obese patients with HF. OBJECTIVES This study investigated whether bariatric surgery is associated with a decreased rate of HF exacerbation. METHODS We performed a self-controlled case series study of obese patients with HF who underwent bariatric surgery, using the population-based emergency department (ED) and inpatient sample in California, Florida, and Nebraska. Primary outcome was ED visit or hospitalization for HF exacerbation from 2005 to 2011. We used conditional logistic regression to compare the outcome event rate during sequential 12-month periods, using pre-surgery months 13 to 24 as the reference period. RESULTS We identified 524 patients with HF who underwent bariatric surgery. During the reference period, 16.2% of patients had an ED visit or hospitalization for HF exacerbation. The rate remained unchanged in the subsequent 12-month pre-surgery period (15.3%; p = 0.67). In the first 12-month period after bariatric surgery, we observed a nonsignificantly reduced rate (12.0%; p = 0.052). However, the rate was significantly lower in the subsequent 13 to 24 months after bariatric surgery (9.9%; adjusted odds ratio: 0.57; p = 0.003). By contrast, there was no significant reduction in the rate of HF exacerbation among obese patients who underwent nonbariatric surgery (i.e., cholecystectomy, hysterectomy). CONCLUSIONS Our findings indicate that bariatric surgery is associated with a decline in the rate of HF exacerbation requiring ED evaluation or hospitalization among obese patients with HF. (C) 2016 by the American College of Cardiology Foundation. C1 [Shimada, Yuichi J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Tsugawa, Yusuke] Harvard Univ, TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Brown, David F. M.; Hasegawa, Kohei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Shimada, YJ (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, 55 Fruit St,Gray Bigelow 800,Mailstop 843, Boston, MA 02114 USA. EM yshimada@partners.org OI Shimada, Yuichi/0000-0002-3494-307X FU American Heart Association National Clinical and Population Research Award; Honjo International Scholarship Foundation; St. Luke's International University FX Dr. Shimada was supported, in part, by an unrestricted grant from the American Heart Association National Clinical and Population Research Award. Drs. Tsugawa and Shimada were supported, in part, by an unrestricted grant from Honjo International Scholarship Foundation. Dr. Tsugawa was supported, in part, by an unrestricted grant from St. Luke's International University. The funding organizations did not have any role in the study design, analysis or interpretation of data, in writing of the report or in the decision to submit the paper for publication. The researchers were independent from the funding organizations. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Shimada and Tsugawa contributed equally to this work. NR 44 TC 3 Z9 3 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 1 PY 2016 VL 67 IS 8 BP 895 EP 903 DI 10.1016/j.jacc.2015.12.016 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DE2XE UT WOS:000370490000001 PM 26916477 ER PT J AU Jaber, WA Fong, PP Weisz, G Lattouf, O Jenkins, J Rosenfield, K Rab, T Ramee, S AF Jaber, Wissam A. Fong, Pete P. Weisz, Giora Lattouf, Omar Jenkins, James Rosenfield, Kenneth Rab, Tanveer Ramee, Stephen TI Acute Pulmonary Embolism With an Emphasis on an Interventional Approach SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE embolectomy; fibrinolysis; interventional management; pulmonary artery ID EXTRACORPOREAL MEMBRANE-OXYGENATION; ACUTE VENOUS THROMBOEMBOLISM; VENA-CAVA FILTERS; THROMBECTOMY DEVICE; SURGICAL-TREATMENT; RESPONSE TEAM; CATHETER; THROMBOLYSIS; RISK; METAANALYSIS AB Compared with recent advances in treatment of serious cardiovascular diseases, such as myocardial infarction and stroke, the treatment and outcome of acute pulmonary embolism (PE) have remained relatively unchanged over the last few decades. This has prompted several experts to call for the formation of multidisciplinary PE response teams with a more proactive approach to the treatment of PE. In the current document, we discuss the formation of such teams and describe the available treatment options beyond anticoagulation, with a focus on the interventional approach. Acknowledging the paucity of data to support widespread adoption of such techniques, we call for the collection of outcomes data in multicenter registries and support for randomized trials to evaluate interventional treatments in patients with high-risk PE. (C) 2016 by the American College of Cardiology Foundation. C1 [Jaber, Wissam A.; Rab, Tanveer] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Fong, Pete P.] Vanderbilt Heart & Vasc Inst, Nashville, TN USA. [Weisz, Giora] Shari Zadek Med Ctr, Div Cardiol, Jerusalem, Israel. [Lattouf, Omar] Emory Univ, Sch Med, Div Cardiothorac Surg, Atlanta, GA 30322 USA. [Jenkins, James] Ochsner Med Ctr, New Orleans, LA USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Div Cardiol, Sect Vasc Med & Intervent, Boston, MA 02114 USA. [Ramee, Stephen] Ochsner Med Ctr, Struct & Valvular Heart Dis Program, New Orleans, LA USA. RP Rab, T (reprint author), Emory Univ Hosp, Div Cardiol, 1364 Clifton Rd Northeast,F-606, Atlanta, GA 30322 USA. EM srab@emory.edu FU National Institutes of Health; Atrium; Lutonix-Bard; Abbott Vascular; Gore FX Dr. Rosenfield has served as a consultant to Abbott, Cardinal Health, Inari Medical, Surmodics, Volcano, Capture Vascular, and Shockwave; has served as a board member for VIVA Physicians, a 501c3 organization; has received research support from the National Institutes of Health, Atrium, Lutonix-Bard, Abbott Vascular, and Gore; and has personal equity in CardioMems, Embolitech, MD Insider, Primacea, and Vortex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 50 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 1 PY 2016 VL 67 IS 8 BP 991 EP 1002 DI 10.1016/j.jacc.2015.12.024 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DE2XE UT WOS:000370490000014 PM 26916490 ER PT J AU Mukherjee, R AF Mukherjee, Rupak TI Forewarned is forearmed: Benefits of remote ischemic preconditioning SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID ISOLATED RAT-HEART; REPERFUSION INJURY; SEVOFLURANE; ISOFLURANE; PROTECTION; MYOCARDIUM C1 [Mukherjee, Rupak] Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg, Charleston, SC 29425 USA. [Mukherjee, Rupak] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Mukherjee, R (reprint author), Div Cardiothorac Surg, MSC 777,114 Doughty St,Ste 338, Charleston, SC 29426 USA. EM mukherr@musc.edu FU NIA NIH HHS [AG036954]; RRD VA [I21 RX001707] NR 14 TC 1 Z9 1 U1 1 U2 2 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 MAR PY 2016 VL 151 IS 3 BP 786 EP 787 DI 10.1016/j.jtcvs.2015.10.089 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DD9KR UT WOS:000370244700051 PM 26628358 ER PT J AU Muniappan, A AF Muniappan, Ashok TI Ischemia reperfusion induced acute lung injury: Using everything and the kitchen SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID TRANSPLANTATION; TRIAL C1 [Muniappan, Ashok] Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. RP Muniappan, A (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM amuniappan@partners.org NR 7 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 MAR PY 2016 VL 151 IS 3 BP 870 EP 871 DI 10.1016/j.jtcvs.2015.11.017 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DD9KR UT WOS:000370244700069 PM 26704059 ER PT J AU Barshes, NR Pisimisis, G Kougias, P AF Barshes, Neal R. Pisimisis, George Kougias, Panos TI Compartment syndrome of the foot associated with a delayed presentation of acute limb ischemia SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID FASCIOTOMY; ANKLE AB Compartment syndrome of the leg is a well-recognized complication known to follow urgent revascularization done for acute limb ischemia, but compartment syndrome of the foot has not been reported after the ischemia-reperfusion sequence. Herein we report a case of foot fasciotomy done for compartment syndrome that occurred after urgent revascularization. We suggest that foot fasciotomies should be considered in particular circumstances of acute lower leg ischemia, such as infrapopliteal thromboembolic events, prolonged ischemia, and persistent or worsening foot symptoms that follow revascularization and calf fasciotomies. C1 [Barshes, Neal R.; Pisimisis, George; Kougias, Panos] Baylor Coll Med, Div Vasc Surg & Endovasc Therapy, Michael E DeBakey Dept Surg, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Barshes, NR (reprint author), Baylor Coll Med, Div Vasc & Endovasc Surg, Michael E DeBakey Dept Surg, Michael E DeBakey Vet Affairs Med Ctr,Surg, 2002 Holcombe Blvd,OCL 112, Houston, TX 77030 USA. EM nbarshes@bcm.tmc.edu NR 16 TC 1 Z9 1 U1 4 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 MAR PY 2016 VL 63 IS 3 BP 819 EP 822 DI 10.1016/j.jvs.2015.01.043 PG 4 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DE6YI UT WOS:000370780400037 PM 25752690 ER PT J AU Ingelfinger, JR Kalantar-Zadeh, K Schaefer, F AF Ingelfinger, Julie R. Kalantar-Zadeh, Kamyar Schaefer, Franz CA World Kidney Day Steering Committ TI Averting the legacy of kidney disease-focus on childhood SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID NEPHROLOGY ASSOCIATION IPNA; RENAL REPLACEMENT THERAPY; LOW-BIRTH-WEIGHT; NONCOMMUNICABLE DISEASES; INTERNATIONAL SOCIETY; CONSENSUS STATEMENT; PROSPECTIVE COHORT; BLOOD-PRESSURE; GLOBAL HEALTH; CHILDREN AB World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and chronic kidney disease in later childhood or in adult life. Children born early or who are small-for-date newborns have a relatively increased risk for the development of chronic kidney disease later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced chronic kidney disease in childhood; there is evidence that children fare better than adults if they receive kidney replacement therapy including dialysis and transplant, whereas only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers, and caregivers about the needs and possibilities surrounding kidney disease in childhood. (C) World Kidney Day 2016 Steering Committee C1 [Ingelfinger, Julie R.] Harvard Univ, Sch Med, Pediat, Boston, MA 02115 USA. [Ingelfinger, Julie R.] Massachusetts Gen Hosp, Mass Gen Hosp Children, Boston, MA 02114 USA. [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Sch Med, Div Nephrol & Hypertens, Long Beach, CA USA. [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Sch Med, Med, Pediat & Publ Hlth, Long Beach, CA USA. [Kalantar-Zadeh, Kamyar] Vet Affairs VA Long Beach Healthcare Syst, Long Beach, CA USA. [Kalantar-Zadeh, Kamyar] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Epidemiol, Los Angeles, CA USA. [Schaefer, Franz] Heidelberg Univ, Div Pediat Nephrol, Ctr Pediat & Adolescent Med Heidelberg, Pediat, Bergheimer Str 58, D-69115 Heidelberg, Germany. RP Ingelfinger, JR (reprint author), Int Soc Nephrol, Rues Fabriques 1B, B-1000 Brussels, Belgium. EM myriam@worldkidneyday.org OI Kalantar-Zadeh, Kamyar/0000-0002-8666-0725 NR 36 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2016 VL 89 IS 3 BP 512 EP 518 DI 10.1016/j.kint.2015.10.014 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DE2QL UT WOS:000370471700001 PM 26880442 ER PT J AU Uribe-Leitz, T Jaramillo, J Maurer, L Fu, R Esquivel, MM Gawande, AA Haynes, AB Weiser, TG AF Uribe-Leitz, Tarsicio Jaramillo, Joshua Maurer, Lydia Fu, Rui Esquivel, Micaela M. Gawande, Atul A. Haynes, Alex B. Weiser, Thomas G. TI Variability in mortality following caesarean delivery, appendectomy, and groin hernia repair in low-income and middle-income countries: a systematic review and analysis of published data SO LANCET GLOBAL HEALTH LA English DT Article ID SUB-SAHARAN AFRICA; PEDIATRIC INGUINAL-HERNIA; MATERNAL MORTALITY; ACUTE APPENDICITIS; COST-EFFECTIVENESS; LAPAROSCOPIC APPENDECTOMY; COMPLICATED APPENDICITIS; TEACHING HOSPITALS; PREGNANCY OUTCOMES; LOCAL-ANESTHESIA AB Background Surgical interventions occur at lower rates in resource-poor settings, and complication and death rates following surgery are probably substantial but have not been well quantified. A deeper understanding of outcomes is a crucial step to ensure that high quality accompanies increased global access to surgical care. We aimed to assess surgical mortality following three common surgical procedures-caesarean delivery, appendectomy, and groin (inguinal and femoral) hernia repair-to quantify the potential risks of expanding access without simultaneously addressing issues of quality and safety. Methods We collected demographic, health, and economic data for 113 countries classified as low income or lower-middle income by the World Bank in 2005. We did a systematic review of Ovid, MEDLINE, PubMed, and Scopus from Jan 1, 2000, to Jan 15, 2015, to identify studies in these countries reporting all-cause mortality following the three commonly undertaken operations. Reports from governmental and other agencies were also identified and included. We modelled surgical mortality rates for countries without reported data using a two-step multiple imputation method. We first used a fully conditional specification (FCS) multiple imputation method to establish complete datasets for all missing variables that we considered potentially predictive of surgical mortality. We then used regression-based predictive mean matching imputation methods, specified within the multiple imputation FCS method, for selected predictors for each operation using the completed dataset to predict mortality rates along with confidence intervals for countries without reported mortality data. To account for variability in data availability, we aggregated results by subregion and estimated surgical mortality rates. Findings From an initial 1302 articles and reports identified, 247 full-text articles met our inclusion criteria, and 124 provided data for surgical mortality for at least one of the three selected operations. We identified 42 countries with mortality data for at least one of the three procedures. Median reported mortality was 7.9 per 1000 operations for caesarean delivery (IQR 2.8-19.9), 2.2 per 1000 operations for appendectomy (0.0-17.2), and 4.9 per 1000 operations for groin hernia (0.0-11.7). Perioperative mortality estimates by subregion ranged from 2.8 (South Asia) to 50.2 (East Asia) per 1000 caesarean deliveries, 2.4 (South Asia) to 54.0 (Central sub-Saharan Africa) per 1000 appendectomies, and 0.3 (Andean Latin America) to 25.5 (Southern sub-Saharan Africa) per 1000 hernia repairs. Interpretation All-cause postoperative mortality rates are exceedingly variable within resource-constrained environments. Eff orts to expand surgical access and provision of services must include a strong commitment to improve the safety and quality of care. Copyright (C) Uribe-Leitz et al. Open Access article distributed under the terms of CC BY. C1 [Uribe-Leitz, Tarsicio; Esquivel, Micaela M.; Weiser, Thomas G.] Stanford Univ, Dept Surg, Sch Med, Stanford, CA 94305 USA. [Jaramillo, Joshua; Maurer, Lydia] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Fu, Rui] Stanford Univ, Management Sci & Engn, Stanford, CA 94305 USA. [Gawande, Atul A.; Haynes, Alex B.] Ariadne Labs, Boston, MA USA. [Gawande, Atul A.; Haynes, Alex B.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 665 Huntington Ave, Boston, MA 02115 USA. [Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Haynes, Alex B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Weiser, TG (reprint author), Stanford Univ, Med Ctr, Dept Surg, Sect Trauma, 300 Pasteur Dr,S067, Stanford, CA 94305 USA. EM tweiser@stanford.edu NR 166 TC 1 Z9 1 U1 4 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD MAR PY 2016 VL 4 IS 3 BP E165 EP E174 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DE5ML UT WOS:000370675000019 PM 26916818 ER PT J AU Devinsky, O Marsh, E Friedman, D Thiele, E Laux, L Sullivan, J Miller, I Flamini, R Wilfong, A Filloux, F Wong, M Tilton, N Bruno, P Bluvstein, J Hedlund, J Kamens, R Maclean, J Nangia, S Singhal, NS Wilson, CA Patel, A Cilio, MR AF Devinsky, Orrin Marsh, Eric Friedman, Daniel Thiele, Elizabeth Laux, Linda Sullivan, Joseph Miller, Ian Flamini, Robert Wilfong, Angus Filloux, Francis Wong, Matthew Tilton, Nicole Bruno, Patricia Bluvstein, Judith Hedlund, Julie Kamens, Rebecca Maclean, Jane Nangia, Srishti Singhal, Nilika Shah Wilson, Carey A. Patel, Anup Cilio, Maria Roberta TI Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial SO LANCET NEUROLOGY LA English DT Article ID REFRACTORY EPILEPSY; MEDICAL MARIJUANA; CLOBAZAM; DISORDERS; CYP2C19; HISTORY AB Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11 0-96 0) at baseline and 15.8 (5 6-57 6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). Interpretation Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. C1 [Devinsky, Orrin; Friedman, Daniel; Bluvstein, Judith; Hedlund, Julie] NYU, Comprehens Epilepsy Ctr, Langone Med Ctr, New York, NY USA. [Marsh, Eric; Kamens, Rebecca; Maclean, Jane] Childrens Hosp Philadelphia, Div Child Neurol, Dept Neurol, Philadelphia, PA 19104 USA. [Marsh, Eric; Kamens, Rebecca; Maclean, Jane] Childrens Hosp Philadelphia, Dept Pediat, Div Child Neurol, Philadelphia, PA 19104 USA. [Marsh, Eric; Kamens, Rebecca; Maclean, Jane] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Thiele, Elizabeth; Bruno, Patricia] Massachusettes Gen Hosp Children, Boston, MA USA. [Laux, Linda; Nangia, Srishti] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Sullivan, Joseph; Tilton, Nicole; Singhal, Nilika Shah; Cilio, Maria Roberta] Univ Calif San Francisco, Dept Neurol, Benioff Childrens Hosp, San Francisco, CA USA. [Sullivan, Joseph; Tilton, Nicole; Singhal, Nilika Shah; Cilio, Maria Roberta] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA USA. [Miller, Ian] Miami Childrens Hosp, Miami, FL USA. [Flamini, Robert] Pediat & Adolescent Neurodev Associates, Atlanta, GA USA. [Wilfong, Angus] Texas Childrens Hosp, Houston, TX 77030 USA. [Filloux, Francis; Wilson, Carey A.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Filloux, Francis; Wilson, Carey A.] Primary Childrens Med Ctr, Salt Lake City, UT USA. [Wong, Matthew] Wake Forest Sch Med, Winston Salem, NC USA. [Patel, Anup] Nationwide Childrens Hosp, Columbus, OH USA. RP Devinsky, O (reprint author), NYU, Langone Med Ctr, New York, NY 10016 USA. EM od4@nyu.edu OI Bluvstein, Judith/0000-0001-9287-0414; Devinsky, Orrin/0000-0003-0044-4632 FU GW Pharmaceuticals; Epilepsy Therapy Project of the Epilepsy Foundation; Finding A Cure for Epilepsy and Seizures FX GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures. NR 26 TC 49 Z9 49 U1 20 U2 48 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2016 VL 15 IS 3 BP 270 EP 278 DI 10.1016/S1474-4422(15)00379-8 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DE1ON UT WOS:000370396400015 PM 26724101 ER PT J AU Dumontet, E Danger, R Vagefi, PA Londono, MC Pallier, A Lozano, JJ Giral, M Degauque, N Soulillou, JP Martinez-Llordella, M Lee, H Latournerie, M Boudjema, K Dulong, J Tarte, K Sanchez-Fueyo, A Feng, S Brouard, S Conchon, S AF Dumontet, Erwan Danger, Richard Vagefi, Parsia A. Londono, Maria-Carlota Pallier, Annaick Jose Lozano, Juan Giral, Magali Degauque, Nicolas Soulillou, Jean-Paul Martinez-Llordella, Marc Lee, Herman Latournerie, Marianne Boudjema, Karim Dulong, Joelle Tarte, Karin Sanchez-Fueyo, Alberto Feng, Sandy Brouard, Sophie Conchon, Sophie TI Peripheral phenotype and gene expression profiles of combined liver-kidney transplant patients SO LIVER INTERNATIONAL LA English DT Article DE combined transplantation; gene expression; human; kidney transplantation; liver transplantation; microRNA; phenotype ID SINGLE-CENTER EXPERIENCE; POSITIVE CROSS-MATCH; OPERATIONAL TOLERANCE; REGULATORY CELLS; GRAFT-SURVIVAL; HLA-G; REJECTION; ACCEPTANCE; RECIPIENTS; HUMANS AB Background and AimsThe beneficial effect of one graft on another has been reported in combined transplantation but the associated mechanisms and biological influence of each graft have not yet been established. MethodsIn multiple analyses, we explored the PBMC phenotype and signature of 45 immune-related messenger RNAs and 754 microRNAs from a total of 235 patients, including combined liver-kidney transplant recipients (CLK), patients with a liver (L-STA) or kidney (K-STA) graft only under classical immunosuppression and patients with tolerated liver (L-TOL) or kidney grafts (K-TOL). ResultsCLK show an intermediary phenotype with a higher percentage of peripheral CD19(+)CD24(+)CD38(Low) memory B cells and Helios(+) Treg cells, two features associated with tolerance profiles, compared to L-STA and K-STA (P<0.05, P<0.01). Very few miRNA were significantly differentially expressed in CLK vs. K-STA and even fewer when compared to L-STA (35 and 8, P<0.05). Finally, CLK are predicted to share common miRNA targets with K-TOL and even more with L-TOL (344 and 411, P=0.005). Altogether CLK display an intermediary phenotype and gene profile, which is closer to that of liver transplant patients, with possible similarities with the profiles of tolerant patients. ConclusionThese data suggest that CLK patients show the immunological influence of both allografts with liver having a greater influence. C1 [Dumontet, Erwan; Danger, Richard; Pallier, Annaick; Giral, Magali; Degauque, Nicolas; Soulillou, Jean-Paul; Brouard, Sophie; Conchon, Sophie] INSERM, UMR 1064, 30 Bd Jean Monnet, F-44093 Nantes, France. [Dumontet, Erwan; Danger, Richard; Pallier, Annaick; Giral, Magali; Degauque, Nicolas; Soulillou, Jean-Paul; Brouard, Sophie] CHU Nantes, ITUN, F-44035 Nantes 01, France. [Dumontet, Erwan; Giral, Magali; Soulillou, Jean-Paul; Brouard, Sophie; Conchon, Sophie] Univ Nantes, Nantes, France. [Dumontet, Erwan; Latournerie, Marianne; Boudjema, Karim; Dulong, Joelle; Tarte, Karin] Ctr Hosp Univ Pontchaillou, Rennes, France. [Danger, Richard; Martinez-Llordella, Marc; Sanchez-Fueyo, Alberto] Kings Coll London Univ, Sch Life Sci & Med, Ctr Transplantat, Dept Liver Studies,MRC, London, England. [Vagefi, Parsia A.] Massachusetts Gen Hosp, Div Transplantat Surg, Boston, MA 02114 USA. [Vagefi, Parsia A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Londono, Maria-Carlota; Jose Lozano, Juan; Martinez-Llordella, Marc; Sanchez-Fueyo, Alberto] Hosp Clin Barcelona, Liver Unit & Bioinformat Platform, Barcelona, Spain. [Giral, Magali; Brouard, Sophie] CIC Biotherapie, Nantes, France. [Lee, Herman; Feng, Sandy] Univ Calif San Francisco, Div Transplantat, Dept Surg, San Francisco, CA 94143 USA. [Dulong, Joelle; Tarte, Karin] EFS Bretagne, Rennes, France. [Dulong, Joelle; Tarte, Karin] INSERM, UMR 917, Rennes, France. [Brouard, Sophie] CHU Nantes, CRB, F-44035 Nantes 01, France. RP Danger, R (reprint author), INSERM, UMR 1064, 30 Bd Jean Monnet, F-44093 Nantes, France. EM richard.danger@univ-nantes.fr RI brouard, sophie/Q-1285-2016 FU "Fondation Centaure" (RTRS); "Fondation pour la Recherche Medicale" (FRM); French National Academia of Medicine; Agence de la Biomedecine; Association Francaise pour l'Etude du Foie, AFEF; ASTS/Novartis Fellowship in Transplantation Award; French government [ANR-10-IBHU-005]; Nantes Metropole; Pays de la Loire Region; Medical Research Council (MRC) Centre for Transplantation, King's College London, UK - MRC [MR/J006742/1]; National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London FX Financial support: R.D. was supported by the "Fondation Centaure" (RTRS) which supports a French research network in transplantation and by a grant from the "Fondation pour la Recherche Medicale" (FRM). E.D. was supported by a grant from the French National Academia of Medicine. INSERM U1064 was supported by the "Agence de la Biomedecine" and by the Association Francaise pour l'Etude du Foie, AFEF. PAV was supported by the ASTS/Novartis Fellowship in Transplantation Award. This work was carried out in the context of the IHU-Cesti project, which received financial support from the French government, managed by the National Research Agency ("Investment Into The Future" program ANR-10-IBHU-005), and from Nantes Metropole and the Pays de la Loire Region. The Institute of Liver Studies (KCL) is supported by the Medical Research Council (MRC) Centre for Transplantation, King's College London, UK - MRC grant no. MR/J006742/1 and by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. NR 39 TC 0 Z9 0 U1 0 U2 2 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 MAR PY 2016 VL 36 IS 3 BP 401 EP 409 DI 10.1111/liv.12917 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE2HR UT WOS:000370448700012 PM 26193627 ER PT J AU Krishnaswamy, P Bonmassar, G Poulsen, C Pierce, ET Purdon, PL Brown, EN AF Krishnaswamy, Pavitra Bonmassar, Giorgio Poulsen, Catherine Pierce, Eric T. Purdon, Patrick L. Brown, Emery N. TI Reference-free removal of EEG-fMRI ballistocardiogram artifacts with harmonic regression SO NEUROIMAGE LA English DT Article DE EEG-fMRI; Ballistocardiogram; Pulse artifact; Artifact removal; Regression; Functional neuroimaging ID INDEPENDENT COMPONENT ANALYSIS; FUNCTIONAL MRI; PULSE ARTIFACT; RECORDINGS; SCANNER; ELECTROENCEPHALOGRAM; ACQUISITION; REDUCTION; SUBTRACTION; POTENTIALS AB Combining electroencephalogram(EEG) recording and functional magnetic resonance imaging (fMRI) offers the potential for imaging brain activity with high spatial and temporal resolution. This potential remains limited by the significant ballistocardiogram (BCG) artifacts induced in the EEG by cardiac pulsation-related head movement within the magnetic field. We model the BCG artifact using a harmonic basis, pose the artifact removal problem as a local harmonic regression analysis, and develop an efficient maximum likelihood algorithm to estimate and remove BCG artifacts. Our analysis paradigm accounts for time-frequency overlap between the BCG artifacts and neurophysiologic EEG signals, and tracks the spatiotemporal variations in both the artifact and the signal. We evaluate performance on: simulated oscillatory and evoked responses constructed with realistic artifacts; actual anesthesia-induced oscillatory recordings; and actual visual evoked potential recordings. In each case, the local harmonic regression analysis effectively removes the BCG artifacts, and recovers the neurophysiologic EEG signals. We further show that our algorithm outperforms commonly used reference-based and component analysis techniques, particularly in low SNR conditions, the presence of significant time-frequency overlap between the artifact and the signal, and/or large spatiotemporal variations in the BCG. Because our algorithm does not require reference signals and has low computational complexity, it offers a practical tool for removing BCG artifacts from EEG data recorded in combination with fMRI. (C) 2015 Elsevier Inc. All rights reserved. C1 [Krishnaswamy, Pavitra; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Krishnaswamy, Pavitra; Brown, Emery N.] Harvard MIT Div Hlth Sci & Technol HST, Cambridge, MA USA. [Bonmassar, Giorgio] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Bonmassar, Giorgio; Purdon, Patrick L.] MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Poulsen, Catherine] Elect Geodes Inc, Eugene, OR USA. [Pierce, Eric T.; Purdon, Patrick L.; Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Krishnaswamy, P; Brown, EN (reprint author), 77 Massachusetts Ave,46-6079, Cambridge, MA 02139 USA. EM pavitrak@mit.edu; enb@neurostat.mit.edu FU National Institutes of Health: NIH Director's Pioneer Award [DP1-OD003646]; NIH Transformative Research Project [TR01-GM104948]; NIH New Innovator Award [DP2-OD006454]; National Center for Research Resources Grant (via the Harvard Clinical and Translational Science Center) [1 UL1 RR025758-04]; NIH/NINDS [R44NS071988] FX We acknowledge clinical data collection assistance from John Walsh, Grace Harrell, Jean Kwo, Daniel Deschler, Margaret Barlow, Rebecca Merhar, Catherine Mullaly, Mary Sullivan, Sharon Maginnis, Debra Skoniecki, and Helen-Anne Higgins at the Massachusetts General Hospital. We also acknowledge helpful discussions with Wasim Malik, Camilo Lamus, and Demba Ba at the Massachusetts Institute of Technology. This work was funded by the National Institutes of Health: NIH Director's Pioneer Award DP1-OD003646 and NIH Transformative Research Project TR01-GM104948 (to E.N.B.), and the NIH New Innovator Award DP2-OD006454 (to P.L.P.). Data acquisition was supported by the National Center for Research Resources Grant 1 UL1 RR025758-04, (via the Harvard Clinical and Translational Science Center), and NIH/NINDS Grant R44NS071988 (to C.P.). P.K.S., P.L.P. and E.N.B. have a patent pending on removal of artifacts from electrophysiologic recordings in the MRI scanner. NR 55 TC 1 Z9 2 U1 6 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2016 VL 128 BP 398 EP 412 DI 10.1016/j.neuroimage.2015.06.088 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DE1KN UT WOS:000370386000036 PM 26151100 ER PT J AU Belanoff, C Declercq, ER Diop, H Gopal, D Kotelchuck, M Luke, B Nguyen, T Stern, JE AF Belanoff, Candice Declercq, Eugene R. Diop, Hafsatou Gopal, Daksha Kotelchuck, Milton Luke, Barbara Thien Nguyen Stern, Judy E. TI Severe Maternal Morbidity and the Use of Assisted Reproductive Technology in Massachusetts SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID IN-VITRO FERTILIZATION; ADVERSE PREGNANCY; UNITED-STATES; OUTCOMES; DATABASE; SUBFERTILITY; PLURALITY; MOSART; SYSTEM; WOMEN AB OBJECTIVE: To assess whether risk of severe maternal morbidity at delivery differed for women who conceived using assisted reproductive technology (ART), those with indicators of subfertility but no ART ("subfertile"), and those who had neither ART nor subfertility ("fertile"). METHODS: This retrospective cohort study was part of the larger Massachusetts Outcomes Study of Assisted Reproductive Technology. To construct the Massachusetts Outcomes Study of Assisted Reproductive Technology database and identify ART deliveries, we linked ART treatment records to birth certificates and maternal and infant hospitalization records occurring in Massachusetts between 2004 and 2010. An algorithm of International Classification of Diseases, 9th Revision, Clinical Modification diagnosis and procedure codes identified severe maternal morbidity. We used logistic generalized estimating equations to estimate odds of severe maternal morbidity associated with fertility status, adjusting for maternal demographic and health factors and gestational age, stratifying on plurality and method of delivery. RESULTS: The prevalence of severe maternal morbidity among this population (n=458,918) was 1.16%. The overall, crude prevalences of severe maternal morbidity among fertile, subfertile, and ART deliveries were 1.09%, 1.44%, and 3.14%, respectively. The most common indicator of severe maternal morbidity was blood transfusion. In multivariable analyses, among singletons, ART was associated with increased odds of severe maternal morbidity compared with both fertile (vaginal: adjusted odds ratio [OR] 2.27, 95% confidence interval [CI] 1.78-2.88; cesarean: adjusted OR 1.67, 95% CI 1.40-1.98, respectively) and subfertile (vaginal: adjusted OR 1.97, 95% CI 1.30-3.00; cesarean: adjusted OR 1.75, 95% CI 1.30-2.35, respectively) deliveries. Among twins, only cesarean ART deliveries had significantly greater severe maternal morbidity compared with cesarean fertile deliveries (adjusted OR 1.48, 95% CI 1.14-1.93). CONCLUSION: Women who conceive through ART may have elevated risk of severe maternal morbidity at delivery, largely indicated by blood transfusion, even when compared with a subfertile population. Further research should elucidate mechanisms underlying this risk. C1 Boston Univ, Sch Publ Hlth, Massachusetts Dept Publ Hlth, Dept Community Hlth Sci, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA USA. Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, E Lansing, MI 48824 USA. Geisel Sch Med Dartmouth, Dept Obstet & Gynecol, Lebanon, NH USA. RP Belanoff, C (reprint author), Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, 801 Massachusetts Ave,Room 429, Boston, MA 02118 USA. EM cbelanof@bu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD064595, R01HD067270] FX Supported by Grants R01HD064595 and R01HD067270 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 24 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2016 VL 127 IS 3 BP 527 EP 534 DI 10.1097/AOG.0000000000001292 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DE6DI UT WOS:000370723400011 PM 26855105 ER PT J AU Lawton, MT Walcott, BP Stapleton, CJ AF Lawton, Michael T. Walcott, Brian P. Stapleton, Christopher J. TI Middle Cerebral Artery-to-Al Anterior Cerebral Artery Intracranial-Intracranial Bypass for Ruptured Dissecting Pseudoaneurysm: 3-Dimensional Operative Video SO OPERATIVE NEUROSURGERY LA English DT Editorial Material C1 [Lawton, Michael T.; Walcott, Brian P.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA USA. [Lawton, Michael T.; Walcott, Brian P.] Univ Calif San Francisco, Cerebrovasc Res Ctr, San Francisco, CA 94143 USA. [Walcott, Brian P.; Stapleton, Christopher J.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Walcott, Brian P.; Stapleton, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP Lawton, MT (reprint author), Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA USA. 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 2332-4252 J9 OPER NEUROSURG JI Oper. Neurosurg. PD MAR PY 2016 VL 12 IS 1 BP 91 EP 91 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DE2ND UT WOS:000370463100024 ER PT J AU Fairbairn, NG Ng-Glazier, J Meppelink, AM Randolph, MA Winograd, JM Redmond, RW AF Fairbairn, Neil G. Ng-Glazier, Joanna Meppelink, Amanda M. Randolph, Mark A. Winograd, Jonathan M. Redmond, Robert W. TI Improving Outcomes in Immediate and Delayed Nerve Grafting of Peripheral Nerve Gaps Using Light-Activated Sealing of Neurorrhaphy Sites with Human Amnion Wraps SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ELECTRICAL-STIMULATION PROMOTES; POOR FUNCTIONAL RECOVERY; CONTRIBUTING FACTORS; AXONAL REGENERATION; REPAIR; INJURY; DENERVATION; RECEPTORS; SPEED; RAT AB Background: Photochemical tissue bonding uses visible light to create sutureless, watertight bonds between two apposed tissue surfaces stained with photoactive dye. When applied to nerve grafting, photochemical tissue bonding can result in superior outcomes compared with suture fixation. Our previous success has focused on immediate repair. It was the aim of this study to assess the efficacy of photochemical tissue bonding when performed following a clinically relevant delay. Methods: Forty male Lewis rats had 15-mm left sciatic nerve gaps repaired with reversed isografts immediately (n = 20) or after a 30-day delay (n = 20). Repairs were secured using either suture or photochemical tissue bonding. Rats were killed after 150 days. Outcomes were assessed using monthly Sciatic Function Index evaluation, muscle mass retention, and nerve histomorphometry. Statistical analysis was performed using analysis of variance and the post hoc Bonferroni test. Results: In both immediate and delayed groups, photochemical tissue bonding showed a trend toward greater recovery of Sciatic Function Index, but these results were not significant. The Sciatic Function Index was significantly greater when performed immediately. Significantly greater muscle mass retention occurred following photochemical tissue bonding in both immediate and delayed repairs. Values did not differ significantly between immediate and delayed groups. Histomorphometric recovery was greatest in the immediate photochemical tissue bonding group and poorest in the delayed suture group. Fiber diameter, axon diameter, myelin thickness, and G-ratio were not significantly different between immediate suture and delayed photochemical tissue bonding. Conclusions: Light-activated sealing of nerve grafts results in significantly better outcomes in comparison with conventional suture. The technique not only remains efficacious but may also help ameliorate the detrimental impacts of surgical delay. C1 Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Fairbairn, NG (reprint author), St Johns Hosp, Dept Plast Surg, Howden Rd West, Livingston EH54 6PP, West Lothian, Scotland. EM ngf174@hotmail.com FU U.S. Department of Defense [USMRAA W81XWH-12-1-0511] FX This article was funded by U.S. Department of Defense (USMRAA W81XWH-12-1-0511). NR 22 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD MAR PY 2016 VL 137 IS 3 BP 887 EP 895 DI 10.1097/01.prs.0000479996.04255.60 PG 9 WC Surgery SC Surgery GA DE7HB UT WOS:000370805400002 PM 26910669 ER PT J AU Richards, EM Mathews, DC Luckenbaugh, DA Ionescu, DF Machado-Vieira, R Niciu, MJ Duncan, WC Nolan, NM Franco-Chaves, JA Hudzik, T Maciag, C Li, S Cross, A Smith, MA Zarate, CA AF Richards, Erica M. Mathews, Daniel C. Luckenbaugh, David A. Ionescu, Dawn F. Machado-Vieira, Rodrigo Niciu, Mark J. Duncan, Wallace C. Nolan, Neal M. Franco-Chaves, Jose A. Hudzik, Thomas Maciag, Carla Li, Shuang Cross, Alan Smith, Mark A. Zarate, Carlos A., Jr. TI A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression SO PSYCHOPHARMACOLOGY LA English DT Article DE Anxiety; Anxious depression; Anxiolytic; Major depressive disorder; Opiate; BDNF; EEG; Preclinical; Biomarkers; AZD2327 ID MESSENGER-RNA EXPRESSION; FORCED-SWIM TEST; STAR-ASTERISK-D; ENDOTHELIAL GROWTH-FACTOR; MAJOR DEPRESSION; ANXIETY DISORDERS; MOOD DISORDERS; NONANXIOUS DEPRESSION; OPIATE RECEPTORS; SUICIDE VICTIMS AB Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders. These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered. C1 [Richards, Erica M.; Mathews, Daniel C.; Luckenbaugh, David A.; Ionescu, Dawn F.; Machado-Vieira, Rodrigo; Niciu, Mark J.; Duncan, Wallace C.; Nolan, Neal M.; Franco-Chaves, Jose A.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Dept Hlth & Human Serv, NIH, 10 Ctr Dr CRC,Room 7-5545, Bethesda, MD 20892 USA. [Hudzik, Thomas; Maciag, Carla; Li, Shuang; Cross, Alan; Smith, Mark A.] AstraZeneca Neurosci Innovat Med, Cambridge, MA USA. [Mathews, Daniel C.] Lundbeck LLC, Chicago, IL USA. [Ionescu, Dawn F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Franco-Chaves, Jose A.] Vet Affairs Caribbean Healthcare Syst, San Juan, PR USA. [Hudzik, Thomas] AbbVie, Chicago, IL USA. [Maciag, Carla] Sage Therapeut, Cambridge, MA USA. RP Richards, EM (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Dept Hlth & Human Serv, NIH, 10 Ctr Dr CRC,Room 7-5545, Bethesda, MD 20892 USA. EM erica.richards@nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Niciu, Mark/J-1766-2014; Ionescu, Dawn/K-5675-2015; Cross, Alan/L-5456-2016 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Niciu, Mark/0000-0002-5612-3021; Cross, Alan/0000-0002-2992-2258 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [NCT00759395, 08-M-0196]; NARSAD; Brain & Behavior Mood Disorders Research Award FX Funding for this work was supported in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; NCT00759395, protocol 08-M-0196), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr. Zarate. These funding sources had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. A patent for the use of ketamine in depression has been awarded that lists Dr. Zarate among the inventors; he has assigned his rights on the patent to the US government, but will share a percentage of any royalties that may be received by the government. Carla Maciag and Drs. Mark Smith, Thomas Hudzik, and Alan Cross were full-time employees of AstraZeneca Neuroscience Innovative Medicines at the time the study was conducted. AstraZeneca Pharmaceuticals provided the study compound. NR 57 TC 5 Z9 5 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2016 VL 233 IS 6 BP 1119 EP 1130 DI 10.1007/s00213-015-4195-4 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DE8ER UT WOS:000370869100019 PM 26728893 ER PT J AU Ford, JM AF Ford, Judith M. TI Studying auditory verbal hallucinations using the RDoC framework SO PSYCHOPHYSIOLOGY LA English DT Article DE RDoC; Agency; Auditory verbal hallucinations; EEG; ERP; N1 ID COROLLARY DISCHARGE; SPEECH PRODUCTION; SCHIZOPHRENIA; CORTEX; SYMPTOMS; INITIATION; RESPONSES; TALKING; SOUNDS; BRAIN AB In this paper, I explain why I adopted a Research Domain Criteria (RDoC) approach to study the neurobiology of auditory verbal hallucinations (AVH), or voices. I explain that the RDoC construct of agency fits well with AVH phenomenology. To the extent that voices sound nonself, voice hearers lack a sense of agency over the voices. Using a vocalization paradigm like those used with nonhuman primates to study mechanisms subserving the sense of agency, we find that the auditory N1 ERP is suppressed during vocalization, that EEG synchrony preceding speech onset is related to N1 suppression, and that both are reduced in patients with schizophrenia. Reduced cortical suppression is also seen across multiple psychotic disorders and in clinically high-risk youth, but it is not related to AVH. The motor activity preceding talking and connectivity between frontal and temporal lobes during talking have both proved sensitive to AVH, suggesting neural activity and connectivity associated with intentions to act may be a better way to study agency and predictions based on agency. C1 [Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Ford, JM (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA.; Ford, JM (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA.; Ford, JM (reprint author), San Francisco VA Med Ctr, Psychiat Serv, 116D,4150 Clement St, San Francisco, CA 94121 USA. EM Judith.Ford@ucsf.edu FU Department of Veterans Affairs [I01CX000497]; National Institute of Mental Health [MH-58262] FX This work was supported by grants to JMF from Department of Veterans Affairs (I01CX000497) and National Institute of Mental Health (MH-58262). I would like to thank all of my coauthors of the work discussed in this paper. Special thanks go to Daniel H. Mathalon for ongoing inspiration and intellectual guidance, Brian J. Roach for making it all happen and his inspired data analysis, John Sweeney and his team for collecting data with our paradigm at his BSNIP site at the University of Illinois in Chicago, James Reilly for the heritability analysis of the BSNIP data, Jun Wang for his MRI-guided source analysis of the BSNIP data, Chi-Ming Chen for his analysis of the intracranial data, Veronica Perez for her analysis of the data from the clinical high-risk sample, Theda Heinks for her work on the pitch perturbation paradigm, Kevin Sitek for his work on the naturalistic formant variation analysis, Vanessa Palzes for her work on the button press paradigms, and to all the patients and their families for participating in this research. NR 64 TC 8 Z9 8 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAR PY 2016 VL 53 IS 3 SI SI BP 298 EP 304 DI 10.1111/psyp.12457 PG 7 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DE2VL UT WOS:000370485200003 PM 26877116 ER PT J AU Van Eylen, L Boets, B Steyaert, J Evers, K Wagemans, J Noens, I AF Van Eylen, Lien Boets, Bart Steyaert, Jean Evers, Kris Wagemans, Johan Noens, Ilse TI Cognitive flexibility in autism spectrum disorder: Explaining the inconsistencies? (vol 5, pg 1390, 2011) SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Correction C1 [Van Eylen, Lien; Noens, Ilse] Katholieke Univ Leuven KU Leuven, Parenting & Special Educ Res Grp, Leuven, Belgium. [Van Eylen, Lien; Boets, Bart; Steyaert, Jean; Evers, Kris] UPC KU Leuven, Dept Child Psychiat, Leuven, Belgium. [Van Eylen, Lien; Evers, Kris; Wagemans, Johan] Katholieke Univ Leuven, Expt Psychol Lab, Leuven, Belgium. [Van Eylen, Lien; Boets, Bart; Steyaert, Jean; Evers, Kris; Wagemans, Johan; Noens, Ilse] Katholieke Univ Leuven, Leuven Autism Res LAuRes, Leuven, Belgium. [Noens, Ilse] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Steyaert, Jean] Univ Hosp Maastricht, Dept Clin Genet, Maastricht, Netherlands. RP Van Eylen, L (reprint author), Katholieke Univ Leuven KU Leuven, Parenting & Special Educ Res Grp, Leuven, Belgium.; Van Eylen, L (reprint author), UPC KU Leuven, Dept Child Psychiat, Leuven, Belgium.; Van Eylen, L (reprint author), Katholieke Univ Leuven, Expt Psychol Lab, Leuven, Belgium.; Van Eylen, L (reprint author), Katholieke Univ Leuven, Leuven Autism Res LAuRes, Leuven, Belgium. EM Lien.VanEylen@ped.kuleuven.be NR 1 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 EI 1878-0237 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD MAR PY 2016 VL 23 BP 245 EP 245 DI 10.1016/j.rasd.2016.01.008 PG 1 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA DE0GP UT WOS:000370303400022 ER PT J AU Cochran, G Gordon, AJ Field, C Bacci, J Dhital, R Ylioja, T Stitzer, M Kelly, T Tarter, R AF Cochran, Gerald Gordon, Adam J. Field, Craig Bacci, Jennifer Dhital, Ranjita Ylioja, Thomas Stitzer, Maxine Kelly, Thomas Tarter, Ralph TI Developing a framework of care for opioid medication misuse in community pharmacy SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Opioid misuse; Adherence; Medication management; Qualitative research ID RANDOMIZED CONTROLLED-TRIAL; BRIEF ALCOHOL INTERVENTIONS; GENERAL-PRACTICE; NONMEDICAL USE; DRUG-USE; THERAPY MANAGEMENT; CLINICAL-TRIAL; SETTINGS; HEALTH; PAIN AB Background: Prescription opioid misuse is a major public health concern in the US. Few resources exist to support community pharmacists engaging patients who misuse or are at risk for misuse. Objectives: This report describes the results of the execution of the ADAPT-ITT model (a model for modifying evidence-based behavioral interventions to new populations and service settings) to guide the development of a behavioral health framework for opioid medication misuse in the community pharmacy setting. Methods: Pharmacy, addiction, intervention, and treatment experts were convened to attend a one-day meeting to review the empirical knowledgebase and discuss adapting the screening, brief intervention, and referral to treatment (SBIRT) protocol for addressing opioid medication misuse in community pharmacy. Qualitative data gathered from the meeting were analyzed by 2 independent coders in a 2-cycle process using objective coding schemes. Percentage of agreement and Cohen's Kappa were calculated to assess coder agreement. Results: First-cycle coding identified 4 distinct themes, with coder percentage of agreement ranging from 93.5 to 99.6% and with Kappa values between 0.81 and 0.93. Second-cycle coding identified 10 sub-themes, with coder percentage of agreement ranging from 83 to 99.8% and with Kappa values between 0.58 and 0.93. Identified themes and sub-themes encompassed patient identification, intervention, prevention, and referral to treatment. Conclusions: Focus of screening efforts in the emerging model should capitalize on pharmacists' knowledge of medication management. Screening likewise should be multidimensional in order to facilitate patient-centered interventions that activate additional disciplines able to interface with patients at risk or involved in medication misuse. (C) 2016 Elsevier Inc. All rights reserved. C1 [Cochran, Gerald; Ylioja, Thomas] Univ Pittsburgh, Sch Social Work, 4200 Fifth Ave, Pittsburgh, PA 15260 USA. [Cochran, Gerald; Kelly, Thomas] Univ Pittsburgh, Dept Psychiat, 3811 Ohara St, Pittsburgh, PA 15213 USA. [Gordon, Adam J.] Univ Pittsburgh, Dept Med, Sch Med, M240 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Univ Dr C 151-C, Pittsburgh, PA 15240 USA. [Field, Craig] Univ Texas El Paso, Dept Psychol, El Paso, TX 79968 USA. [Bacci, Jennifer] Univ Pittsburgh, Sch Pharm, 501 Terrace St, Pittsburgh, PA 15213 USA. [Dhital, Ranjita] Kings Coll London, Florence Nightingale Fac Nursing & Midwifery, James Clerk Maxwell Bldg,57 Waterloo Rd, London SE1 8WA, England. [Stitzer, Maxine] Johns Hopkins Med, Behav Pharmacol Res Unit, 5510 Nathan Shock Dr, Baltimore, MD 21224 USA. RP Cochran, G (reprint author), Univ Pittsburgh, Sch Social Work, 4200 Fifth Ave, Pittsburgh, PA 15260 USA. EM gcochran@pitt.edu FU Staunton Farm Foundation FX This project was supported by a grant from the Staunton Farm Foundation, which had no involvement in the conceptualization, execution, or submission of this work. NR 49 TC 3 Z9 3 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD MAR-APR PY 2016 VL 12 IS 2 BP 293 EP 301 DI 10.1016/j.sapharm.2015.05.001 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DE1NB UT WOS:000370392600007 PM 26048710 ER PT J AU Piskulic, D Liu, L Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Bearden, CE Mathalon, DH Addington, J AF Piskulic, Danijela Liu, Lu Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Bearden, Carrie E. Mathalon, Daniel H. Addington, Jean TI Social cognition over time in individuals at clinical high risk for psychosis: Findings from the NAPLS-2 cohort SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Social cognition; Theory of mind; Social perception; Emotion perception; Clinical high risk; Psychosis ID ULTRA-HIGH RISK; EMOTION RECOGNITION; SCHIZOPHRENIA; PERCEPTION; MIND; METAANALYSIS; JUDGMENTS; SYMPTOMS; DEFICITS AB Deficits in social cognition arewell established in schizophrenia and have been observed prior to the illness onset. Compared to healthy controls (HCs), individuals at clinical high risk of psychosis (CHR) are said to show deficits in social cognition similar to those observed in patients experiencing a first episode of psychosis. These deficits have been observed in several domains of social cognition, such as theory of mind (ToM), emotion perception and social perception. In the current study, the stability of three domains of social cognition (ToM, social perception and facial emotion perception) was assessed over time along and their association with both clinical symptoms and the later development of psychosis. Six hundred and seventy-five CHR individuals and 264 HC participants completed four tests of social cognition at baseline. Of those, 160 CHR and 155 HC participants completed assessments at all three time points (baseline, 1 year and 2 years) as part of their participation in the North American Prodrome Longitudinal Study. The CHR group performed poorer on all tests of social cognition across all time points compared to HCs. Social cognition was not associated with attenuated positive symptoms at any time point in the study. CHR individuals who developed a psychotic disorder during the course of the study did not differ in social cognition compared to those who did not develop psychosis. This longitudinal study demonstrated mild to moderate, but persistent ToM and social perception impairments in those at CHR for psychosis compared to HCs. (C) 2016 Elsevier B.V. All rights reserved. C1 [Piskulic, Danijela; Liu, Lu; Addington, Jean] Univ Calgary, Dept Psychiat, Hotchkiss Brain Inst, Calgary, AB T2N 4Z6, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Queens, NY USA. [McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsuang, Ming T.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, Daniel H.] Psychiat Serv, San Francisco, CA USA. RP Addington, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health [U01 MH081984, U01 MH081928, P50 MH080272]; National Institute of Mental Health (Commonwealth of Massachusetts) [SCDMH82101008006, R01 MH60720, U01 MH082022, K24 MH76191, U01 MH081902, P50 MH066286, U01 MH082004, U01 MH081988, U01 MH081857-05] FX This study was supported by the National Institute of Mental Health (grant U01 MH081984 to Dr. Addington; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to Dr. Seidman; grants R01 MH60720, U01 MH082022 and K24 MH76191 to Dr. Cadenhead; grant U01 MH081902 to Dr. Cannon; P50 MH066286 (Prodromal Core) to Dr. Bearden; grant U01 MH082004 to Dr. Perkins; grant U01 MH081988 to Dr. Walker; grant U01 MH082022 to Dr. Woods; and U01 MH081857-05 grant to Dr. Cornblatt. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 29 TC 2 Z9 2 U1 2 U2 7 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 MAR PY 2016 VL 171 IS 1-3 BP 176 EP 181 DI 10.1016/j.schres.2016.01.017 PG 6 WC Psychiatry SC Psychiatry GA DE1GS UT WOS:000370375700025 PM 26785807 ER PT J AU Huang, AJ Balza, R Torriani, M Bredella, MA Chang, CY Simeone, FJ Palmer, WE AF Huang, Ambrose J. Balza, Rene Torriani, Martin Bredella, Miriam A. Chang, Connie Y. Simeone, Frank J. Palmer, William E. TI Radiation dose and intra-articular access: comparison of the lateral mortise and anterior midline approaches to fluoroscopically guided tibiotalar joint injections SO SKELETAL RADIOLOGY LA English DT Article DE Ankle; Tibiotalar joint; Injection; Fluoroscopy; Radiation dose ID ANKLE; FOOT; ARTHROGRAPHY; PAIN; LOCALIZATION; DIAGNOSIS AB Purpose To compare the lateral mortise and anterior midline approaches to fluoroscopically guided tibiotalar joint injections with respect to successful intra-articular needle placement, fluoroscopy time, radiation dose, and dose area product (DAP). Materials and methods This retrospective study was IRB-approved and HIPAA-compliant. 498 fluoroscopically guided tibiotalar joint injections were performed or supervised by one of nine staff radiologists from 11/1/2010-12/31/2013. The injection approach was determined by operator preference. Images were reviewed on a PACS workstation to determine the injection approach (lateral mortise versus anterior midline) and to confirm intra-articular needle placement. Fluoroscopy time (minutes), radiation dose (mGy), and DAP (mu Gy-m(2)) were recorded and compared using the student's t-test (fluoroscopy time) or the Wilcoxon rank sum test (radiation dose and DAP). Results There were 246 lateral mortise injections and 252 anterior midline injections. Two lateral mortise injections were excluded from further analysis because no contrast was administered. Intra-articular location of the needle tip was documented in 242/244 lateral mortise injections and 252/ 252 anterior midline injections. Mean fluoroscopy time was shorter for the lateral mortise group than the anterior midline group (0.7 +/- 0.5 min versus 1.2 +/- 0.8 min, P< 0.0001). Mean radiation dose and DAP were less for the lateral mortise group than the anterior midline group (2.1 +/- 3.7 mGy versus 2.5 +/- 3.5 mGy, P= 0.04; 11.5 +/- 15.3 mu Gy-m(2) versus 13.5 +/- 17.3 mu Gy-m(2), P= 0.006). Conclusion Both injection approaches resulted in nearly 100 % rates of intra-articular needle placement, but the lateral mortise approach used approximately 40 % less fluoroscopy time and delivered 15 % lower radiation dose and DAP to the patient. C1 [Huang, Ambrose J.; Torriani, Martin; Bredella, Miriam A.; Chang, Connie Y.; Simeone, Frank J.; Palmer, William E.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Balza, Rene] Ctr Med Occidente, Dept Radiol, Maracaibo, Venezuela. 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; renebalza@gmail.com; mtorriani@mgh.harvard.edu; mbredella@mgh.harvard.edu; cychang@mgh.harvard.edu; fsimeone@mgh.harvard.edu; wpalmer@mgh.harvard.edu NR 17 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2016 VL 45 IS 3 BP 367 EP 373 DI 10.1007/s00256-015-2300-8 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DE0ZB UT WOS:000370353300008 PM 26613732 ER PT J AU Driscoll, SJ Zhong, WY Torriani, M Mao, HQ Wood, KB Cha, TD Li, GA AF Driscoll, Sean J. Zhong, Weiye Torriani, Martin Mao, Haiqing Wood, Kirkham B. Cha, Thomas D. Li, Guoan TI In-vivo T2-relaxation times of asymptomatic cervical intervertebral discs SO SKELETAL RADIOLOGY LA English DT Article DE T2 mapping; Cervical spine; Intervertebral disc; Magnetic resonance imaging; In vivo ID T2 RELAXATION-TIMES; AGE-RELATED-CHANGES; LOW-BACK-PAIN; DISCOGENIC PAIN; GRADING SYSTEM; LUMBAR DISC; MRI CHANGES; DEGENERATION; SPINE; POPULATION AB Limited research exists on T2-mapping techniques for cervical intervertebral discs and its potential clinical utility. The objective of this research was to investigate the in-vivo T2r-elaxation times of cervical discs, including C2-C3 through C7-T1. Ten asymptomatic subjects were imaged using a 3.0 T MR scanner and a sagittalmulti-slicemulti-echo sequence. Using the mid-sagittal image, intervertebral discs were divided into five regions-of-interest (ROIs), centered along the mid-line of the disc. Average T2 relaxation time values were calculated for each ROI using a mono-exponential fit. Differences in T2 values between disc levels and across ROIs of the same disc were examined. For a given ROI, the results showed a trend of increasing relaxation times moving down the spinal column, particularly in the middle regions (ROIs 2, 3 and 4). The C6-C7 and C7-T1 discs had significantly greater T2 values compared to superior discs (discs between C2 and C6). The results also showed spatial homogeneity of T2 values in the C3-C4, C4-C5, and C5-C6 discs, while C2-C3, C6-C7, and C7-T1 showed significant differences between ROIs. The findings indicate there may be inherent differences in T2-relaxation time properties between different cervical discs. Clinical evaluations utilizing T2-mapping techniques in the cervical spine may need to be level-dependent. C1 [Driscoll, Sean J.; Zhong, Weiye; Mao, Haiqing; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. [Zhong, Weiye] Second Xiangya Hosp, Dept Spinal Surg, 139 Middle Renmin Rd, Changsha, Hunan, Peoples R China. [Zhong, Weiye] Cent S Univ, 139 Middle Renmin Rd, Changsha, Hunan, Peoples R China. [Torriani, Martin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW 6E, Boston, MA 02114 USA. [Wood, Kirkham B.; Cha, Thomas D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Spine Serv,Dept Orthopaed Surg, 55 Fruit St,YAW3A, Boston, MA 02114 USA. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@mgh.harvard.edu FU National Institutes of Health [R21AR057989]; K2M Group Holdings, Inc.; Department of Orthopaedic Surgery at Massachusetts General Hospital/Harvard Medical School FX The authors would like to gratefully acknowledge financial support from the National Institutes of Health (R21AR057989), K2M Group Holdings, Inc., and the Department of Orthopaedic Surgery at Massachusetts General Hospital/Harvard Medical School. NR 48 TC 1 Z9 1 U1 12 U2 14 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 MAR PY 2016 VL 45 IS 3 BP 393 EP 400 DI 10.1007/s00256-015-2307-1 PG 8 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DE0ZB UT WOS:000370353300011 PM 26643385 ER PT J AU Wallace, AN Huang, AJ Vaswani, D Chang, RO Jennings, JW AF Wallace, Adam N. Huang, Ambrose J. Vaswani, Devin Chang, Randy O. Jennings, Jack W. TI Combination acetabular radiofrequency ablation and cementoplasty using a navigational radiofrequency ablation device and ultrahigh viscosity cement: technical note SO SKELETAL RADIOLOGY LA English DT Article DE Metastatic bone disease; Acetabulum; Radiofrequency ablation; Cementoplasty ID BONE METASTASES; MANAGEMENT; PAIN AB Background Percutaneous radiofrequency ablation and cementoplasty is an alternative palliative therapy for painful metastases involving axial load-bearing bones. This technical report describes the use of a navigational radiofrequency probe to ablate acetabular metastases from an anterior approach followed by instillation of ultrahigh viscosity cement under CT-fluoroscopic guidance. Materials and methods The tumor ablation databases of two institutions were retrospectively reviewed to identify patients who underwent combination acetabular radiofrequency ablation and cementoplasty using the STAR Tumor Ablation and StabiliT Vertebral Augmentation Systems (DFINE; San Jose, CA). Pre-procedure acetabular tumor volume was measured on cross-sectional imaging. Pre-and post-procedure pain scores were measured using the Numeric Rating Scale (10point scale) and compared. Partial pain improvement was categorically defined as >= 2-point pain score reduction. Patients were evaluated for evidence of immediate complications. Electronic medical records were reviewed for evidence of delayed complications. Results During the study period, 12 patients with acetabular metastases were treated. The median tumor volume was 54.3 mL (range, 28.3-109.8 mL). Pre-and post-procedure pain scores were obtained from 92 % (11/12) of the cohort. The median pre-procedure pain score was 8 (range, 3-10). Post-procedure pain scores were obtained 7 days (82 %; 9/11), 11 days (9.1 %; 1/11) or 21 days (9.1 %; 1/11) after treatment. The median post-treatment pain score was 3 (range, 1-8), a statistically significant difference compared with pretreatment (P= 0.002). Categorically, 73 % (8/11) of patients reported partial pain relief after treatment. No immediate symptomatic complications occurred. Three patients (25 %; 3/12) were discharged to hospice within 1 week of treatment. No delayed complications occurred in the remaining 75 % (9/12) of patients during median clinical follow-up of 62 days (range, 14-178 days). Conclusions Palliative percutaneous acetabular radiofrequency ablation and cementoplasty can be feasibly performed from an anterior approach using a navigational ablation probe and ultrahigh viscosity cement instilled under CT-fluoroscopic guidance. C1 [Wallace, Adam N.; Vaswani, Devin; Jennings, Jack W.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 South Kingshighway Blvd, St Louis, MO 63110 USA. [Huang, Ambrose J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Chang, Randy O.] Washington Univ, Sch Med, 660 South Euclid Ave, St Louis, MO 63110 USA. RP Wallace, AN (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 South Kingshighway Blvd, St Louis, MO 63110 USA. EM wallacea@mir.wustl.edu NR 14 TC 3 Z9 3 U1 0 U2 2 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 MAR PY 2016 VL 45 IS 3 BP 401 EP 405 DI 10.1007/s00256-015-2263-9 PG 5 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DE0ZB UT WOS:000370353300012 PM 26408315 ER PT J AU Chang, CY Kreher, J Torriani, M AF Chang, Connie Y. Kreher, Jeffrey Torriani, Martin TI Dynamic sonography of snapping hip due to gluteus maximus subluxation over greater trochanter SO SKELETAL RADIOLOGY LA English DT Article DE External snapping hip; Gluteus maximus; Greater trochanter; Iliotibial band ID SURGICAL TECHNIQUE; ATHLETE; RELEASE; TENDON AB We report on the dynamic sonographic findings of a 10-year-old avid female dancer who presented with symptoms of abrupt left hip motion and associated painful snapping sensation while performing lateral motions of the pelvis suggesting external snapping hip syndrome. Dynamic sonographic evaluation of both hips demonstrated that symptoms were due to gluteus maximus subluxation over the greater trochanter. This etiology of external snapping hip syndrome is rare with limited imaging descriptions in the literature. We present case history, physical examination, and dynamic ultrasound examination, including multiple still images and cine clips, comprehensively characterizing this uncommon source of external snapping hip syndrome. C1 [Chang, Connie Y.; Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. [Chang, Connie Y.; Torriani, Martin] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kreher, Jeffrey] Massachusetts Gen Hosp, Dept Orthopaed, Div Pediat Orthopaed, Boston, MA 02114 USA. RP Chang, CY (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA.; Chang, CY (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM cychang@mgh.harvard.edu NR 14 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2016 VL 45 IS 3 BP 409 EP 412 DI 10.1007/s00256-015-2265-7 PG 4 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DE0ZB UT WOS:000370353300014 PM 26490678 ER PT J AU Youn, B Soley-Bori, M Soria-Saucedo, R Ryan, CM Schneider, JC Haynes, AB Cabral, HJ Kazis, LE AF Youn, Bora Soley-Bori, Marina Soria-Saucedo, Rene Ryan, Colleen M. Schneider, Jeffrey C. Haynes, Alex B. Cabral, Howard J. Kazis, Lewis E. TI Patient cost-sharing and insurance arrangements are associated with hospital readmissions after abdominal surgery: Implications for access and quality health care SO SURGERY LA English DT Article ID 30-DAY READMISSION; RATES; REHOSPITALIZATIONS; PREDICTORS; OUTCOMES; PROGRAM; ADULTS; TRIAL; PLANS AB Background. Readmission rates after operative procedures are used increasingly as a measure of hospital care quality. Patient access to care may influence readmission rates. The objective of this study was to determine the relationship between patient cost-sharing, insurance arrangements, and the risk of postoperative readmissions. Methods. Using the MarketScan Research Database (n = 121,002), we examined privately insured, nonelderly patients who underwent abdominal surgery in 2010. The main outcome measures were risk adjusted unplanned readmissions within 7 days and 30 days of discharge. Odds of readmissions were compared with multivariable logistic regression models. Results. In adjusted models, $1,284 increase in patient out-of-pocket payments during index admission (a difference of one standard deviation) was associated with 19% decrease in the odds of 7-day readmission (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.78-0.85) and 17% decrease in the odds of 30 day readmission (OR 0.83, 95% CI 0.81-0.86). Patients in the noncapitated point-of-service plans (OR 1.1 9, 95% CI 1.07-1.33), preferred provider organization plans (OR 1.11, 95 % CI 1.03-1.19), and high-deductible plans (OR 1.12, 95 % CI 1.00-1.26) were more likely to be readmitted within 30 days compared with patients in the capitated health maintenance organization and point-of-service plans. Conclusion. Among privately insured, nonelderly patients, increased patient cost-sharing was associated with lower odds of 7-day and 30-day readmission after abdominal surgery. Insurance arrangements also were significantly associated with postoperative readmissions. Patient cost sharing and insurance arrangements need consideration in the provision of equitable access for quality care. C1 [Youn, Bora; Cabral, Howard J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Soley-Bori, Marina; Soria-Saucedo, Rene; Kazis, Lewis E.] Boston Univ, Sch Publ Hlth, CAPP, Dept Hlth Policy & Management, Boston, MA USA. [Ryan, Colleen M.; Haynes, Alex B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Ryan, Colleen M.; Schneider, Jeffrey C.; Haynes, Alex B.] Harvard Univ, Sch Med, Boston, MA USA. [Ryan, Colleen M.] Shriners Hosp Children, Boston, MA USA. [Schneider, Jeffrey C.] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Haynes, Alex B.] Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, Boston, MA 02114 USA. [Haynes, Alex B.] Harvard Univ, Sch Publ Hlth, Ariadne Labs, 665 Huntington Ave, Boston, MA 02115 USA. [Haynes, Alex B.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM lek@bu.edu NR 43 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAR PY 2016 VL 159 IS 3 BP 919 EP 929 DI 10.1016/j.surg.2015.09.007 PG 11 WC Surgery SC Surgery GA DE0KG UT WOS:000370313200027 PM 26477477 ER PT J AU Falchook, AD Martin, NE Basak, R Smith, AB Milowsky, MI Chen, RC AF Falchook, Aaron D. Martin, Neil E. Basak, Ramsankar Smith, Angela B. Milowsky, Matthew I. Chen, Ronald C. TI Stage at presentation and survival outcomes of patients with Gleason 8-10 prostate cancer and low prostate-specific antigen SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE High-risk prostate cancer; PSA; Survival; NCDB ID RADICAL PROSTATECTOMY; PREOPERATIVE PSA; LEVEL; PROGRESSION; CARCINOMA; MEN AB Objective: To evaluate outcomes for men with high Gleason score and low prostate-specific antigen (PSA) prostate cancer. Low PSA levels among men with Gleason 8-10 prostate cancer may be owing to cellular dedifferentiation rather than low disease burden. We hypothesized that men with Gleason 8-10 prostate cancer and low PSA levels have increased risk for advanced disease and worse survival. Materials and methods: Men diagnosed from 2004 to 2007 with Gleason 8-10 prostate adenocarcinoma in the National Cancer Data Base were included. Patients were stratified by PSA levels at diagnosis: 0.1 to 3.9, 4.0 to 9.9, 10.0 to 19.9, and >20.0 ng/ml. Outcomes were clinical TNM category, pathologic stage (for prostatectomy patients), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards models were used. Results: A total of 37,283 patients were included. Men with PSA levels of <4.0 ng/ml were more likely than those with PSA levels of 4 to 9.9 ng/ml to present with clinical T3-4 disease (15% vs. 10%, P < 0.001), nodal (4% vs. 2%, P < 0.001) and distant (5% vs. 3%, P < 0.001) metastasis. However, among patients treated with prostatectomy, lower PSA levels were not associated with increased likelihood of pathologic T3-4 disease or nodal metastasis. Six-year OS was 89.1% (PSA: 0.1-3.9 ng/ml) vs. 91.0% (PSA: 4.0-9.9 ng/ml) for prostatectomy (log-rank P < 0.001), and 75.8% vs. 81.0% for radiotherapy (P < 0.001). Multivariable analyses showed OS of patients with PSA levels of 0.1 to 3.9 ng/ml to be similar to those with PSA levels of 10 to 19.9 ng/ml. Conclusions: Patients with Gleason 8-10 cancer and PSA levels of <4.0 ng/ml have more aggressive disease than those with PSA levels of 4 to 9.9 ng/ml; these low PSA cancers behave more like those with PSA levels of 10 to 19.9 ng/ml. Further study is needed to evaluate potential biological differences in these patients with low PSA-producing cancers. (C) 2016 Elsevier Inc. All rights reserved. C1 [Falchook, Aaron D.; Basak, Ramsankar; Chen, Ronald C.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. [Martin, Neil E.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Martin, Neil E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Smith, Angela B.] Univ N Carolina, Dept Urol, Chapel Hill, NC USA. [Smith, Angela B.; Milowsky, Matthew I.; Chen, Ronald C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Milowsky, Matthew I.] Univ N Carolina, Dept Med, Div Hematol Oncol, Chapel Hill, NC USA. [Chen, Ronald C.] Univ N Carolina, Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. RP Chen, RC (reprint author), Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA.; Chen, RC (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Chen, RC (reprint author), Univ N Carolina, Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. EM Ronald_chen@med.unc.edu NR 9 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 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD MAR PY 2016 VL 34 IS 3 AR 119.e19 DI 10.1016/j.urolonc.2015.09.014 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DD9RA UT WOS:000370262100004 PM 26526383 ER PT J AU Fink, M Fricchione, G Rummans, T Shorter, E AF Fink, M. Fricchione, G. Rummans, T. Shorter, E. TI Catatonia is a systemic medical syndrome SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Letter C1 [Fink, M.] SUNY Stony Brook, Dept Psychiat, Sch Med, St James, NY USA. [Fink, M.] SUNY Stony Brook, Dept Neurol, Sch Med, St James, NY USA. [Fricchione, G.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rummans, T.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [Shorter, E.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Shorter, E.] Univ Toronto, Hist Med Program, Toronto, ON, Canada. RP Fink, M (reprint author), SUNY Stony Brook, Dept Psychiat, Sch Med, St James, NY USA.; Fink, M (reprint author), SUNY Stony Brook, Dept Neurol, Sch Med, St James, NY USA. EM max.fink@stonybrookmedicine.edu NR 1 TC 1 Z9 1 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD MAR PY 2016 VL 133 IS 3 BP 250 EP 251 DI 10.1111/acps.12510 PG 2 WC Psychiatry SC Psychiatry GA DD7BF UT WOS:000370078000011 PM 26426740 ER PT J AU Walker, M El-Serag, HB Sada, Y Mittal, S Ying, J Duan, Z Richardson, P Davila, JA Kanwal, F AF Walker, M. El-Serag, H. B. Sada, Y. Mittal, S. Ying, J. Duan, Z. Richardson, P. Davila, J. A. Kanwal, F. TI Cirrhosis is under-recognised in patients subsequently diagnosed with hepatocellular cancer SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FATTY LIVER-DISEASE; PRIMARY-CARE PROVIDERS; UNITED-STATES; HEPATITIS-C; CARCINOMA; FIBROSIS; SURVEILLANCE; PROGNOSIS; POPULATION; ARTICLE AB BackgroundMost clinical practice guidelines recommend screening for HCC in patients with cirrhosis. However, patients with compensated cirrhosis are often asymptomatic and may remain unrecognised for years. AimsTo determine the extent to which cirrhosis is unrecognised in a US Veteran population with HCC, and to evaluate the association between lack of cirrhosis recognition and stage of HCC at diagnosis. MethodsWe reviewed the electronic medical records of a random sample of HCC cases diagnosed in the national Veterans Affairs system between 2005 and 2011. We conducted multivariable analyses adjusting for patients' demographics, comorbidity, aetiology of underlying disease and healthcare utilisation including HCC surveillance. ResultsOf 1201 patients with HCC and cirrhosis, 24.6% had unrecognised cirrhosis prior to HCC diagnosis. Older patients [>65 years, odds ratio (OR) 2.32], African Americans (OR 1.93), patients with alcoholic or NAFLD liver disease (OR 1.69 and 4.77 respectively), HIV (OR 3.02), and fewer comorbidities (Deyo 0 vs. 3, OR 2.42) had significantly higher odds of having unrecognised cirrhosis than comparison groups. Furthermore, patients with unrecognised cirrhosis were 6.5 times more likely to have advanced stage HCC at diagnosis. The effect of cirrhosis recognition on HCC stage remained significant after adjusting for pre-specified covariates (OR 3.37). ConclusionsIn one quarter of patients, cirrhosis was unrecognised prior to HCC diagnosis, and this group was significantly more likely to have advanced stage HCC. These findings emphasise the importance of timely evaluation for cirrhosis in at-risk populations as a critical step to improving outcomes for patients with HCC. C1 [Walker, M.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Houston, TX 77030 USA. [El-Serag, H. B.; Sada, Y.; Mittal, S.; Ying, J.; Duan, Z.; Richardson, P.; Davila, J. A.; Kanwal, F.] Michael E DeBakey VA Med Ctr, Ctr Innovat Qual Effect & Safety IQuESt, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. [El-Serag, H. B.; Mittal, S.; Kanwal, F.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. [El-Serag, H. B.; Mittal, S.; Kanwal, F.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Hepatol, Houston, TX 77030 USA. [Sada, Y.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Hematol & Oncol, Houston, TX 77030 USA. [Richardson, P.; Davila, J. A.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Davila, JA; Kanwal, F (reprint author), Michael E DeBakey VA Med Ctr, Ctr Innovat Qual Effect & Safety IQuESt, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM jdavila@bcm.edu; fasiha.kanwal@va.gov FU National Cancer Institute [R01 CA160738]; Center for Innovations in Quality, Effectiveness and Safety [CIN 13-413] FX This material is based upon work supported by the National Cancer Institute (R01 CA160738, PI: Davila), and in part by the Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413). NR 31 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR PY 2016 VL 43 IS 5 BP 621 EP 630 DI 10.1111/apt.13505 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA DD5QU UT WOS:000369980000007 PM 26784271 ER PT J AU Bergman, J Ballon-Landa, E Lorenz, KA Saucedo, J Saigal, CS Bennett, CJ Litwin, MS AF Bergman, Jonathan Ballon-Landa, Eric Lorenz, Karl A. Saucedo, Josemanuel Saigal, Christopher S. Bennett, Carol J. Litwin, Mark S. TI Community-Partnered Collaboration to Build an Integrated Palliative Care Clinic: The View From Urology SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE adult; attitude of health personnel; delivery of health care; integrated; interviews as topic; palliative care; patient care team; patient preference; physician's role; physicians; psychology; quality improvement; quality of health care; terminal care; urology ID END-OF-LIFE; ADVANCED CANCER; SUPPORTIVE CARE; QUALITY; HEALTH; INTERVENTION; PROVIDERS; ATTITUDES; OUTCOMES; PROJECT AB Background: We partnered with patients, families, and palliative care clinicians to develop an integrated urology-palliative care clinic for patients with metastatic cancer. We assessed clinician satisfaction with a multidisciplinary palliative care clinic model. Methods: We conducted semi-structured interviews with 18 clinicians who practice in our integrated clinic. We analyzed transcripts using a multistage, cutting-and-sorting technique in an inductive approach based on grounded theory analysis. Finally, we administered a validated physician job satisfaction survey. Results: Clinicians found that referring a patient to palliative care in the urology clinic was feasible and appropriate. Patients were receptive to supportive care, and clinicians perceived that quality of care improved following the intervention. Conclusion: An integrated, patient-centered model for individuals with advanced urologic malignancies is feasible and well received by practitioners. C1 [Bergman, Jonathan; Saucedo, Josemanuel; Saigal, Christopher S.; Bennett, Carol J.; Litwin, Mark S.] Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, 924 Westwood Blvd,Suite 1000, Los Angeles, CA 90024 USA. [Bergman, Jonathan] Univ Calif Los Angeles, David Geffen Sch Med, Dept Family Med, Los Angeles, CA 90024 USA. [Bergman, Jonathan; Lorenz, Karl A.; Saigal, Christopher S.; Bennett, Carol J.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Ballon-Landa, Eric] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA 90024 USA. [Ballon-Landa, Eric] UC Irvine Sch Med, Irvine, CA USA. [Lorenz, Karl A.; Saigal, Christopher S.] RAND Corp, Santa Monica, CA USA. [Litwin, Mark S.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90024 USA. RP Bergman, J (reprint author), Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, 924 Westwood Blvd,Suite 1000, Los Angeles, CA 90024 USA. EM jbergman@mednet.ucla.edu RI Kausar, Nadia/D-7414-2016 NR 34 TC 1 Z9 1 U1 2 U2 7 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 MAR PY 2016 VL 33 IS 2 BP 164 EP 170 DI 10.1177/1049909114555156 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DD8TW UT WOS:000370200800009 PM 25326489 ER PT J AU Reinke, LF Feemster, LC Backhus, LM Gylys-Colwell, I Au, DH AF Reinke, Lynn F. Feemster, Laura C. Backhus, Leah M. Gylys-Colwell, Ina Au, David H. TI Assessment and Management of Symptoms for Outpatients Newly Diagnosed With Lung Cancer SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE lung cancer; newly diagnosed; symptom assessment; management ID OBSTRUCTIVE PULMONARY-DISEASE; EARLY PALLIATIVE CARE; ADULTS RECEIVING TREATMENT; HOME NURSING-CARE; OF-LIFE CARE; PROGNOSTIC INFORMATION; DISTRESS; COMMUNICATION; INTERVENTION; PREFERENCES AB Rationale: Little is known about symptom assessment around the time of lung cancer diagnosis. The purpose of this pilot study was to assess symptoms within 2 months of diagnosis and the frequency with which clinicians addressed symptoms among a cohort of veterans (n = 20) newly diagnosed with lung cancer. We administered questionnaires and then reviewed medical records to identify symptom assessment and management provided by subspecialty clinics for 6 months following diagnosis. Results: Half (50%) of the patients were diagnosed with early-stage non-small-cell lung cancer (NSCLC), stage I or II. At baseline, 45% patients rated their overall symptoms as severe. There were no significant differences in symptoms among patients with early- or late-stage NSCLC or small-cell lung cancer. Of the 212 clinic visits over 6 months, 70.2% occurred in oncology. Clinicians most frequently addressed pain although assessment differed by clinic. Conclusions: Veterans with newly diagnosed lung cancer report significant symptom burden. Despite ample opportunities to address patients' symptoms, variations in assessment exist among subspecialty services. Coordinated approaches to symptom assessment are likely needed among patients newly diagnosed with lung cancer. C1 [Reinke, Lynn F.; Feemster, Laura C.; Backhus, Leah M.; Gylys-Colwell, Ina; Au, David H.] Puget Sound Hlth Care Syst, Dept Vet Affairs, Hlth Serv R&D, Seattle, WA USA. [Reinke, Lynn F.] Univ Washington, Sch Nursing, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Feemster, Laura C.; Au, David H.] Univ Washington, Sch Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Backhus, Leah M.] Univ Washington, Sch Surg, Div Cardiothorac Surg, Seattle, WA 98195 USA. RP Reinke, LF (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv R&D, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM reinkl@uw.edu RI Kausar, Nadia/D-7414-2016 FU Office of Nursing Services from United States (US) Department of Veterans Affairs [NRI-01-001] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported a pilot project award from the Office of Nursing Services, #NRI-01-001 from the United States (US) Department of Veterans Affairs. NR 31 TC 2 Z9 2 U1 2 U2 6 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 MAR PY 2016 VL 33 IS 2 BP 178 EP 183 DI 10.1177/1049909114557635 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DD8TW UT WOS:000370200800011 PM 25376224 ER PT J AU Cavender, MA Scirica, BM Raz, I Steg, G McGuire, DK Leiter, LA Hirshberg, B Davidson, J Cahn, A Mosenzon, O Im, K Braunwald, E Bhatt, DL AF Cavender, Matthew A. Scirica, Benjamin M. Raz, Itamar Steg, Gabriel McGuire, Darren K. Leiter, Lawrence A. Hirshberg, Boaz Davidson, Jaime Cahn, Avivit Mosenzon, Ofri Im, KyungAh Braunwald, Eugene Bhatt, Deepak L. TI Cardiovascular Outcomes of Patients in SAVOR-TIMI 53 by Baseline Hemoglobin A1c SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Coronary artery disease; Diabetes mellitus; Glycated hemoglobin assay; Randomized clinical trials ID HEART-FAILURE; DIABETES-MELLITUS; SAXAGLIPTIN ASSESSMENT; MYOCARDIAL-INFARCTION; GLYCATED HEMOGLOBIN; GLYCEMIC CONTROL; GLUCOSE CONTROL; RISK; EVENTS; TRIAL AB BACKGROUND: The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we analyzed the SAVOR-TIMI 53 trial to compare the cardiovascular effects of saxagliptin vs placebo according to baseline HbA1c. METHODS: A total of 16,492 patients with type 2 diabetes (HbA1c 6.5%-12.0% in the 6 months before randomization) and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS: Patients were stratified by HbA1c at randomization into the following prespecified groups: <7%, 7%-<8%, 8%-<9%, and >= 9%. Baseline HbA1c >= 7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (adjusted hazard ratio [HRadj] 1.35; 95% confidence interval [CI], 1.17-1.58) but not hospitalization for heart failure (HRadj 1.09; 95% CI, 0.88-1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in patients with HbA1c <7% (HR 1.01; 95% CI, 0.78-1.31), 7%-<8% (HR 0.98; 95% CI, 0.80-1.20), 8%-<9% (HR 1.09; 95% CI, 0.85-1.39), >= 9% (HR 0.95; 95% CI, 0.77-1.18) (P-interaction = .89). CONCLUSIONS: Baseline HbA1c is associated with increased risk of macrovascular events but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values. (C) 2016 Elsevier Inc. All rights reserved. C1 [Cavender, Matthew A.; Scirica, Benjamin M.; Im, KyungAh; Braunwald, Eugene; Bhatt, Deepak L.] Brigham & Womens Hosp, Thrombolysis Myocardial Infarct TIMI Study Grp, Heart & Vasc Ctr, Boston, MA 02115 USA. [Cavender, Matthew A.; Scirica, Benjamin M.; Im, KyungAh; Braunwald, Eugene; Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Raz, Itamar; Cahn, Avivit; Mosenzon, Ofri] Hadassah Hebrew Univ Hosp, Diabet Unit, Dept Internal Med, Jerusalem, Israel. [Steg, Gabriel] Univ Paris Diderot, Hop Bichat, AP HP,HUPNVS, FACT,DHU FIRE,Sorbonne Paris Cite,LVTS,INSERM,U11, Paris, France. [Steg, Gabriel] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, NHLI, London, England. [McGuire, Darren K.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX 75390 USA. [Leiter, Lawrence A.] Univ Toronto, Div Endocrinol & Metab, Keenan Res Ctr, Li Ka Shing Knowledge Inst,St Michaels Hosp, Toronto, ON M5S 1A1, Canada. [Hirshberg, Boaz] AstraZeneca Res & Dev, Gaithersburg, MD USA. [Davidson, Jaime] Univ Texas SW Med Ctr Dallas, Touchstone Diabet Ctr, Dept Internal Med, Dallas, TX 75390 USA. Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Med Sch,Heart & Vasc Ctr, Boston, MA 02115 USA. RP Bhatt, DL (reprint author), Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Med Sch,Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA. EM dlbhattmd@post.harvard.edu FU AstraZeneca; Bristol-Myers Squibb FX SAVOR-TIMI 53 was funded by AstraZeneca and Bristol-Myers Squibb. NR 23 TC 4 Z9 4 U1 0 U2 2 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 MAR PY 2016 VL 129 IS 3 AR 340.e1 DI 10.1016/j.amjmed.2015.09.022 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DD5FE UT WOS:000369947300032 PM 26524706 ER PT J AU Sharma, A Albergotti, WG Duvvuri, U AF Sharma, Arun Albergotti, W. Greer Duvvuri, Umamaheswar TI Applications of Evolving Robotic Technology for Head and Neck Surgery SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE head and neck; head and neck cancer; robotic surgery; transoral robotic surgery; thyroid ID SQUAMOUS-CELL CARCINOMA; CANCER AB Objective: Assess the use and potential benefits of a new robotic system for transoral radical tonsillectomy, transoral supraglottic laryngectomy, and retroauricular thyroidectomy in a cadaver dissection. Methods: Three previously described robotic procedures (transoral radical tonsillectomy, transoral supraglottic laryngectomy, and retroauricular thyroidectomy) were performed in a cadaver using the da Vinci Xi Surgical System. Surgical exposure and access, operative time, and number of collisions were examined objectively. Results: The new robotic system was used to perform transoral radical tonsillectomy with dissection and preservation of glossopharyngeal nerve branches, transoral supraglottic laryngectomy, and retroauricular thyroidectomy. There was excellent exposure without any difficulties in access. Robotic operative times (excluding set-up and docking times) for the 3 procedures in the cadaver were 12.7, 14.3, and 21.2 minutes (excluding retroauricular incision and subplatysmal elevation), respectively. No robotic arm collisions were noted during these 3 procedures. The retroauricular thyroidectomy was performed using 4 robotic ports, each with 8 mm instruments. Conclusions: The use of updated and evolving robotic technology improves the ease of previously described robotic head and neck procedures and may allow surgeons to perform increasingly complex surgeries. C1 [Sharma, Arun] So Illinois Univ, Div Otolaryngol Head & Neck Surg, Springfield, IL USA. [Albergotti, W. Greer; Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA 15213 USA. [Duvvuri, Umamaheswar] Vet Affairs Pittsburgh Hlth Syst, Dept Otolaryngol, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Head & Neck Robot Surg,Eye & Ear Inst, Pittsburgh, PA 15213 USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Head & Neck Robot Surg,Eye & Ear Inst, 200 Lothrop St,Suite 500, Pittsburgh, PA 15213 USA. EM duvvuriu@upmc.edu FU Department of Veterans Affairs, Biomedical and Laboratory Science Research and Development group FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part from funds from the Department of Veterans Affairs, Biomedical and Laboratory Science Research and Development group. This works does not reflect the views of the Department of Veterans Affairs or the US government. NR 15 TC 1 Z9 2 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD MAR PY 2016 VL 125 IS 3 BP 207 EP 212 DI 10.1177/0003489415606448 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA DD6YN UT WOS:000370070800004 PM 26391091 ER PT J AU Kong, WH Sung, DK Kim, H Yang, JA Ieronimakis, N Kim, KS Lee, J Kim, DH Yun, SH Hahn, SK AF Kong, Won Ho Sung, Dong Kyung Kim, Hyemin Yang, Jeong-A Ieronimakis, Nicholas Kim, Ki Su Lee, Jeehun Kim, Deok-Ho Yun, Seok Hyun Hahn, Sei Kwang TI Self-adjuvanted hyaluronate - antigenic peptide conjugate for transdermal treatment of muscular dystrophy SO BIOMATERIALS LA English DT Article DE Hyaluronate; Peptide; Conjugate; Transdermal; Vaccine ID SKELETAL-MUSCLE MASS; DENDRITIC CELLS; AUTOIMMUNE-DISEASES; MYOSTATIN; IMMUNOTHERAPY; INCREASES; MOUSE; MICE; MDX; INHIBITION AB Duchenne's muscular dystrophy (DMD) is a neuromuscular disorder accompanied with muscle weakness and wasting. Since myostatin was reported to be a key regulator of muscle wasting, myostatin inhibitors have been investigated as therapeutic candidates for the treatment of muscular diseases. Here, we report an antigenic peptide of myostatin fragment (MstnF) conjugated to hyaluronate (HA) with a low molecular weight (MW, 17 kDa) for transdermal immunotherapy of DMD. Facilitating the transdermal delivery, the low MW HA showed a boosting effect on the immunization of MstnF possibly by engaging both toll-like receptors and cluster of differentiation 44 (CD44). In vivo two-photon microscopy clearly visualized the effective transdermal penetration of HA-MstnF conjugates into deep intact skin layers. The transdermal immunization of mdx mice significantly increased antibody titers against myostatin. Furthermore, the mdx mice immunized with HA-MstnF conjugates resulted in statistically significant improvement in the biochemical and pathological status of skeletal musculature as well as functional behaviors. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Kong, Won Ho; Kim, Hyemin; Yang, Jeong-A; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 790784, Kyungbuk, South Korea. [Sung, Dong Kyung; Lee, Jeehun] Sungkyunkwan Univ, Sch Med, Dept Pediat, Samsung Med Ctr, 50 Irwon Dong, Seoul 135710, South Korea. [Ieronimakis, Nicholas; Kim, Deok-Ho] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Kim, Ki Su; Yun, Seok Hyun] Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Kim, Ki Su; Yun, Seok Hyun] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. RP Hahn, SK (reprint author), Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 790784, Kyungbuk, South Korea. EM skhanb@postech.ac.kr FU Korean Health Technology R&D Project, Ministry of Health and Welfare, Korea [HI14C1658]; Bio & Medical Technology Development Program through the National Research Foundation (NRF) of Korea - MEST [2012M3A9C6049791] FX This research was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Korea (HI14C1658). This study was supported by the Bio & Medical Technology Development Program (No. 2012M3A9C6049791) through the National Research Foundation (NRF) of Korea grant funded by the MEST. NR 36 TC 3 Z9 3 U1 4 U2 38 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 MAR PY 2016 VL 81 BP 93 EP 103 DI 10.1016/j.biomaterials.2015.12.007 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DD7KQ UT WOS:000370103700009 PM 26724457 ER PT J AU Khalili, H AF Khalili, Hamed TI Risk of Inflammatory Bowel Disease with Oral Contraceptives and Menopausal Hormone Therapy: Current Evidence and Future Directions SO DRUG SAFETY LA English DT Article ID CROHNS-DISEASE; ULCERATIVE-COLITIS; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; BARRIER FUNCTION; SEX-DIFFERENCES; METAANALYSIS; CELLS; IBD; TESTOSTERONE AB Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel diseases, are archetypical inflammatory disorders of the gastrointestinal tract with rising incidence worldwide. Although the role of genetic factors in disease development has been highlighted by genome-wide association studies, environmental risk factors likely play a pivotal role in development of CD and UC. Prior observational studies have suggested a link between exogenous hormone use and risk of CD and UC. Specifically, studies have shown an association between oral contraceptive use and risk of CD and menopausal hormone therapy and risk of UC. Although the exact mechanism of these associations is largely unknown, a number of hypotheses have been proposed. First, oral estrogen has been shown to modify intestinal permeability, a critical step in the pathophysiology of inflammatory bowel disease. Second, exogenous hormone use through its effect on endogenous levels of hormones may enhance the development of T(h)1- and T(h)2-mediated inflammatory diseases. Lastly, recent data have linked modification in the gut microbiome to endogenous levels of androgens, which are also known to be altered with exogenous hormone use and influence the development of autoimmune diseases. This supports the intriguing hypothesis that the gut microbiome lies at the crossroads of pathways linking exogenous hormone use with innate and adaptive immunity. Future studies should therefore focus on bridging these epidemiologic findings to disease pathogenesis through comprehensive understanding of the complex interaction between exogenous hormone use, sex steroid biomarkers, genetic risk loci, and alterations in the intestinal microbial environment in the etiology of CD and UC. C1 [Khalili, Hamed] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Khalili, Hamed] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Khalili, Hamed] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Khalili, Hamed] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Digest Healthcare Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. RP Khalili, H (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA.; Khalili, H (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA.; Khalili, H (reprint author), Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA.; Khalili, H (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Digest Healthcare Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM hkhalili@mgh.harvard.edu FU American Gastroenterological Association (AGA); National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK099681] FX Dr. Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681). NR 38 TC 1 Z9 1 U1 2 U2 7 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 MAR PY 2016 VL 39 IS 3 BP 193 EP 197 DI 10.1007/s40264-015-0372-y PG 5 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DD8JH UT WOS:000370172200001 PM 26658991 ER PT J AU Kawano, T Tsugawa, Y Nishiyama, K Morita, H Yamamura, O Hasegawa, K AF Kawano, T. Tsugawa, Y. Nishiyama, K. Morita, H. Yamamura, O. Hasegawa, K. TI Shelter crowding and increased incidence of acute respiratory infection in evacuees following the Great Eastern Japan Earthquake and tsunami SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Community epidemics; epidemiology; infectious disease control; infectious disease epidemiology; respiratory infections ID PNEUMONIA; INFLUENZA; CARE AB Although outbreaks of acute respiratory infection (ARI) at shelters are hypothesized to be associated with shelter crowding, no studies have examined this relationship. We conducted a retrospective study by reviewing medical records of evacuees presenting to one of the 37 clinics at the shelters in Ishinomaki city, Japan, during the 3-week period after the Great Eastern Japan Earthquake and tsunami in 2011. On the basis of a locally weighted scatter-plot smoothing technique, we categorized 37 shelters into crowded (mean space <5.5 m(2)/per person) and non-crowded (>= 5.5 m(2)) shelters. Outcomes of interest were the cumulative and daily incidence rate of ARI/10 000 evacuees at each shelter. We found that the crowded shelters had a higher median cumulative incidence rate of ARI [5.4/10 000 person-days, interquartile range (IQR) 0-24.6, P = 0.04] compared to the non-crowded shelters (3.5/10 000 person-days, IQR 0-8.7) using Mann-Whitney U test. Similarly, the crowded shelters had an increased daily incidence rate of ARI of 19.1/10 000 person-days (95% confidence interval 5.9-32.4, P < 0.01) compared to the non-crowded shelters using quasi-least squares method. In sum, shelter crowding was associated with an increased incidence rate of ARI after the natural disaster. C1 [Kawano, T.; Morita, H.] Univ Fukui Hosp, Dept Emergency Med, Matsuoka Shimoaigetsu 23-3, Heiheiji Town, Fukui, Japan. [Tsugawa, Y.] Harvard Interfac Initiat Hlth Policy, Cambridge, MA USA. [Nishiyama, K.] Kyoto Univ, Grad Sch Med, Dept Primary Care & Emergency Med, Sakyo Ward, Kyoto, Japan. [Yamamura, O.] Univ Fukui Hosp, Dept Community Hlth Care Promot, Yoshida, Fukui, Japan. [Hasegawa, K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Kawano, T (reprint author), Univ Fukui Hosp, Dept Emergency Med, Matsuoka Shimoaigetsu 23-3, Heiheiji Town, Fukui, Japan. EM kawano@u-fukui.ac.jp FU Daiwa Securities Health Foundation; Japan Society for the Promotion of Science (JSPS) FX Support was received from Daiwa Securities Health Foundation and Grant-in-Aid for Young Scientist (B) of Japan Society for the Promotion of Science (JSPS). None of the sponsors had any role in any area of this study: data collection, management, analysis, and interpretation. NR 27 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD MAR PY 2016 VL 144 IS 4 BP 787 EP 795 DI 10.1017/S0950268815001715 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DD1VY UT WOS:000369712100015 PM 26243450 ER PT J AU Pastormerlo, LE Maffei, S Della Latta, D Chubuchny, V Susini, C Berti, S Clerico, A Prontera, C Passino, C Januzzi, JL Emdin, M Chiappino, D AF Pastormerlo, Luigi E. Maffei, Stefano Della Latta, Daniele Chubuchny, Vladislav Susini, Carla Berti, Sergio Clerico, Aldo Prontera, Concetta Passino, Claudio Januzzi, James L., Jr. Emdin, Michele Chiappino, Dante TI N-terminal prob-type natriuretic peptide is a marker of vascular remodelling and subclinical atherosclerosis in asymptomatic hypertensives SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Arterial hypertension; natriuretic peptide; subclinical atherosclerosis ID CARDIOVASCULAR EVENTS; ENDOTHELIAL FUNCTION; COMPUTED-TOMOGRAPHY; HEART-FAILURE; PREDICTION; DISEASE; RISK; ECHOCARDIOGRAPHY; QUANTIFICATION; ASSOCIATION AB Background Arterial hypertension is a main determinant of arterial remodelling and atherosclerosis. Coronary artery calcium score and carotid intima-media thickness are recognized indices of vascular remodelling. Established biohumoral markers for the diagnosis of atherosclerosis are still lacking in asymptomatic subjects with hypertension. Objectives We aimed to test the association of plasma N-terminal pro B-type natriuretic peptide concentrations with either coronary artery calcium score or carotid intima-media thickness in asymptomatic hypertensive subjects. Methods We conducted a case-control study on 436 hypertensi.ve and 436 age/sex-matched normotensive subjects from the population of the Montignoso HEart and Lung Project, a community-based study of asymptomatic general population 45 years. Subjects underwent N-terminal pro B-type natriuretic peptide measurement, echocardiography and evaluation of coronary artery calcium score and carotid intima-media thickness. Results Hypertensive subjects had higher median coronary artery calcium score (60 (interquartile range, 30-112) vs. 15 (interquartile range 3-70) Agatson units, p=0.007), carotid intima-media thickness (8.6 (interquartile range 7.5-9.1) vs. 7.9 (7.1-8.4) mu m, p<0.001) and indexed left ventricular mass (101 (interquartile range 82-126) vs. 87 (63-91) mg/m2, p=0.03) than controls, with no differences in left ventricular ejection fraction, diameters, E/E, left atrial area. N-terminal pro B-type natriuretic peptide concentrations were higher in hypertensive subjects with either coronary artery calcium score (p=0.008) or carotid intima-media thickness >75th (p<0.006) percentile and highest in combined coronary artery calcium score/carotid intima-media thickness >75th percentile (p=0.021). In multivariable analysis, N-terminal pro B-type natriuretic peptide independently predicted either coronary artery calcium score or carotid intima-media thickness >75th percentile, but only in hypertensive subjects (odds ratio=1.87, 95% confidence interval 1.30-2.74, p=0.001 and odds ratio=1.99, 95% confidence interval 1.43-2.76, p=0.001). Conclusions In asymptomatic subjects with hypertension, N-terminal pro B-type natriuretic peptide is a marker of hypertension-mediated preclinical vascular disease. C1 [Pastormerlo, Luigi E.; Maffei, Stefano; Della Latta, Daniele; Chubuchny, Vladislav; Susini, Carla; Berti, Sergio; Clerico, Aldo; Prontera, Concetta; Emdin, Michele; Chiappino, Dante] Fdn G Monasterio CNR Reg Toscana Pisa Massa, Pisa, Italy. [Passino, Claudio] Scuola Super Sant Anna, St Anna, Italy. [Januzzi, James L., Jr.] Harvard Univ, Div Cardiol, Dept Med, Massachusetts Gen Hosp,Med Sch, Cambridge, MA 02138 USA. RP Pastormerlo, LE (reprint author), Fdn Toscana Gabriele Monasterio, Div Cardiol & Cardiovasc Med, CNR Reg Toscana, Via Giuseppe Moruzzi 1, I-56124 Pisa, Italy. EM pastormerlo@ftgm.it RI Della Latta, Daniele/K-9283-2016; OI Della Latta, Daniele/0000-0003-0628-2312; Pastormerlo, Luigi Emilio/0000-0003-2403-3766 NR 26 TC 1 Z9 1 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD MAR PY 2016 VL 23 IS 4 BP 366 EP 376 DI 10.1177/2047487315569675 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD6YS UT WOS:000370071300004 PM 25644699 ER PT J AU Levi, B Ibrahim, A Mathews, K Wojcik, B Gomez, J Fagan, S Austen, WG Goverman, J AF Levi, Benjamin Ibrahim, Amir Mathews, Katie Wojcik, Brandon Gomez, Jason Fagan, Shawn Austen, William Gerald, Jr. Goverman, Jeremy TI The Use of CO2 Fractional Photothermolysis for the Treatment of Burn Scars SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID CARBON-DIOXIDE LASER; HYPERTROPHIC SCARS; ACNE SCARS; KELOIDS; MANAGEMENT; CO2-LASER AB A recent advancement in the treatment of burn scars has been the use of the carbon dioxide (CO2) laser to perform fractional photothermolysis. In this analysis, we describe our results and patient-reported outcomes with the use of fractional CO2 laser for the treatment of burn-related scarring. We performed a retrospective study of all patients who underwent CO2 laser procedures for treatment of symptomatic burn scars and skin grafts at one accredited regional burn center. Burn injury and laser treatment demographics, as well as complications, are reported. A questionnaire was administered to all patients and included patient-reported outcome measures aimed at understanding the patient experience and their subjective response to treatment. A total of 387 CO2 laser procedures were performed on 131 patients for the treatment of symptomatic burn scars and skin grafts between October 1, 2011, and May 1, 2014 (average, 2.95 procedures/patient; range, 1-11). Average time between injury and first laser was 597.35 days (range, 60-13,475). Average time between laser treatments (when multiple) was 117.73 days (range, 22-514). There were no infections requiring treatment with oral antibiotics. Overall patient satisfaction with laser therapy was 96.7%. Patients reported reductions in neuropathic pain, tightness (contracture), and pruritus (54.0, 50.6, and 49.0%, respectively). Fractional photothermolysis utilizing the CO2 laser is a safe and effective modality for the treatment of symptomatic burn scars, donor sites, and skin grafts. Patient satisfaction with this procedure is high, and complications are low. Significant improvements in scar appearance, pliability, tightness, neuropathic pain, and pruritus were commonly reported. C1 [Levi, Benjamin; Ibrahim, Amir; Mathews, Katie; Wojcik, Brandon; Gomez, Jason; Fagan, Shawn; Austen, William Gerald, Jr.; Goverman, Jeremy] Harvard Univ, Sch Med, Div Burns, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Goverman, J (reprint author), Massachusetts Gen Hosp, Frasier Outpatient Burn Ctr, Bigelow 13,55 Fruit St, Boston, MA 02114 USA. EM Jgoverman@partners.org NR 28 TC 2 Z9 3 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD MAR-APR PY 2016 VL 37 IS 2 BP 106 EP 114 DI 10.1097/BCR.0000000000000285 PG 9 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA DD4AS UT WOS:000369865400004 PM 26536539 ER PT J AU Chung, KK Rhie, RY Lundy, JB Cartotto, R Henderson, E Pressman, MA Joe, VC Aden, JK Driscoll, IR Faucher, LD McDermid, RC Mlcak, RP Hickerson, WL Jeng, JC AF Chung, Kevin K. Rhie, Ryan Y. Lundy, Jonathan B. Cartotto, Robert Henderson, Elizabeth Pressman, Melissa A. Joe, Victor C. Aden, James K. Driscoll, Ian R. Faucher, Lee D. McDermid, Robert C. Mlcak, Ronald P. Hickerson, William L. Jeng, James C. TI A Survey of Mechanical Ventilator Practices Across Burn Centers in North America SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; FREQUENCY PERCUSSIVE VENTILATION; RANDOMIZED CONTROLLED-TRIAL; END-EXPIRATORY PRESSURE; INHALATION INJURY; OSCILLATORY VENTILATION; TIDAL VOLUMES; TRACHEOSTOMY; METAANALYSIS AB Burn injury introduces unique clinical challenges that make it difficult to extrapolate mechanical ventilator (MV) practices designed for the management of general critical care patients to the burn population. We hypothesize that no consensus exists among North American burn centers with regard to optimal ventilator practices. The purpose of this study is to examine various MV practice patterns in the burn population and to identify potential opportunities for future research. A researcher designed, 24-item survey was sent electronically to 129 burn centers. The (2), Fisher's exact, and Cochran-Mantel-Haenszel tests were used to determine if there were significant differences in practice patterns. We analyzed 46 questionnaires for a 36% response rate. More than 95% of the burn centers reported greater than 100 annual admissions. Pressure support and volume assist control were the most common initial MV modes used with or without inhalation injury. In the setting of Berlin defined mild acute respiratory distress syndrome (ARDS), ARDSNet protocol and optimal positive end-expiratory pressure were the top ventilator choices, along with fluid restriction/diuresis as a nonventilator adjunct. For severe ARDS, airway pressure release ventilation and neuromuscular blockade were the most popular. The most frequently reported time frame for mechanical ventilation before tracheostomy was 2 weeks (25 of 45, 55%); however, all respondents reported in the affirmative that there are certain clinical situations where early tracheostomy is warranted. Wide variations in clinical practice exist among North American burn centers. No single ventilator mode or adjunct prevails in the management of burn patients regardless of pulmonary insult. Movement toward American Burn Association-supported, multicenter studies to determine best practices and guidelines for ventilator management in burn patients is prudent in light of these findings. C1 [Chung, Kevin K.; Rhie, Ryan Y.; Lundy, Jonathan B.; Aden, James K.; Driscoll, Ian R.] US Army, Inst Surg Res, 3698 Chambers Pass, Ft Sam Houston, TX 78234 USA. [Chung, Kevin K.; Lundy, Jonathan B.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Cartotto, Robert] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Henderson, Elizabeth] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pressman, Melissa A.] Arizona Burn Ctr, Phoenix, AZ USA. [Joe, Victor C.] Univ Calif Irvine, Reg Burn Ctr, Orange, CA USA. [Faucher, Lee D.] Univ Wisconsin Hosp, Madison, WI USA. [McDermid, Robert C.] Univ Alberta, Edmonton, AB, Canada. [Mlcak, Ronald P.] Shriners Hosp Children, Galveston, TX 77550 USA. [Hickerson, William L.] Memphis Burn Ctr, Memphis, TN USA. [Jeng, James C.] Mt Sinai Beth Israel Med Ctr, New York, NY USA. RP Chung, KK (reprint author), US Army, Inst Surg Res, 3698 Chambers Pass, Ft Sam Houston, TX 78234 USA. EM Kevin.k.chung.mil@mail.mil FU American Burn Association FX This project was commissioned by the Organization and Delivery of Burn Care Committee and funded in part by the American Burn Association. NR 41 TC 5 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD MAR-APR PY 2016 VL 37 IS 2 BP E131 EP E139 DI 10.1097/BCR.0000000000000270 PG 9 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA DD4AZ UT WOS:000369866100005 PM 26135527 ER PT J AU Lee, CI Bogart, A Germino, JC Goldman, LE Hubbard, RA Haas, JS Hill, DA Tosteson, ANA Alford-Teaster, JA DeMartini, WB Lehman, CD Onega, TL AF Lee, Christoph I. Bogart, Andy Germino, Jessica C. Goldman, L. Elizabeth Hubbard, Rebecca A. Haas, Jennifer S. Hill, Deirdre A. Tosteson, Anna N. A. Alford-Teaster, Jennifer A. DeMartini, Wendy B. Lehman, Constance D. Onega, Tracy L. TI Availability of Advanced Breast Imaging at Screening Facilities Serving Vulnerable Populations SO JOURNAL OF MEDICAL SCREENING LA English DT Article DE breast cancer; screening mammography; disparities; access; advanced breast imaging ID DIAGNOSTIC MAMMOGRAPHY; FOLLOW-UP; CANCER; WOMEN; OUTCOMES; TIMELINESS; ETHNICITY; TRENDS; RISK AB Objective: Among vulnerable women, unequal access to advanced breast imaging modalities beyond screening mammography may lead to delays in cancer diagnosis and unfavourable outcomes. We aimed to compare on-site availability of advanced breast imaging services (ultrasound, magnetic resonance imaging [MRI], and image-guided biopsy) between imaging facilities serving vulnerable patient populations and those serving non-vulnerable populations. Setting: 73 imaging facilities across five Breast Cancer Surveillance Consortium regional registries in the United States during 2011 and 2012. Methods: We examined facility and patient characteristics across a large, national sample of imaging facilities and patients served. We characterized facilities as serving vulnerable populations based on the proportion of mammograms performed on women with lower educational attainment, lower median income, racial/ethnic minority status, and rural residence. We performed multivariable logistic regression to determine relative risks of on-site availability of advanced imaging at facilities serving vulnerable women versus facilities serving non-vulnerable women. Results: Facilities serving vulnerable populations were as likely (Relative risk [RR] for MRI=0.71, 95% Confidence Interval [CI] 0.42, 1.19; RR for MRI-guided biopsy=1.07 [0.61, 1.90]; RR for stereotactic biopsy=1.18 [0.75, 1.85]) or more likely (RR for ultrasound=1.38 [95% CI 1.09, 1.74]; RR for ultrasound-guided biopsy=1.67 [1.30, 2.14]) to offer advanced breast imaging services as those serving non-vulnerable populations. Conclusions: Advanced breast imaging services are physically available on-site for vulnerable women in the United States, but it is unknown whether factors such as insurance coverage or out-of-pocket costs might limit their use. C1 [Lee, Christoph I.; Germino, Jessica C.; Lehman, Constance D.] Univ Washington, Sch Med, Dept Radiol, 825 Eastlake Ave East, Seattle, WA 98109 USA. [Lee, Christoph I.] Univ Washington, Dept Hlth Serv, Sch Publ Hlth, 825 Eastlake Ave East, Seattle, WA 98109 USA. [Bogart, Andy] Grp Hlth Res Inst, 1730 Minor Ave 1600, Seattle, WA 98101 USA. [Goldman, L. Elizabeth] Univ Calif San Francisco, Sch Med, Dept Internal Med, 1001 Potrero Ave,Box 1364, San Francisco, CA 94110 USA. [Hubbard, Rebecca A.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, 423 Guardian Dr, Philadelphia, PA 19104 USA. [Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. [Haas, Jennifer S.] Harvard Univ, Sch Med, Dept Med, 1620 Tremont St, Boston, MA 02120 USA. [Haas, Jennifer S.] Dana Farber Harvard Canc Inst, 1620 Tremont St, Boston, MA 02120 USA. [Haas, Jennifer S.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 1620 Tremont St, Boston, MA 02120 USA. [Hill, Deirdre A.] Univ New Mexico, Dept Internal Med, Canc Res & Treatment Ctr, 1201 Camino Salud NE,1 Univ New Mexico, Albuquerque, NM 87102 USA. [Tosteson, Anna N. A.; Alford-Teaster, Jennifer A.; Onega, Tracy L.] Geisel Sch Med, Norris Cotton Canc Ctr, Dartmouth Inst Hlth Policy & Clin Practice, Dept Med, One Med Ctr Dr, Lebanon, NH 03756 USA. [Tosteson, Anna N. A.; Alford-Teaster, Jennifer A.; Onega, Tracy L.] Geisel Sch Med, Norris Cotton Canc Ctr, Dartmouth Inst Hlth Policy & Clin Practice, Dept Community & Family Med, One Med Ctr Dr, Lebanon, NH 03756 USA. [DeMartini, Wendy B.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, 600 Highland Ave, Madison, WI 53792 USA. RP Lee, CI (reprint author), Univ Washington, Schools Med & Publ Hlth, 825 Eastlake Ave East,G3-200, Seattle, WA 98109 USA. EM stophlee@uw.edu FU National Cancer Institute [RC2CA148577]; Breast Cancer Surveillance Consortium (BCSC) [P01CA154292, HHSN261201100031C]; American Cancer Society [MRSG-14-160-01-CPHPS] FX This work was supported by grants from the National Cancer Institute (RC2CA148577 and, for the Breast Cancer Surveillance Consortium (BCSC), P01CA154292 and HHSN261201100031C), as well by a grant from the American Cancer Society (MRSG-14-160-01-CPHPS). NR 25 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0969-1413 EI 1475-5793 J9 J MED SCREEN JI J. Med. Screen. PD MAR PY 2016 VL 23 IS 1 BP 24 EP 30 DI 10.1177/0969141315591616 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD6XF UT WOS:000370067200004 PM 26078275 ER PT J AU Ranasinghe, S Soghoian, DZ Lindqvist, M Ghebremichael, M Donaghey, F Carrington, M Seaman, MS Kaufmann, DE Walker, BD Porichis, F AF Ranasinghe, Srinika Soghoian, Damien Z. Lindqvist, Madelene Ghebremichael, Musie Donaghey, Faith Carrington, Mary Seaman, Michael S. Kaufmann, Daniel E. Walker, Bruce D. Porichis, Filippos TI HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4(+) T Cell Responses SO JOURNAL OF VIROLOGY LA English DT Article ID FOLLICULAR HELPER-CELLS; VACCINE DEVELOPMENT; VIRAL-PROTEINS; RHESUS-MONKEYS; IMMUNE CONTROL; INFECTION; BROAD; GAG; ENVELOPE; HEMAGGLUTININ AB Antigen-specific CD4(+) T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4(+) T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4(+) T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4(+) T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4(+) T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4(+) T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4(+) T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4(+) T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4(+) T cells and, to a lesser extent, gp41-specific CD4(+) T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies. IMPORTANCE One of the earliest discoveries related to CD4(+) T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4(+) T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4(+) T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4(+) T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4(+) T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag-and gp41-specific CD4(+) T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection. C1 [Ranasinghe, Srinika; Soghoian, Damien Z.; Lindqvist, Madelene; Ghebremichael, Musie; Donaghey, Faith; Carrington, Mary; Kaufmann, Daniel E.; Walker, Bruce D.; Porichis, Filippos] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Ranasinghe, Srinika; Soghoian, Damien Z.; Lindqvist, Madelene; Ghebremichael, Musie; Donaghey, Faith; Carrington, Mary; Kaufmann, Daniel E.; Walker, Bruce D.; Porichis, Filippos] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Ranasinghe, Srinika; Kaufmann, Daniel E.; Walker, Bruce D.; Porichis, Filippos] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Carrington, Mary] NCI, Canc & Inflammat Program, HLA Immunogenet Sect, Leidos Biomed Res Inc, Frederick, MD 21701 USA. [Seaman, Michael S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Kaufmann, Daniel E.] Univ Montreal, Ctr Hosp, Ctr Rech, Montreal, PQ, Canada. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Ranasinghe, S; Porichis, F (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA USA.; Ranasinghe, S; Porichis, F (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA.; Ranasinghe, S; Porichis, F (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. EM sranasinghe@mgh.harvard.edu; fporichis@mgh.harvard.edu FU U.S. National Institutes of Health (NIH) Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1-AI100663]; Bill and Melinda Gates Foundation [1066973, 1032144]; NIH [1R01 AI118544]; Research Scholar Career Award of the Quebec Health Research Fund; Harvard CFAR [2P30 AI060354, P30 AI060354]; Mark and Lisa Schwartz Foundation; CAVD; International HIV Controllers Study - Bill and Melinda Gates Foundation; AIDS Healthcare Foundation; Intramural Research Program of the NIH; Center for Cancer Research [HHSN261200800001E]; Frederick National Lab FX This study was funded by the U.S. National Institutes of Health (NIH) Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID and 1UM1-AI100663) to B.D.W. and D.E.K. This project has also been funded in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery, CAVD grant 1066973 to B.D.W. and CAVD grant 1032144 to M.S.S. F.P is funded by a NIH 1R01 AI118544. D.E.K is supported by a Research Scholar Career Award of the Quebec Health Research Fund. M.G. is supported by Harvard CFAR 2P30 AI060354. The HIV Controller Cohort was supported by the Mark and Lisa Schwartz Foundation, the CAVD, and in part by the International HIV Controllers Study, funded by the Bill and Melinda Gates Foundation, the AIDS Healthcare Foundation, and Harvard CFAR (P30 AI060354). This research was also supported in part by funding from the Intramural Research Program of the NIH, Frederick National Lab, and Center for Cancer Research to M.C. under contract number HHSN261200800001E. NR 42 TC 5 Z9 5 U1 0 U2 11 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 MAR PY 2016 VL 90 IS 5 BP 2208 EP 2220 DI 10.1128/JVI.02278-15 PG 13 WC Virology SC Virology GA DD6AF UT WOS:000370005400005 ER PT J AU Castro, VM Roberson, AM McCoy, TH Wiste, A Cagan, A Smoller, JW Rosenbaum, JF Ostacher, M Perlis, RH AF Castro, Victor M. Roberson, Ashlee M. McCoy, Thomas H. Wiste, Anna Cagan, Andrew Smoller, Jordan W. Rosenbaum, Jerrold F. Ostacher, Michael Perlis, Roy H. TI Stratifying Risk for Renal Insufficiency Among Lithium-Treated Patients: An Electronic Health Record Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID LOW SERUM-LEVELS; BIPOLAR DISORDER; MAINTENANCE TREATMENT; DOSING FREQUENCY; MEDICATIONS; ENTERPRISE; ADHERENCE; STANDARD; TRIAL AB Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk. C1 [Castro, Victor M.; Roberson, Ashlee M.; McCoy, Thomas H.; Wiste, Anna; Cagan, Andrew; Smoller, Jordan W.; Rosenbaum, Jerrold F.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Castro, Victor M.; Cagan, Andrew] One Constitut Ctr, Partners Res Informat Syst & Comp, Partners HealthCare Syst, Boston, MA USA. [Ostacher, Michael] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Perlis, RH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Psychiat & Neurodev Genet Unit,Dept Psychiat, Simches Res Bldg MGH,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI Ostacher, Michael/0000-0003-0353-7535; McCoy, Thomas/0000-0002-5624-0439 NR 28 TC 5 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2016 VL 41 IS 4 BP 1138 EP 1143 DI 10.1038/npp.2015.254 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DD2YA UT WOS:000369786900021 PM 26294109 ER PT J AU Sonis, ST Hashemi, S Epstein, JB Nair, RG Raber-Durlacher, JE AF Sonis, Stephen T. Hashemi, Sepehr Epstein, Joel B. Nair, Raj G. Raber-Durlacher, Judith E. TI Could the biological robustness of low level laser therapy (Photobiomodulation) impact its use in the management of mucositis in head and neck cancer patients SO ORAL ONCOLOGY LA English DT Review DE Photobiomodulation; Low level laser therapy; Head and neck cancer; Oral mucositis; Tumor behavior; Radioprotection ID SQUAMOUS-CELL CARCINOMA; FIBROBLAST-GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; SIGNALING PATHWAY; PROSTATE-CANCER; TGF-BETA; IN-VITRO; CLINICOPATHOLOGICAL SIGNIFICANCE; PI3K/AKT/MTOR PATHWAY; IRRADIATION PROMOTES AB Low level laser therapy (LLLT) has been noted to be effective in mitigating the development of oral mucositis among patients being treated with chemoradiation for cancers of the head and neck. To explain the biological basis for this observation we performed a comprehensive literature search. Our investigation identified a substantial number of LLLT-activated pathways that have been strongly associated with negative tumor outcomes including proliferation, invasion, angiogenesis, metastases and cancer-treatment resistance. In light of these findings, we suggest an investigational strategy to assure that LLLT's anti-mucositis efficacy is independent of its possible potential to enhance threatening tumor behaviors. Included are appropriate pre-clinical modeling, short-and long-term follow-up of LLLT-treated patients, and the requirement for consistency of LLLT parameters. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Sonis, Stephen T.] Brigham & Womens Hosp, Div Oral Med, 75 Francis St, Boston, MA 02115 USA. [Sonis, Stephen T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sonis, Stephen T.] Biomodels LLC, Watertown, MA USA. [Hashemi, Sepehr] Harvard Univ, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. [Epstein, Joel B.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Inst, Los Angeles, CA 90048 USA. [Epstein, Joel B.] City Hope Natl Med Ctr, Div Otolaryngol & Head & Neck Surg, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Nair, Raj G.] Griffith Univ, Menzies Hlth Inst Queensland, Discipline Oral Med Oral Pathol & Human Dis, Nathan, Qld 4111, Australia. [Nair, Raj G.] Queensland Hlth, Gold Coast Univ Hosp, Hematol & Oncol, Brisbane, Qld, Australia. [Raber-Durlacher, Judith E.] Acad Med Ctr, Dept Oral & Maxillofacial Surg, Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Univ Amsterdam, ACTA, Dept Med Dent Interact, Amsterdam, Netherlands. RP Sonis, ST (reprint author), Brigham & Womens Hosp, Div Oral Med, 75 Francis St, Boston, MA 02115 USA. EM ssonis@partners.org NR 80 TC 9 Z9 9 U1 2 U2 8 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 MAR PY 2016 VL 54 BP 7 EP 14 DI 10.1016/j.oraloncology.2016.01.005 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DD6AK UT WOS:000370005900012 PM 26852286 ER PT J AU Kang, WS Nguyen, K McKenna, CE Sewell, WF McKenna, MJ Jung, DH AF Kang, Woo Seok Nguyen, Kim McKenna, Charles E. Sewell, William F. McKenna, Michael J. Jung, David H. TI Intracochlear Drug Delivery Through the Oval Window in Fresh Cadaveric Human Temporal Bones SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Bisphosphonates; Fluorescence imaging; Human inner ear; Inner ear drug delivery; Otosclerosis ID INNER-EAR; COCHLEAR IMPLANTATION; PERILYMPHATIC SCALAE; SPIRAL LIGAMENT; BISPHOSPHONATE; OTOSCLEROSIS; COMMUNICATION AB Hypothesis:Drug delivered to the oval window can diffuse to the apex of the human cochlea.Background:We have previously demonstrated that zoledronate, a nitrogen-containing bisphosphonate, can arrest the sensorineural hearing loss in cochlear otosclerosis. We have also shown that, in animals, delivery of bisphosphonate into the cochlea can dramatically increase delivery efficiency. Intracochlear drug delivery has the potential to increase local concentration of drug while decreasing the risk of systemic toxicity. In the present study, a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) was introduced into the human cochlea through the oval window and its distribution within the temporal bone was quantified.Methods:In three fresh human temporal bones, we introduced 6-FAM-ZOL via the oval window. We compared these specimens to control specimens treated with artificial perilymph alone. Specimens were then processed, embedded into methyl methacrylate, and ground to the mid-modiolar axis. We quantified the fluorescence in confocal images.Results:We found 6-FAM-ZOL to be distributed up to the apical cochlear turn. In specimens treated with 6-FAM-ZOL, we identified a strong baso-apical gradient of fluorescent signal along the lateral cochlear wall and the modiolus both in the scala vestibuli and in the scala tympani.Conclusion:Bisphosphonate introduced via the oval window in the human cochlea can be delivered up to the apical cochlear turn. Interscalar communication is likely to play an important role in determining patterns of drug delivery in the inner ear. C1 [Kang, Woo Seok; McKenna, Michael J.; Jung, David H.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Kang, Woo Seok; Sewell, William F.; McKenna, Michael J.; Jung, David H.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Kang, Woo Seok; McKenna, Michael J.; Jung, David H.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Nguyen, Kim; McKenna, Charles E.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. RP Jung, DH (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM david_jung@meei.harvard.edu FU NIDCD [R01 DC009837] FX The authors thank Kris Kristiansen for excellent technical support. The authors also thank Diane Jones of the Massachusetts Eye and Ear Infirmary Temporal Bone Histopathology Laboratory for assistance in procuring the cadaveric specimens and Jeananne Phillips for assistance in using the Massachusetts Eye and Ear Infirmary Surgical Skills Laboratory. This work was primarily supported by NIDCD grant R01 DC009837. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University and its affiliated academic health care centers, or the National Institutes of Health. NR 26 TC 3 Z9 3 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD MAR PY 2016 VL 37 IS 3 BP 218 EP 222 DI 10.1097/MAO.0000000000000964 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DD5UK UT WOS:000369989800002 PM 26859540 ER PT J AU Barber, SR Remenschneider, AK Kozin, ED Cunnane, ME Nahed, BV Leslie-Mazwi, T Quesnel, AM AF Barber, Samuel R. Remenschneider, Aaron K. Kozin, Elliott D. Cunnane, Mary E. Nahed, Brian V. Leslie-Mazwi, Thabele Quesnel, Alicia M. TI Cochlear Implantation in a Patient With Pfeiffer Syndrome and Temporal Bone Vascular Anomalies SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear implant; Computed tomography; Craniosynostosis; Pfeiffer syndrome; Vascular malformation AB Objective:Pfeiffer syndrome is a rare craniosynostotic disorder resulting in premature bony fusion of the skull, which can result in abnormal temporal bone and vascular anatomy and hearing loss. Cochlear implantation in these patients requires thoughtful surgical planning given the potential for limited access to the cochlea because of subcutaneous or intratemporal vasculature. Herein, we present a patient with Pfeiffer syndrome who underwent successful cochlear implantation using preoperative Doppler ultrasound to identify large extracranial venous anatomy followed by a modified transcanal surgical approach.Patients:An adult female patient with Pfeiffer syndrome.Intervention(s):Preoperative axial computed tomography, catheter angiography, Doppler ultrasound, and right side cochlear implant.Main Outcome Measure(s):Surgical feasibility and audiometric outcomes including aided thresholds and word recognition score.Results:Successful cochlear implantation was performed via a modified transcanal approach with blind sac closure of the external auditory meatus. Full electrode insertion was obtained through a round window approach. No extracranial or intratemporal vessels were encountered during surgery.Conclusion:Patients with significant craniosynostoses and vascular malformations of the temporal bone can undergo successful cochlear implantation. Careful preoperative planning with high-resolution CT, MRA, and MRV, and/or traditional catheter angiography can assist in determining surgical feasibility and minimizing risk. We recommend preoperative Doppler ultrasound of abnormal extracranial vessels to assist in safe placement of incisions and hardware. C1 [Barber, Samuel R.; Remenschneider, Aaron K.; Kozin, Elliott D.; Quesnel, Alicia M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Remenschneider, Aaron K.; Kozin, Elliott D.; Quesnel, Alicia M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kozin, Elliott D.; Cunnane, Mary E.] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Nahed, Brian V.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Leslie-Mazwi, Thabele] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Remenschneider, AK (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Aaron_Remenschneider@MEEI.HARVARD.EDU RI Kozin, Elliott/J-1225-2014 OI Kozin, Elliott/0000-0002-0305-0682 NR 7 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 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD MAR PY 2016 VL 37 IS 3 BP 241 EP 243 DI 10.1097/MAO.0000000000000965 PG 3 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DD5UK UT WOS:000369989800006 PM 26825670 ER PT J AU Ong, W Nowak, P Cu, Y Schopf, L Bourassa, J Enlow, E Moskowitz, SM Chen, HM AF Ong, Winston Nowak, Pawel Cu, Yen Schopf, Lisa Bourassa, James Enlow, Elizabeth Moskowitz, Samuel M. Chen, Hongming TI Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers SO PHARMACEUTICAL RESEARCH LA English DT Article DE antibiotics; drug delivery; meropenem; mucus; nanoparticle; prodrug ID HUMAN MUCUS BARRIER; CYSTIC-FIBROSIS; DEHYDROPEPTIDASE-I; BETA-LACTAMS; NANOPARTICLES; STABILITY; LUNG; MEROPENEM; PARTICLES; PRODRUGS AB Traditional polymeric nanoparticle formulations for prolonged local action during inhalation therapy are highly susceptible to muco-ciliary clearance. In addition, polymeric carriers are typically administered in high doses due to finite drug loading. For toxicological reasons, these carriers and their degradation byproducts are undesirable for inhalation therapy, particularly for chronic use, due to potential lung accumulation. We synthesized a novel, insoluble prodrug (MRPD) of a time-dependent beta-lactam, meropenem, and formulated MRPD into mucus-penetrating crystals (MRPD-MPCs). After characterizing their mucus mobility (in vitro) and stability, we evaluated the lung pharmacokinetics of intratracheally-instilled MRPD-MPCs and a meropenem solution in guinea pigs. Meropenem levels rapidly declined in the lungs of guinea pigs receiving meropenem solution compared to those given MRPD-MPCs. At 9 h after dosing, drug levels in the lungs of animals that received meropenem solution dropped to 12 ng/mL, whereas those that received MRPD-MPCs maintained an average drug level of a parts per thousand yen1,065 ng/mL over a 12-h period. This work demonstrated that the combination of prodrug chemistry and mucus-penetrating platform created nanoparticles that produced sustained levels of meropenem in guinea pig lungs. This strategy represents a novel approach for sustained local drug delivery to the lung without using encapsulating matrices. C1 [Ong, Winston; Nowak, Pawel; Cu, Yen; Schopf, Lisa; Bourassa, James; Enlow, Elizabeth; Chen, Hongming] Kala Pharmaceut Inc, Waltham, MA 02453 USA. [Moskowitz, Samuel M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Moskowitz, Samuel M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ong, W (reprint author), Kala Pharmaceut Inc, 100 Beaver St,Suite 201, Waltham, MA 02453 USA. EM winston.ong@kalarx.com FU National Heart, Lung and Blood Institute [R43HL106899] FX The work described was partially supported by Award Number R43HL106899 from the National Heart, Lung and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung and Blood Institute or the National Institutes of Health. NR 32 TC 1 Z9 1 U1 3 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD MAR PY 2016 VL 33 IS 3 BP 563 EP 572 DI 10.1007/s11095-015-1808-x PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DD5EV UT WOS:000369946400003 PM 26508478 ER PT J AU Yewle, J Wattamwar, P Tao, ZM Ostertag, EM Ghoroghchian, PP AF Yewle, Jivan Wattamwar, Paritosh Tao, Zhimin Ostertag, Eric M. Ghoroghchian, P. Peter TI Progressive Saturation Improves the Encapsulation of Functional Proteins in Nanoscale Polymer Vesicles SO PHARMACEUTICAL RESEARCH LA English DT Article DE encapsulation; myoglobin; polymersome; protein; vesicle ID INFRARED-EMISSIVE POLYMERSOMES; IN-VIVO; DIBLOCK COPOLYMERS; OXYGEN CARRIER; HEMOGLOBIN; DELIVERY; DRUG; PERFORMANCE; STABILITY; REDUCTION AB To develop a technique that maximizes the encapsulation of functional proteins within neutrally charged, fully PEGylated and nanoscale polymer vesicles (i.e., polymersomes). Three conventional vesicle formation methods were utilized for encapsulation of myoglobin (Mb) in polymersomes of varying size, PEG length, and membrane thickness. Mb concentrations were monitored by UV-Vis spectroscopy, inductively coupled plasma optical emission spectroscopy (ICP-OES) and by the bicinchoninic acid (BCA) assay. Suspensions were subject to protease treatment to differentiate the amounts of surface-associated vs. encapsulated Mb. Polymersome sizes and morphologies were monitored by dynamic light scattering (DLS) and by cryogenic transmission electron microscopy (cryo-TEM), respectively. Binding and release of oxygen were measured using a Hemeox analyzer. Using the established "thin-film rehydration" and "direct hydration" methods, Mb was found to be largely surface-associated with negligible aqueous encapsulation within polymersome suspensions. Through iterative optimization, a novel "progressive saturation" technique was developed that greatly increased the final concentrations of Mb (from < 0.5 to > 2.0 mg/mL in solution), the final weight ratio of Mb-to-polymer that could be reproducibly obtained (from < 1 to > 4 w/w% Mb/polymer), as well as the overall efficiency of Mb encapsulation (from < 5 to > 90%). Stable vesicle morphologies were verified by cryo-TEM; the suspensions also displayed no signs of aggregate formation for > 2 weeks as assessed by DLS. "Progressive saturation" was further utilized for the encapsulation of a variety of other proteins, ranging in size from 17 to 450 kDa. Compared to established vesicle formation methods, "progressive saturation" increases the quantities of functional proteins that may be encapsulated in nanoscale polymersomes. C1 [Yewle, Jivan; Wattamwar, Paritosh; Ostertag, Eric M.; Ghoroghchian, P. Peter] Vindico Pharmaceut Inc, Lexington, KY 40506 USA. [Tao, Zhimin; Ghoroghchian, P. Peter] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Ghoroghchian, P. Peter] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ghoroghchian, PP (reprint author), Vindico Pharmaceut Inc, A169 ASTeCC Bldg, Lexington, KY 40506 USA. EM ppg@mit.edu FU National Institutes of Health [1R43CA159527-01A1, 1R43AI096605-01]; Kentucky Science and Technology Corporation [KSTC-18-OCIS-194, KSTC-184-512-12-135, KSTC-184-512-13-156]; Charles W. and Jennifer C. Johnson Clinical Investigator fund; Kathryn Fox Samway Foundation; Misrock Foundation FX This work was partially supported by grants from the National Institutes of Health (1R43CA159527-01A1 and 1R43AI096605-01) as well as awards from the Kentucky Science and Technology Corporation (KSTC-18-OCIS-194, KSTC-184-512-12-135, KSTC-184-512-13-156). PPG acknowledges support from the Charles W. and Jennifer C. Johnson Clinical Investigator fund and from the Kathryn Fox Samway Foundation. ZT is thankful for the generous support of the Misrock Foundation. NR 53 TC 3 Z9 3 U1 7 U2 31 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD MAR PY 2016 VL 33 IS 3 BP 573 EP 589 DI 10.1007/s11095-015-1809-9 PG 17 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DD5EV UT WOS:000369946400004 PM 26508477 ER PT J AU Ross, AE D'Amico, AV Freedland, SJ AF Ross, A. E. D'Amico, A. V. Freedland, S. J. TI Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Review ID CYCLE PROGRESSION SCORE; RADICAL PROSTATECTOMY; RADIATION-THERAPY; ANDROGEN-DEPRIVATION; GENOMIC CLASSIFIER; PROGNOSTIC VALUE; PTEN LOSS; SALVAGE RADIOTHERAPY; GENE REARRANGEMENTS; RISK STRATIFICATION AB An increased molecular understanding of localized prostate cancer and the improved ability for molecular testing of pathologic tissue has led to the development of multiple clinical assays. Here we review the relevant molecular biology of localized prostate cancer, currently available tissue-based tests and describe which is best supported for use in various clinical scenarios. Literature regarding testing of human prostate cancer tissue with Ki-67, PTEN (by immunohistochemistry (IHC) or fluroescence in situ hybridization (FISH)), ProMark, Prolaris, OncotypeDX Prostate and Decipher was reviewed to allow for generation of expert opinions. At diagnosis, evaluation of PTEN status, use of ProMark or OncotypeDX Prostate in men with Gleason 6 or 3+4 = 7 disease may help guide the use of active surveillance. For men with Gleason 7 or above disease considering watchful waiting, Ki-67 and Prolaris add independent prognostic information. For those men who have undergone prostatectomy and have adverse pathology, Decipher testing may aid in the decision to undergo adjuvant radiation. Newly available molecular tests bring opportunities to improve decision making for men with localized prostate cancer. A review of the currently available data suggests clinical scenarios for which each of these tests may have the greatest utility. C1 [Ross, A. E.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Dept Urol, Baltimore, MD 21205 USA. [Ross, A. E.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Dept Oncol, Baltimore, MD 21205 USA. [Ross, A. E.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Dept Pathol, Baltimore, MD 21205 USA. [D'Amico, A. V.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Freedland, S. J.] Cedars Sinai Med Ctr, Dept Surg, Div Urol, Los Angeles, CA 90048 USA. RP Ross, AE (reprint author), Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Marburg 134,600 North Wolfe St, Baltimore, MD 21287 USA. EM aross2@jhmi.edu FU Johns Hopkins Clinician Scientist Award; Patrick Walsh Research Fund; DOD Prostate Cancer Physician Research Training Award FX AER is funded by the Johns Hopkins Clinician Scientist Award, Patrick Walsh Research Fund and the DOD Prostate Cancer Physician Research Training Award. NR 52 TC 18 Z9 18 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD MAR PY 2016 VL 19 IS 1 BP 1 EP 6 DI 10.1038/pcan.2015.31 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DD3IT UT WOS:000369816300001 PM 26123120 ER PT J AU Bader, MK Laux, C Guanci, MM Figueroa, SA Francis, KE Livesay, SL Mathiesen, C AF Bader, Mary Kay Laux, Chris Guanci, Mary McKenna Figueroa, Stephen A. Francis, Kerry E. Livesay, Sarah L. Mathiesen, Claranne TI Clinical Q & A: Translating Therapeutic Temperature Management from Theory to Practice SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter ID CARDIAC-ARREST; HYPERTHERMIA C1 [Bader, Mary Kay] Mission Hosp, Surg Neuro Intens Care Unit, Mission Viejo, CA USA. [Laux, Chris] Univ Washington, Harborview Med Ctr, 325 9Th Ave, Seattle, WA 98104 USA. [Guanci, Mary McKenna] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Figueroa, Stephen A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Francis, Kerry E.] VCU Hlth Syst, Richmond, VA USA. [Livesay, Sarah L.] Rush Univ, Sch Nursing, Chicago, IL 60612 USA. [Mathiesen, Claranne] Lehigh Valley Hosp, Allentown, PA USA. RP Bader, MK (reprint author), Mission Hosp, Surg Neuro Intens Care Unit, Mission Viejo, CA USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD MAR 1 PY 2016 VL 6 IS 1 BP 52 EP 52 DI 10.1089/ther.2016.29009.mkb PG 1 WC Critical Care Medicine SC General & Internal Medicine GA DD5NV UT WOS:000369971800010 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI One of our intensivists maintains that fever is good for fighting infection and will not give us orders to treat fever in aneurysmal subarachnoid hemorrhage. Should fever (elevations in temperature greater than 37.5 degrees) be treated in aneurysmal subarachnoid hemorrhage patients? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter ID IMPACT; INJURY C1 [Guanci, Mary McKenna] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD MAR 1 PY 2016 VL 6 IS 1 BP 53 EP 53 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA DD5NV UT WOS:000369971800011 ER PT J AU Biswas, A Shouval, D Goettel, J Field, M Griffith, A Pai, SY Notarangelo, L Geha, R Snapper, S AF Biswas, Amlan Shouval, Dror Goettel, Jeremy Field, Michael Griffith, Alexandra Pai, Sung-Yun Notarangelo, Luigi Geha, Raif Snapper, Scott TI Aberrant Anti-inflammatory Macrophage Function and Differentiation in Wiskott-Aldrich Syndrome Protein-Deficient Mice and Humans SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Biswas, Amlan; Shouval, Dror; Goettel, Jeremy; Field, Michael; Griffith, Alexandra; Notarangelo, Luigi; Geha, Raif; Snapper, Scott] Boston Childrens Hosp, Boston, MA USA. [Goettel, Jeremy; Snapper, Scott] Harvard Med Scool, Boston, MA USA. [Pai, Sung-Yun] Dana Farber Canc Inst, Boston, MA 02115 USA. RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 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 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA O-008 BP S3 EP S3 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400009 PM 26849726 ER PT J AU Hui, K Fernandez-Hernandez, H Hu, JZ Pankratz, N Rivas, M Carmik, S Haritunians, T Atzmon, G Brant, S Daly, M Duerr, R McGovern, D Ostrerkk, H Rioux, J Silverberg, M Foroud, T Pe'erk, I Schadt, E Cho, J Peter, I AF Hui, Ken Fernandez-Hernandez, Heriberto Hu, Jianzhong Pankratz, Nathan Rivas, Manuel Carmik, Shai Haritunians, Talin Atzmon, Gil Brant, Steven Daly, Mark Duerr, Richard McGovern, Dermot Ostrerkk, Harry Rioux, John Silverberg, Mark Foroud, Tatiana Pe'erk, Itsik Schadt, Eric Cho, Judy Peter, Inga TI Pleiotropic Effects of Novel Functional LRRK2 Variation on Crohn's Disease and Parkinson's Disease Risk SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Hui, Ken] Yale Univ, New Haven, CT USA. [Fernandez-Hernandez, Heriberto; Hu, Jianzhong; Cho, Judy; Peter, Inga] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Pankratz, Nathan] Univ Minnesota, Minneapolis, MN USA. [Rivas, Manuel] Broad Inst, Cambridge, MA USA. [Carmik, Shai; Pe'erk, Itsik] Columbia Univ, New York, NY USA. [Haritunians, Talin; McGovern, Dermot] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Atzmon, Gil; Ostrerkk, Harry] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Brant, Steven] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Daly, Mark] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Duerr, Richard] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Rioux, John] Univ Montreal, Montreal, PQ, Canada. [Silverberg, Mark] Mt Sinai Hosp, Toronto, ON, Canada. [Foroud, Tatiana] Indiana Univ, Indianapolis, IN 46204 USA. [Schadt, Eric] Mt Sinai, New York, NY USA. 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 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA P-175 BP S62 EP S63 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400197 ER PT J AU Liu, TC Gurram, B Baldridge, M Head, R Lam, V Luo, CW Cao, YM Simpson, P Hayward, M Holtz, M Noe, J Lerner, D Cabrera, J Biank, V Stephens, M Huttenhower, C McGovern, D Xavier, R Stappenbeck, T Salzman, N AF Liu, Ta-Chiang Gurram, Bhaskar Baldridge, Megan Head, Richard Lam, Vy Luo, Chengwei Cao, Yumei Simpson, Pippa Hayward, Michael Holtz, Mary Noe, Joshua Lerner, Diana Cabrera, Jose Biank, Vincent Stephens, Michael Huttenhower, Curtis McGovern, Dermot Xavier, Ramnik Stappenbeck, Thaddeus Salzman, Nita TI Paneth Cell Phenotypes Define a Subtype of Pediatric Crohn's Disease Through Alterations in Host-Microbial Interactions SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Liu, Ta-Chiang; Baldridge, Megan; Head, Richard; Stappenbeck, Thaddeus] Washington Univ, Sch Med, St Louis, MO USA. [Gurram, Bhaskar; Lam, Vy; Cao, Yumei; Simpson, Pippa; Hayward, Michael; Holtz, Mary; Noe, Joshua; Lerner, Diana; Cabrera, Jose; Stephens, Michael] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Luo, Chengwei] Broad Inst, Cambridge, MA USA. [Biank, Vincent] NorthShore Med Grp, Evanston, IL USA. [Huttenhower, Curtis] Broad Inst, Boston, MA USA. [McGovern, Dermot] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Xavier, Ramnik] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Salzman, Nita] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. NR 0 TC 1 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA O-011 BP S4 EP S4 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400012 PM 26849729 ER PT J AU Lochhead, P Khalili, H Ananthakrishnan, A Richter, J Chan, A AF Lochhead, Paul Khalili, Hamed Ananthakrishnan, Ashwin Richter, James Chan, Andrew TI Circulating C-Reactive Protein and Interleukin-6 and Risk of Inflammatory Bowel Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Lochhead, Paul; Khalili, Hamed; Ananthakrishnan, Ashwin; Richter, James; Chan, Andrew] Massachusetts Gen Hosp, Boston, MA 02114 USA. 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 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA P-014 BP S13 EP S14 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400040 ER PT J AU Peloquin, J Goel, G Huang, HL Haritunians, T Sartor, R Daly, M Newberry, R McGovern, D Lira, S Xavier, R AF Peloquin, Joanna Goel, Gautam Huang, Hailiang Haritunians, Talin Sartor, Ryan Daly, Mark Newberry, Rodney McGovern, Dermot Lira, Sergio Xavier, Ramnik TI Genes in IBD-Associated Risk Loci Demonstrate Genotype-, Tissue-, and Inflammation-Specific Patterns of Expression in Terminal Ileum and Colon Mucosal Tissue SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Peloquin, Joanna] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Goel, Gautam; Huang, Hailiang; Daly, Mark] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haritunians, Talin; McGovern, Dermot] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Sartor, Ryan] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Newberry, Rodney] Washington Univ, St Louis, MO USA. [Lira, Sergio] Mt Sinai Sch Med, New York, NY USA. [Xavier, Ramnik] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA O-002 BP S1 EP S1 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400003 PM 26849719 ER PT J AU Sarmento, O Xiong, YN Sun, ZF Svingen, P Bamidele, A Smyrk, T Nair, A Baheti, S McGovern, D Friton, J Papadakis, K Goel, G Xavier, R Urrutia, R Faubion, W AF Sarmento, Olga Xiong, Yuning Sun, Zhifu Svingen, Phyllis Bamidele, Adebowale Smyrk, Thomas Nair, Asha Baheti, Saurabh McGovern, Dermot Friton, Jessica Papadakis, Konstantinos Goel, Gautam Xavier, Ramnik Urrutia, Raul Faubion, William TI Alterations in the FOXP3-EZH2 Pathway Associates with Increased Susceptibility to Colitis in Both Mice and Human SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Sarmento, Olga; Xiong, Yuning; Sun, Zhifu; Svingen, Phyllis; Bamidele, Adebowale; Smyrk, Thomas; Nair, Asha; Baheti, Saurabh; Friton, Jessica; Papadakis, Konstantinos; Urrutia, Raul; Faubion, William] Mayo Clin, Rochester, MN USA. [McGovern, Dermot] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Goel, Gautam] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Xavier, Ramnik] Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA O-015 BP S5 EP S6 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400016 PM 26849732 ER PT J AU Subramaniam, R Low, D Lin, L Aomatsu, T Mizoguchi, A Ng, A Degrutttola, A Lee, CG Elias, J Andoh, A Mino-Kenudson, M Mizoguchi, E AF Subramaniam, Renuka Low, Daren Lin, Li Aomatsu, Tomoki Mizoguchi, Atsushi Ng, Aylwin Degrutttola, Arianna Lee, Chun Geun Elias, Jack Andoh, Akira Mino-Kenudson, Mari Mizoguchi, Emiko TI Chitinase 3-Like 1 and RAGE Interaction Induces Survival and Proliferation of Intestinal Epithelial Cells in Colitis-Associated Cancer SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 10-12, 2015 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Subramaniam, Renuka; Low, Daren; Ng, Aylwin; Degrutttola, Arianna; Mino-Kenudson, Mari; Mizoguchi, Emiko] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Subramaniam, Renuka; Low, Daren; Ng, Aylwin; Degrutttola, Arianna; Mino-Kenudson, Mari; Mizoguchi, Emiko] Harvard Med Sch, Boston, MA USA. [Lin, Li] NIA, Baltimore, MD 21224 USA. [Aomatsu, Tomoki] Shiga Univ Med Sci, Otsu, Shiga, Japan. [Mizoguchi, Atsushi] Kurume Univ, Sch Med, Kurume, Fukuoka, Japan. [Lee, Chun Geun; Elias, Jack] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. [Andoh, Akira] Shiga Univ Med Sci, Div Mucosal Immunol, Otsu, Shiga, 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 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2016 VL 22 SU 1 MA P-131 BP S49 EP S50 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4KU UT WOS:000393896400154 ER PT J AU Jenkins, RW Sullivan, RJ AF Jenkins, Russell W. Sullivan, Ryan J. TI NRAS mutant melanoma: an overview for the clinician for melanoma management SO MELANOMA MANAGEMENT LA English DT Review DE BRAF; immunotherapy; melanoma; MEK; NRAS; PD-1 ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CONGENITAL MELANOCYTIC NEVI; METASTATIC MELANOMA; BRAF MUTATIONS; RAS MUTATIONS; N-RAS; ACQUIRED-RESISTANCE; UNTREATED MELANOMA; THERAPEUTIC TARGET; CUTANEOUS MELANOMA AB Melanoma is the deadliest form of skin cancer and the incidence continues to rise in the United States and worldwide. Activating mutations in RAS oncogenes are found in roughly a third of all human cancers. Mutations in NRAS occur in approximately a fifth of cutaneous melanomas and are associated with aggressive clinical behavior. Cells harboring oncogenic NRAS mutations exhibit activation of multiple signaling cascades, including PI3K/Akt, MEK-ERK and RAL, which collectively stimulate cancer growth. While strategies to target N-Ras itself have proven ineffective, targeting one or more N-Ras effector pathways has shown promise in preclinical models. Despite promising preclinical data, current therapies for NRAS mutant melanoma remain limited. Immune checkpoint inhibitors and targeted therapies for BRAF mutant melanoma are transforming the treatment of metastatic melanoma, but the ideal treatment for NRAS mutant melanoma remains unknown. Improved understanding of NRAS mutant melanoma and relevant N-Ras effector signaling modules will be essential to develop new treatment strategies. C1 [Jenkins, Russell W.; Sullivan, Ryan J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Sullivan, RJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM rsullivan7@partners.org NR 126 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2045-0885 EI 2045-0893 J9 MELANOMA MANAG JI Melanoma Manag. PD MAR PY 2016 VL 3 IS 1 BP 47 EP 59 DI 10.2217/mmt.15.40 PG 13 WC Oncology SC Oncology GA EK0SD UT WOS:000393636500007 ER PT J AU Ceyhan-Birsoy, O Pugh, TJ Bowser, MJ Hynes, E Frisella, AL Mahanta, LM Lebo, MS Amr, SS Funke, BH AF Ceyhan-Birsoy, Ozge Pugh, Trevor J. Bowser, Mark J. Hynes, Elizabeth Frisella, Ashley L. Mahanta, Lisa M. Lebo, Matt S. Amr, Sami S. Funke, Birgit H. TI Next generation sequencing-based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Article DE Cardiomyopathies; DNA copy number variants; genetic heterogeneity; molecular diagnostics; next-generation sequencing ID HYPERTROPHIC CARDIOMYOPATHY; DILATED CARDIOMYOPATHY; DANON-DISEASE; ARRHYTHMOGENIC CARDIOMYOPATHY; MUTATIONS; VARIANTS; EVOLUTION; GENOME; DEFECT; CNVS AB Background Diagnostic testing for genetic cardiomyopathies has undergone dramatic changes in the last decade with next generation sequencing (NGS) expanding the number of genes that can be interrogated simultaneously. Exon resolution copy number analysis is increasingly incorporated into routine diagnostic testing via cytogenomic arrays and more recently via NGS. While NGS is an attractive option for laboratories that have no access to array platforms, its higher false positive rate requires weighing the added cost incurred by orthogonal confirmation against the magnitude of the increase in diagnostic yield. Although copy number variants (CNVs) have been reported in various cardiomyopathy genes, their contribution has not been systematically studied. Methods We performed single exon resolution NGS-based deletion/duplication analysis for up to 46 cardiomyopathy genes in >1400 individuals with cardiomyopathies including HCM, DCM, ARVC, RCM, and LVNC. Results and Conclusion Clinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders. C1 [Ceyhan-Birsoy, Ozge; Bowser, Mark J.; Hynes, Elizabeth; Frisella, Ashley L.; Mahanta, Lisa M.; Lebo, Matt S.; Amr, Sami S.; Funke, Birgit H.] Partners HealthCare Personalized Med, Mol Med Lab, 65 Landsdowne St, Cambridge, MA 02139 USA. [Ceyhan-Birsoy, Ozge; Lebo, Matt S.; Amr, Sami S.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Ceyhan-Birsoy, Ozge; Lebo, Matt S.; Amr, Sami S.; Funke, Birgit H.] Harvard Med Sch, Boston, MA USA. [Pugh, Trevor J.] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Biophys, Toronto, ON, Canada. [Funke, Birgit H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Funke, BH (reprint author), Partners HealthCare Personalized Med, Mol Med Lab, 65 Landsdowne St, Cambridge, MA 02139 USA. EM bfunke@partners.org OI Lebo, Matthew/0000-0002-9733-5207 FU Partners HealthCare Personalized Medicine FX This work was funded by internal operating funds of the Partners HealthCare Personalized Medicine. The Laboratory for Molecular Medicine is a nonprofit, fee-for-service laboratory offering testing for cardiomyopathy. NR 45 TC 2 Z9 2 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2324-9269 J9 MOL GENET GENOM MED JI Mol. Genet. Genom. Med. PD MAR PY 2016 VL 4 IS 2 BP 143 EP 151 DI 10.1002/mgg3.187 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EJ7OA UT WOS:000393410700004 PM 27066507 ER PT J AU Kassab, K Hariri, H Gharibeh, L Fahed, AC Zein, M El-Rassy, I Nemer, M El-Rassi, I Bitar, F Nemer, G AF Kassab, Kameel Hariri, Hadla Gharibeh, Lara Fahed, Akl C. Zein, Manal El-Rassy, Inaam Nemer, Mona El-Rassi, Issam Bitar, Fadi Nemer, Georges TI GATA5 mutation homozygosity linked to a double outlet right ventricle phenotype in a Lebanese patient SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Article DE Congenital; GATA5; heart; homozygous; recessive; transcription ID CONGENITAL HEART-DISEASE; BICUSPID AORTIC-VALVE; FAMILIAL ATRIAL-FIBRILLATION; SEQUENCE VARIANTS; TRANSCRIPTIONAL ACTIVATION; GREAT-ARTERIES; OUTFLOW TRACT; FIELD; RARE; DIFFERENTIATION AB Background GATA transcription factors are evolutionary conserved zinc finger proteins with multiple roles in cell differentiation/proliferation and organogenesis. GATA5 is only transiently expressed in the embryonic heart, and the inactivation of both Gata5 alleles results in a partially penetrant bicuspid aortic valve (BAV) phenotype in mice. We hypothesized that only biallelic mutations in GATA5 could be disease causing. Methods A total of 185 patients with different forms of congenital heart disease (CHD) were screened along 150 healthy individuals for GATA4, 5, and 6. All patients' phenotypes were diagnosed with echocardiography. Results Sequencing results revealed eight missense variants (three of which are novel) in cases with various conotruncal and septal defects. Out of these, two were inherited in recessive forms: the p.T67P variant, which was found both in patients and in healthy individuals, and the previously described p.Y142H variant which was only found in a patient with a double outlet right ventricle (DORV). We characterized the p.Y142H variant and showed that it significantly reduced the transcriptional activity of the protein over cardiac promoters by 30-40%. Conclusion Our results do prove that p.Y142H is associated with DORV and suggests including GATA5 as a potential gene to be screened in patients with this phenotype. C1 [Kassab, Kameel; Hariri, Hadla; Zein, Manal; El-Rassy, Inaam; Bitar, Fadi; Nemer, Georges] Amer Univ Beirut, Dept Biochem & Mol Genet, Bliss St,POB 11-0236, Beirut, Lebanon. [Gharibeh, Lara; Nemer, Mona] Univ Ottawa, Dept Biochem, Ottawa, ON, Canada. [Fahed, Akl C.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Fahed, Akl C.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Bitar, Fadi] Amer Univ Beirut, Dept Surg, Beirut, Lebanon. [El-Rassi, Issam] Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut, Lebanon. RP Nemer, G (reprint author), Amer Univ Beirut, Dept Biochem & Mol Genet, Bliss St,POB 11-0236, Beirut, Lebanon. EM gn08@aub.edu.lb FU Medical Practice Plan (MPP) from the Faculty of Medicine at the American University of Beirut; Universiy Research Board (URB) from the Faculty of Medicine at the American University of Beirut FX This work is supported by a grant from the Medical Practice Plan (MPP) and Universiy Research Board (URB) from the Faculty of Medicine at the American University of Beirut. NR 47 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2324-9269 J9 MOL GENET GENOM MED JI Mol. Genet. Genom. Med. PD MAR PY 2016 VL 4 IS 2 BP 160 EP 171 DI 10.1002/mgg3.190 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA EJ7OA UT WOS:000393410700006 PM 27066509 ER PT J AU Huang, W Chen, YY Fedorov, A Li, X Jajamovich, GH Malyarenko, DI Aryal, MP LaViolette, PS Oborski, MJ O'Sullivan, F Abramson, RG Jafari-Khouzani, K Afzal, A Tudorica, A Moloney, B Gupta, SN Besa, C Kalpathy-Cramer, J Mountz, JM Laymon, CM Muzi, M Kinahan, PE Schmainda, K Cao, Y Chenevert, TL Taouli, B Yankeelov, TE Fennessy, F Li, X AF Huang, Wei Chen, Yiyi Fedorov, Andriy Li, Xia Jajamovich, Guido H. Malyarenko, Dariya I. Aryal, Madhava P. LaViolette, Peter S. Oborski, Matthew J. O'Sullivan, Finbarr Abramson, Richard G. Jafari-Khouzani, Kourosh Afzal, Aneela Tudorica, Alina Moloney, Brendan Gupta, Sandeep N. Besa, Cecilia Kalpathy-Cramer, Jayashree Mountz, James M. Laymon, Charles M. Muzi, Mark Kinahan, Paul E. Schmainda, Kathleen Cao, Yue Chenevert, Thomas L. Taouli, Bachir Yankeelov, Thomas E. Fennessy, Fiona Li, Xin TI The Impact of Arterial Input Function Determination Variations on Prostate Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacokinetic Modeling: A Multicenter Data Analysis Challenge SO TOMOGRAPHY LA English DT Article DE DCE-MRI; Arterial Input Function; Prostate Cancer; Variation; Pharmacokinetic Analysis ID INDEPENDENT COMPONENT ANALYSIS; DCE-MRI PARAMETERS; BREAST-CANCER; REFERENCE TISSUES; REPRODUCIBILITY; FEASIBILITY; SIMULATIONS; EXTRACTION; BENIGN; TRACER AB Pharmacokinetic analysis of dynamic contrast-enhanced (DCE) MRI data allows estimation of quantitative imaging biomarkers such as K-trans (rate constant for plasma/interstitium contrast reagent (CR) transfer) and v(e) (extravascular and extracellular volume fraction). However, the use of quantitative DCE-MRI in clinical practice is limited with uncertainty in arterial input function (AIF) determination being one of the primary reasons. In this multicenter study to assess the effects of AIF variations on pharmacokinetic parameter estimation, DCE-MRI data acquired at one center from 11 prostate cancer patients were shared among nine centers. Individual AIF from each data set was determined by each center and submitted to the managing center. These AIFs, along with a literature population averaged AIF, and their reference-tissue-adjusted variants were used by the managing center to perform pharmacokinetic data analysis using the Tofts model (TM). All other variables, including tumor region of interest (ROI) definition and pre-contrast T1, were kept constant to evaluate parameter variations caused solely by AIF discrepancies. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) of K-trans obtained with unadjusted AIFs being as high as 0.74. AIF-caused variations were larger in K-trans than v(e) and both were reduced when reference-tissue-adjusted AIFs were used. These variations were largely systematic, resulting in nearly unchanged parametric map patterns. The intravasation rate constant, k(ep) (similar to K-trans/v(e)), was less sensitive to AIF variation than K-trans (wCV for unadjusted AIFs: 0.45 vs. 0.74), suggesting that it might be a more robust imaging biomarker of prostate microvasculature than K-trans. C1 [Huang, Wei; Chen, Yiyi; Afzal, Aneela; Tudorica, Alina; Moloney, Brendan; Li, Xin] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Fedorov, Andriy; Fennessy, Fiona] Brigham & Womens Hosp, Boston, MA USA. [Fedorov, Andriy; Jafari-Khouzani, Kourosh; Kalpathy-Cramer, Jayashree; Fennessy, Fiona] Harvard Med Sch, Boston, MA USA. [Li, Xia; Gupta, Sandeep N.] Gen Elect Global Res, New York, NY USA. [Jajamovich, Guido H.; Besa, Cecilia; Taouli, Bachir] Icahn Sch Med Mt Sinai, New York, NY USA. [Malyarenko, Dariya I.; Aryal, Madhava P.; Cao, Yue; Chenevert, Thomas L.] Univ Michigan, Ann Arbor, MI USA. [LaViolette, Peter S.; Schmainda, Kathleen] Med Coll Wisconsin, Milwaukee, WI USA. [Mountz, James M.; Laymon, Charles M.] Univ Pittsburgh, Pittsburgh, PA USA. [O'Sullivan, Finbarr] Univ Coll, Cork, Ireland. [Abramson, Richard G.; Yankeelov, Thomas E.] Vanderbilt Univ, Nashville, TN USA. [Jafari-Khouzani, Kourosh; Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kinahan, Paul E.] Univ Washington, Seattle, WA USA. RP Huang, W; Li, X (reprint author), Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. EM huangwe@ohsu.edu; lxin@ohsu.edu OI Li, Xin/0000-0002-7414-5734 FU National Institutes of Health [U01-CA154602, U01-CA151261, U01-CA183848, U01-CA154601, U01-CA148131, U01-CA176110, U01-CA172320, U01-CA142565, U01-CA166104, U01-CA140230] FX This study was supported by National Institutes of Health grants U01-CA154602, U01-CA151261, U01-CA183848, U01-CA154601, U01-CA148131, U01-CA176110, U01-CA172320, U01-CA142565, U01-CA166104, and U01-CA140230. Other than OHSU (which was the managing center) and BWH (which provided the shared prostate DCE-MRI data), all other participating QIN centers contributed equally to this study. NR 39 TC 4 Z9 4 U1 0 U2 0 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD MAR PY 2016 VL 2 IS 1 BP 56 EP 66 DI 10.18383/j.tom.2015.00184 PG 11 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4AC UT WOS:000393868500008 PM 27200418 ER PT J AU Brierley, CK Steensma, DP AF Brierley, Charlotte K. Steensma, David P. TI Allogeneic stem cell transplantation in myelodysplastic syndromes: does pretransplant clonal burden matter? SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE allogeneic transplantation; azacitidine; clonal burden; decitabine; myelodysplastic syndromes; somatic mutations ID PROGNOSTIC SCORING SYSTEM; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; MONOSOMAL KARYOTYPE; HYPOMETHYLATING AGENTS; HIGH-RISK; DE-NOVO; INDUCTION CHEMOTHERAPY; IDENTICAL SIBLINGS; SOMATIC MUTATIONS AB Purpose of reviewCurrently, the only potential curative therapy for myelodysplastic syndromes (MDS) is allogeneic hematopoietic stem cell transplantation (alloSCT). As alloSCT confers both a short-term mortality risk compared with conservative management, and a longer-term risk of chronic health burden from graft-versus-host disease and other complications, careful patient selection for alloSCT is essential. Here, we review data on disease burden and transplant outcomes in MDS, describing which patients stand to benefit most (and least) from alloSCT. Evidence for timing of alloSCT and modifying tumor burden prior to transplant is also discussed.Recent findingsAlthough patients who undergo alloSCT with excess blasts have poorer outcomes than those transplanted with fewer blasts, the effect of clone size in patients with MDS without increased blast proportion is poorly studied, and it is also not yet known whether posttransplant outcomes can be modified with pretransplant therapy such as intensive induction chemotherapy or hypomethylating agent treatment. Randomized data are lacking. Most hematopoietic cells in patients with MDS are clonal, even in cases without increased marrow blast proportion. Certain high-risk point mutations such as TP53 seem to be associated with a worse outcome even when subclonal.SummaryPatients with more than 10% blasts should be considered for cytoreductive therapy before transplant, especially if reduced intensity conditioning (alloSCT) is planned. Patients with less than 10% blasts who are appropriate candidates for transplant can proceed straight to transplant, though it appears better to delay transplant for those with lower-risk disease. Hypomethylating agent therapy may be useful as a bridge to transplant. Randomized data are eagerly awaited. C1 [Brierley, Charlotte K.] Oxford Univ Hosp NHS Trust, Dept Haematol, Oxford, England. [Steensma, David P.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Steensma, DP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Adult Leukemia Program,Dept Med Oncol, 450 Brookline Ave,Dana 2037, Boston, MA 02215 USA. EM david_steensma@dfci.harvard.edu NR 59 TC 3 Z9 3 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD MAR PY 2016 VL 23 IS 2 BP 167 EP 174 DI 10.1097/MOH.0000000000000217 PG 8 WC Hematology SC Hematology GA DD0YP UT WOS:000369647900013 PM 26717194 ER PT J AU Lundquist, AL Nigwekar, SU AF Lundquist, Andrew L. Nigwekar, Sagar U. TI Optimal management of bone mineral disorders in chronic kidney disease and end stage renal disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE chronic kidney disease-mineral bone disorder; fibroblast growth factor 23; secondary hyperparathyroidism ID FIBROBLAST GROWTH FACTOR-23; VITAMIN-D ANALOGS; RANDOMIZED CONTROLLED-TRIAL; CINACALCET HCL THERAPY; EVENTS EVOLVE TRIAL; D-BINDING PROTEIN; SECONDARY HYPERPARATHYROIDISM; HEMODIALYSIS-PATIENTS; CLINICAL-OUTCOMES; ENDOTHELIAL FUNCTION AB Purpose of reviewThe review summarizes recent studies on chronic kidney disease-mineral bone disorders, with a focus on new developments in disease management.Recent findingsThe term chronic kidney disease-mineral bone disorder has come to describe an increasingly complex network of alterations in minerals and skeletal disorders that contribute to the significant cardiovascular morbidity and mortality seen in patients with chronic kidney disease and end stage renal disease. Clinical studies continue to suggest associations with clinical outcomes, yet current clinical trials have failed to support causality. Variability in practice exists as current guidelines for management of mineral bone disorders are often based on weak evidence. Recent studies implicate novel pathways for therapeutic intervention in clinical trials.SummaryMineral bone disorders in chronic kidney disease arise from alterations in a number of molecules in an increasingly complex physiological network interconnecting bone and the cardiovascular system. Despite extensive associations with improved outcomes in a number of molecules, clinical trials have yet to prove causality and there is an absence of new therapies available to improve patient outcomes. Additional clinical trials that can incorporate the complexity of mineral bone disorders, and with the ability to intervene on more than one pathway, are needed to advance patient care. C1 [Lundquist, Andrew L.; Nigwekar, Sagar U.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lundquist, AL (reprint author), 165 Cambridge St,Suite 302, Boston, MA 02114 USA. EM alundquist@mgh.harvard.edu FU American Heart Association's NCRP Winter Fellow-to-Faculty Transition Award [15FTF25980003]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institutes of Health); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [KL2 TR001100] FX S.U.N. has received funding support from the American Heart Association's NCRP Winter 2015 Fellow-to-Faculty Transition Award (15FTF25980003) and from the KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100). 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 49 TC 0 Z9 0 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAR PY 2016 VL 25 IS 2 BP 120 EP 126 DI 10.1097/MNH.0000000000000203 PG 7 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA DD1HL UT WOS:000369671800009 PM 26785065 ER PT J AU Sullivan, RJ AF Sullivan, Ryan J. TI The role of mitogen-activated protein targeting in melanoma beyond BRAF(V600) SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE ERK inhibitors; MEK inhibitors; NF1; NRAS; The Cancer Genome Atlas ID CYSTEINE-RICH DOMAIN; INHIBITOR AZD6244 ARRY-142886; RANDOMIZED CONTROLLED-TRIAL; METASTATIC UVEAL MELANOMA; BRAF-MUTATED MELANOMA; PHASE-III TRIAL; KINASE INHIBITOR; MEK INHIBITION; OPEN-LABEL; CONCURRENT BIOCHEMOTHERAPY AB Purpose of reviewTargeted therapy in melanoma is well established for patients with tumors harboring BRAF(V600) mutations, but less so for other molecularly defined subsets. In this review, emerging preclinical, genomic, and early clinical data are discussed regarding the use of mitogen-activated protein (MAPK) pathway inhibitors in other molecular subsets of melanoma.Recent findingsThere are now four well defined subsets of melanoma based on The Cancer Genome Atlas: BRAF driven, NRAS driven, NF1 mutant, and triple wild type'. The former three subtypes predict signaling through the MAPK pathway and sensitivity to inhibitors of this pathway's mediators. With ongoing translation of preclinical findings into clinical trials, there is great hope that these strategies will improve the care of patients who fall into these other molecular subsets.SummaryA more comprehensive understanding of genetically defined subtypes of melanoma is emerging. Efforts in the clinic are already underway, but additional, well designed trials of MAPK-targeted therapy planned and needed. C1 [Sullivan, Ryan J.] Massachusetts Gen Hosp, Ctr Canc, Ctr Melanoma, Boston, MA 02114 USA. RP Sullivan, RJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM rsullivan7@mgh.harvard.edu NR 72 TC 2 Z9 2 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAR PY 2016 VL 28 IS 2 BP 185 EP 191 DI 10.1097/CCO.0000000000000271 PG 7 WC Oncology SC Oncology GA DC9JV UT WOS:000369538700014 PM 26844986 ER PT J AU Pasquale, LR AF Pasquale, Louis R. TI Vascular and autonomic dysregulation in primary open-angle glaucoma SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Review DE autonomic dysfunction; high-tension glaucoma; normal-tension glaucoma; primary open-angle glaucoma; vascular dysfunction ID NORMAL-TENSION GLAUCOMA; NITRIC-OXIDE SYNTHASE; VISUAL-FIELD CHARACTERISTICS; ENDOTHELIN-1 PLASMA-LEVELS; NORMAL-PRESSURE GLAUCOMA; HEART-RATE-VARIABILITY; OCULAR BLOOD-FLOW; INTRAOCULAR-PRESSURE; FAMILIAL DYSAUTONOMIA; HEALTHY-SUBJECTS AB Purpose of reviewThe purpose of this review is to discuss whether vascular dysfunction and autonomic dysfunction are related to primary open-angle glaucoma stratified by the intraocular pressure (IOP) level.Recent findingsPatients with primary open angle glaucoma (POAG) across the spectrum of IOP exhibit a variety of ocular and nonocular vascular abnormalities. Interestingly, common genetic variation in nitric oxide synthase 3 (NOS3) and the caveolin 1/caveolin 2 (CAV1/CAV2) genomic regions, which code for proteins involved in setting vascular tone, are associated with POAG. These markers seem to stratify with POAG subtypes stratified by sex or pattern of initial visual field loss and not by IOP level. Overall, it is clear that there is also cardiovascular autonomic dysfunction in high-tension glaucoma and normal-tension glaucoma but it is unclear if this dysfunction is more common in normal-tension glaucoma compared with high-tension glaucoma.SummaryOverall, POAG is likely a heterogeneous disease but stratifying cases by IOP level associated with initial optic nerve damage may be less useful than using other endophenotype approaches. Embracing the evidence suggesting systemic endothelial and autonomic dysfunction are operative in POAG will help us move beyond an IOP-centric view of the disease and facilitate tearing down the wall' that divides treating physicians and a better understanding of POAG pathogenesis. C1 [Pasquale, Louis R.] Brigham & Womens Hosp, Mass Eye & Ear Infirm, 75 Francis St, Boston, MA 02115 USA. [Pasquale, Louis R.] Brigham & Womens Hosp, Div Network Med, 75 Francis St, Boston, MA 02115 USA. RP Pasquale, LR (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Louis_Pasquale@meei.harvard.edu FU NEI [R01 EY015473, R21 EY020987, R01 EY022746-01]; NHGRI [HG 004728]; Harvard Glaucoma Center of Excellence; Harvard Medical School Distinguished Scholar Award; NIH/NEI [R01EY022305]; National Eye Institute [HG005259-01]; National Institutes of Health [HHSN268200782096C]; National Eye Institute through ARRA [3R01EY015872-05S1, 3R01EY019126-02S1]; NIH [EY015543, EY006827, HL73042, HL073389, EY13315, CA87969, CA49449, UM1 CA186107, UM1 CA 167552, EY009149, HG004608, EY008208, EY015473, EY012118, EY015682, EY011671, EY09580, EY013178, RR015574, EY015872, EY010886, EY009847, EY011008, EY144428, EY144448, EY18660, EY09611, CA055075]; Harvard Catalyst-the Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]; Harvard University; Glaucoma Research Foundation; American Heart Association [11FTF7290032]; NCRR [1S10RR022586]; Massachusetts Lions Eye Research Fund; FWO-Flanders; UGent-GOA funds; [HG004728]; [U01-HG004424]; [U01 HG004446] FX NEI R01 EY015473, NHGRI HG 004728, the Harvard Glaucoma Center of Excellence and a Harvard Medical School Distinguished Scholar Award provide overall support for this work.; The discovery of the role caveolin and sGC genes play in POAG was supported by a large collaborative effort between several institutions enrolled in the NEIGHBOR (National Eye Institute Glaucoma Human Genetics Collaboration). The NEIGHBOR data collection and analysis is supported by NIH/NEI R01EY022305 (Janey L. Wiggs). Support for collection of cases, controls and analysis for individual datasets is as follows. Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through grant HG005259-01 (J. L. Wiggs). Additionally, CIDR is funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268200782096C. Genotyping for the Mass Eye and Ear dataset and some Nurses Health Study and Health Professionals Follow-up Study cases was completed at the Broad Institute and supported by project grant HG004728 (L. R. Pasquale) and U01-HG004424 (Broad Institute). Genotype data cleaning and analysis for the GLAUGEN study was supported by U01 HG004446 (Cathy Laurie). Collecting and processing samples for the NEIGHBOR dataset was supported by the National Eye Institute through ARRA grants 3R01EY015872-05S1 (J. L. Wiggs) and 3R01EY019126-02S1 (Michael A. Hauser). Funding for the collection of NEIGHBOR cases and controls was provided by NIH grants: EY015543 (R. R. Allingham), EY006827 (Douglas Gaasterland); HL73042, HL073389, EY13315 (M. A. Hauser); CA87969, CA49449, UM1 CA186107, UM1 CA 167552, EY009149 (Paul R. Lichter), HG004608 (Cathy McCarty), EY008208 (Felipe A. Medeiros), EY015473 (L. R. Pasquale), EY012118 (M. Pericak-Vance), EY015682 (Anthony Realini), EY011671 (Julia E. Richards), EY09580 (J. E. Richards), EY013178 (Joel S. Schuman), RR015574, EY015872 (J. L. Wiggs), EY010886 (J. L. Wiggs), EY009847 (J. L. Wiggs), EY011008, EY144428 (Khang Zhang), EY144448 (K. Zhang), EY18660 (K. Zhang).; The discovery that sGC knockout mice have a phenotype resembling POAG with vascular dysfunction was also supported by several grants including a Harvard Catalyst-the Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758) with financial contributions from Harvard University and its affiliated academic healthcare centers (Emmanuel S. Buys and Bruce R. Ksander). A Shaffer Fund Grant from the Glaucoma Research Foundation (E. S. Busy), NEI R21 EY020987 (E. S. Buys, B. R. Ksander), NEI R01 EY022746-01 (E. S. Buys), an American Heart Association Fellow-to-Faculty Transition Award #11FTF7290032 (Rajeev Malhotra), NCRR 1S10RR022586 (Marielle Scherrer-Crosbie), NIH CA87969, CA49449, EY09611, CA055075 (all to Jae Hee Kang), the Massachusetts Lions Eye Research Fund (H. G., R. R.); and the FWO-Flanders and UGent-GOA funds (Peter Brouckaert) also supported this effort. NR 74 TC 4 Z9 4 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD MAR PY 2016 VL 27 IS 2 BP 94 EP 101 DI 10.1097/ICU.0000000000000245 PG 8 WC Ophthalmology SC Ophthalmology GA DD1CU UT WOS:000369659600002 PM 26720776 ER PT J AU Bober, SL Reese, JB Barbera, L Bradford, A Carpenter, KM Goldfarb, S Carter, J AF Bober, Sharon L. Reese, Jennifer B. Barbera, Lisa Bradford, Andrea Carpenter, Kristen M. Goldfarb, Shari Carter, Jeanne TI How to ask and what to do: a guide for clinical inquiry and intervention regarding female sexual health after cancer SO CURRENT OPINION IN SUPPORTIVE AND PALLIATIVE CARE LA English DT Review DE cancer; provider communication; sexual health ID STEM-CELL TRANSPLANTATION; VERSUS-HOST-DISEASE; IMMEDIATE BREAST RECONSTRUCTION; HELP-SEEKING BEHAVIOR; POSTMENOPAUSAL WOMEN; UNITED-STATES; INDEX FSFI; CARE; DYSFUNCTION; MANAGEMENT AB Purpose of reviewAs the number of female cancer survivors continues to grow, there is a growing need to bridge the gap between the high rate of women's cancer-related sexual dysfunction and the lack of attention and intervention available to the majority of survivors who suffer from sexual problems. Previously identified barriers that hinder communication for providers include limited time, lack of preparation, and a lack of patient resources and access to appropriate referral sources.Recent findingsThis study brings together a recently developed model for approaching clinical inquiry about sexual health with a brief problem checklist that has been adapted for use for female cancer survivors, as well as practical evidence-based strategies on how to address concerns identified on the checklist. Examples of patient education sheets are provided as well as strategies for building a referral network.SummaryBy providing access to a concise and efficient tool for clinical inquiry, as well as targeted material resources and practical health-promoting strategies based on recent evidence-based findings, we hope to begin eliminating the barriers that hamper oncology providers from addressing the topic of sexual/vaginal health after cancer. C1 [Bober, Sharon L.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Bober, Sharon L.] Harvard Univ, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA. [Reese, Jennifer B.] Fox Chase Canc Ctr, Canc Prevent & Control Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Reese, Jennifer B.] Temple Univ, Coll Publ Hlth, Dept Social & Behav Sci, Philadelphia, PA 19122 USA. [Barbera, Lisa] Univ Toronto, Dept Radiat Oncol, Toronto, ON M5S 1A1, Canada. [Barbera, Lisa] Odette Canc Ctr, Toronto, ON, Canada. [Bradford, Andrea] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX USA. [Carpenter, Kristen M.] Ohio State Univ, Columbus, OH 43210 USA. [Goldfarb, Shari] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Goldfarb, Shari] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Goldfarb, Shari] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Carter, Jeanne] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. [Carter, Jeanne] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10021 USA. [Carter, Jeanne] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. RP Bober, SL (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Bober, SL (reprint author), Harvard Univ, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA. EM sharon_bober@dfci.harvard.edu FU NCI NIH HHS [P30 CA008748] NR 68 TC 0 Z9 0 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1751-4258 EI 1751-4266 J9 CURR OPIN SUPPORT PA JI Curr. Opin Support Palliat. Car. PD MAR PY 2016 VL 10 IS 1 BP 44 EP 54 DI 10.1097/SPC.0000000000000186 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DC7UT UT WOS:000369426700010 PM 26716390 ER PT J AU Agarwal, S Grajo, JR Fuentes-Orrego, JM Abtahi, SM Harisinghani, MG Saini, S Hahn, PF AF Agarwal, Sheela Grajo, Joseph R. Fuentes-Orrego, Jorge M. Abtahi, Seyed Mahdi Harisinghani, Mukesh G. Saini, Sanjay Hahn, Peter F. TI Distinguishing hemangiomas from metastases on liver MRI performed with gadoxetate disodium: Value of the extended washout sign SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Hepatobiliary; Gadoxetate disodium; Hemangioma; Metastasis ID HEPATIC HEMANGIOMA; ENHANCED MRI; PHASE; CT AB Objective: To describe the enhancement pattern of hemangiomas with gadoxetate disodium and propose a new sign - the "extended washout sign" - to diagnose hemangiomas on hepatobiliary MR imaging. Materials and methods: In this retrospective IRB approved study, quantitative and qualitative image analysis of 45 hemangiomas and 37 metastases in 77 patients was performed. Gadoxetate disodiumenhanced MR imaging was obtained during arterial and portal venous phases as well as with delays of 3, 8, and 20 min. Lesion signal intensity was measured at each phase. Quantitatively, extended washout was defined as a 10% or greater decrease in signal intensity from 8 to 20 min on 3D gradient echo images. Statistical analysis was performed using unpaired Student's t-test. Qualitative analysis was also performed to assess observer confidence based on T2-weighted images, dynamic images, and combined early (8 min) and late (20 min) hepatobiliary phases. Extended washout was defined as a perceptible change in signal from 8 to 20 min. Results: On quantitative analysis, 84% of hemangiomas demonstrated a positive extended washout sign while only 18% of metastases did. Qualitatively, 78% of hemangiomas demonstrated a perceptible change in signal from 8 to 20 min, while only 5.4% of metastases did. When extended washout was used in combination with T2 hyperintensity, specificity increased to 100%, with a sensitivity of 87% and area under the curve of 0.99. Conclusions: When combined with T2 signal intensity, the extended washout sign can be used to increase accuracy of differentiating hemangiomas from metastases on gadoxetate disodium-enhanced MRI. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Agarwal, Sheela; Grajo, Joseph R.; Fuentes-Orrego, Jorge M.; Abtahi, Seyed Mahdi; Harisinghani, Mukesh G.; Saini, Sanjay; Hahn, Peter F.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA 02114 USA. [Grajo, Joseph R.] Univ Florida, Coll Med, Dept Radiol, 1600 SW Archer Rd,POB 100374, Gainesville, FL 32610 USA. [Fuentes-Orrego, Jorge M.] Sanatorio Nuestra Senora del Pilar, 3a Calle 10-71 Zona 15, Guatemala City, Guatemala. [Abtahi, Seyed Mahdi] Metro West Med Ctr, 115 Lincoln St, Framingham, MA USA. RP Grajo, JR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA 02114 USA.; Grajo, JR (reprint author), Univ Florida, Coll Med, Dept Radiol, 1600 SW Archer Rd,POB 100374, Gainesville, FL 32610 USA. EM joegrajo@gmail.com; jorge.fuentesmd@gmail.com; arash.abtahi1@gmail.com OI Fuentes-Orrego, Jorge/0000-0002-9254-0746 NR 15 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD MAR PY 2016 VL 85 IS 3 BP 635 EP 640 DI 10.1016/j.ejrad.2015.12.028 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DD0MM UT WOS:000369614100018 PM 26860678 ER PT J AU Qu, JR Qin, L Cheng, SC Leung, K Li, X Li, HL Dai, JP Jiang, T Akgoz, A Seethamraju, R Wang, QF Rahman, R Li, SW Ai, L Jiang, TZ Young, GS AF Qu, Jinrong Qin, Lei Cheng, Suchun Leung, Katherine Li, Xiang Li, Hailiang Dai, Jianping Jiang, Tao Akgoz, Ayca Seethamraju, Ravi Wang, Qifeng Rahman, Rifaquat Li, Shaowu Ai, Lin Jiang, Tianzi Young, Geoffrey S. TI Residual low ADC and high FA at the resection margin correlate with poor chemoradiation response and overall survival in high-grade glioma patients SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Magnetic resonance imaging; Apparent diffusion coefficient; Fractional anisotropy; High grade glioma; Survival analysis ID NEWLY-DIAGNOSED GLIOBLASTOMA; DIFFUSION TENSOR MRI; FRACTIONAL ANISOTROPY; BRAIN-TUMORS; RECURRENT GLIOBLASTOMA; APPARENT DIFFUSION; CELL-DENSITY; CHEMOTHERAPY; BEVACIZUMAB; PROGRESSION AB Purpose: We hypothesized that ADC and FA of enhancing tumor (ET) and/or non -enhancing tumor (NT) adjacent to the operative resection margin before and during temozolomide and/or chemoradiation may allow prediction of chemoradiation response and patient survival. Material and methods: DTI was acquired in 37 patients with newly diagnosed HGG at two time points: after resection at the time of pre-RT planning MRI (Baseline) and after 30 Gy of radiation therapy (midRT). ADC and FA at each time point and change in ADC and FA between the two time points were assessed by hot spot method in both residual ET and NT within 2 cm of the resection margin and correlated with overall survival (OS) using receiver operating characteristics (ROC) area under curve (AUC) analysis and log-rank testing. Results: At baseline NT ADC < 104 x 10(-5) mm(2)/s was strongly correlated with shorter 15 month OS (95% CI: 227-412 days vs 492-695 days) compared to patients with higher ADC (AUC 0.82). There was good separation between the groups and significance at log-rank testing (p=0.0002). Baseline NT FA > 0.257 also correlated with shorter OS (95% CI: 300-515 days vs 438-686 days), compared with patients with lower FA (AUC 0.74), but there was considerable overlap between the groups and non -significance at log rank testing (p = 0.089). Residual ET ADC increased significantly (p = 0.0004) and FA decreased significantly (p = 0.03) for all patients during early RT but the change in ADC and FA was less strongly correlated with OS than baseline NT metrics. Conclusion: Post-operative pre-radiation baseline low ADC in non-enhancing tumor at the resection margin correlates strongly with worse treatment response and decreased overall survival in a heterogeneous sample of high grade glioma patients treated with radiation and/or temozolamide chemoradiation. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Qu, Jinrong; Li, Xiang; Li, Hailiang] Zhengzhou Univ, Henan Canc Hosp, Affiliated Canc Hosp, Dept Radiol, Zhengzhou 450052, Peoples R China. [Qin, Lei; Young, Geoffrey S.] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Cheng, Suchun] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Leung, Katherine; Li, Xiang; Akgoz, Ayca; Rahman, Rifaquat; Young, Geoffrey S.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Dai, Jianping; Jiang, Tao; Li, Shaowu; Ai, Lin] Capital Med Univ, Beijing Tiantan Hosp, Dept Neuroradiol DJP, LSW,LA, Beijing, Peoples R China. [Dai, Jianping; Jiang, Tao; Li, Shaowu; Ai, Lin] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg TJ, Beijing, Peoples R China. [Seethamraju, Ravi] Siemens Med Solut Inc, MR R&D, Boston, MA USA. [Wang, Qifeng; Jiang, Tianzi] Chinese Acad Sci, Dept Automat, Beijing, Peoples R China. [Qin, Lei; Young, Geoffrey S.] Harvard Univ, Sch Med, Boston, MA USA. RP Qu, JR (reprint author), Zhengzhou Univ, Henan Canc Hosp, Affiliated Canc Hosp, Dept Radiol, Zhengzhou 450052, Peoples R China.; Young, GS (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM qjryq@126.com; gsyoung@partners.org OI Leung, Katherine/0000-0003-3705-1082 FU National Key Project of Science and Technology Supporting Programs of China [2007BAI05B08]; National Natural Science Foundation of China [30770617, 30730035]; International Cooperation Project of Henan Science and Technology Supporting Programs of China [114300510016]; Special funding of the Henan Health Science and Technology Innovation Talent Project [201004057] FX This study was supported by the National Key Project of Science and Technology Supporting Programs of China (No. 2007BAI05B08) and the National Natural Science Foundation of China (No. 30770617, 30730035), the International Cooperation Project of Henan Science and Technology Supporting Programs of China (No. 114300510016), and Special funding of the Henan Health Science and Technology Innovation Talent Project (No. 201004057). NR 28 TC 2 Z9 3 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD MAR PY 2016 VL 85 IS 3 BP 657 EP 664 DI 10.1016/j.ejrad.2015.12.026 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DD0MM UT WOS:000369614100021 PM 26860681 ER PT J AU Bertuccelli, G Zerbinati, N Marcellino, M Kumar, NSN He, F Tsepakolenko, V Cervi, J Lorenzetti, A Marotta, F AF Bertuccelli, Giuseppe Zerbinati, Nicola Marcellino, Massimiliano Kumar, Navalpur Shanmugam Nanda He, Fang Tsepakolenko, Vladimir Cervi, Joseph Lorenzetti, Aldo Marotta, Francesco TI Effect of a quality-controlled fermented nutraceutical on skin aging markers: An antioxidant-control, double-blind study SO EXPERIMENTAL AND THERAPEUTIC MEDICINE LA English DT Article DE fermented papaya preparation; skin aging; photoaging; gene expression; skin elasticity; skin moisturization; antioxidant defence ID PAPAYA PREPARATION; PARKINSONS-DISEASE; OXIDATIVE DAMAGE; DOWN-REGULATION; PROLIFERATION; MECHANISM; STRESS; CD147; SUPPLEMENTATION; INFLAMMATION AB The aim of the present study was to determine whether oral supplementation with a fermented papaya preparation (FPP-treated group) or an antioxidant cocktail (antioxidant-control group, composed of 10 mg trans-resveratrol, 60 mu g selenium, 10 mg vitamin E and 50 mg vitamin C) was able to improve the skin antioxidant capacity and the expression of key skin genes, while promoting skin antiaging effects. The study enrolled 60 healthy non-smoker males and females aged 40-65 years, all of whom showed clinical signs of skin aging. The subjects were randomly divided into two matched groups, and were administered FPP or antioxidant treatment of a 4.5 g/day sachet sublingually twice a day for 90 days in a double-blind fashion. The parameters investigated were: Skin surface, brown spots, skin evenness, skin moisturization, elasticity (face), redox balance, nitric oxide (NO) concentration, and the expression levels of key genes (outer forearm sample). As compared with the baseline (day 0) and antioxidant-control values, FPP-treated subjects showed a significant improvement in skin evenness, moisturization and elasticity. The two treatments improved the MDA and SOD skin concentrations, but only the FPP-treated group showed a higher SOD level and a significant NO increase, along with significant upregulation of acquaporin-3 and downregulation of the potentially pro-aging/carcinogenetic cyclophilin-A and CD147 genes (P<0.05). Progerin was unaffected in both treatment groups. In conclusion, these findings suggest that orally-administered FPP showed a consistent biological and gene-regulatory improvement in the skin, as was also demonstrated in previous experimental and clinical trials testing other tissues, while common oral antioxidants had only a minor effect. C1 [Bertuccelli, Giuseppe; Marcellino, Massimiliano; Cervi, Joseph; Lorenzetti, Aldo; Marotta, Francesco] ReGenera Res Grp Aging Intervent, 12 Piazza Firenze, I-20154 Milan, Italy. [Zerbinati, Nicola] CMP Med Ctr & Labs, Dermatol Unit, I-27100 Pavia, Italy. [Kumar, Navalpur Shanmugam Nanda] Massachusetts Gen Hosp, Dept Pediat, Mucosal Immunol & Biol Res Ctr, Boston, MA 02114 USA. [Kumar, Navalpur Shanmugam Nanda] Harvard Univ, Sch Med, Boston, MA 02114 USA. [He, Fang] Sichuan Univ, West China Sch Publ Hlth, Dept Nutr & Food Hyg, Chengdu 610065, Sichuan, Peoples R China. [Tsepakolenko, Vladimir] Ukraine Inst Plast Surg & Dermatol, Virtus Med Ctr, UA-68355 Odessa, Ukraine. RP Marotta, F (reprint author), ReGenera Res Grp Aging Intervent, 12 Piazza Firenze, I-20154 Milan, Italy. EM fmarchimede@libero.it NR 55 TC 0 Z9 0 U1 5 U2 13 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-0981 EI 1792-1015 J9 EXP THER MED JI Exp. Ther. Med. PD MAR PY 2016 VL 11 IS 3 BP 909 EP 916 DI 10.3892/etm.2016.3011 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DC9PV UT WOS:000369554400031 ER PT J AU O'Farrell, TJ Schreiner, A Schumm, J Murphy, M AF O'Farrell, Timothy J. Schreiner, Amy Schumm, Jeremiah Murphy, Marie TI Do outcomes after behavioral couples therapy differ based on the gender of the alcohol use disorder patient? SO ADDICTIVE BEHAVIORS LA English DT Article DE Alcohol use disorder; Couples therapy; Gender differences; Treatment outcome ID RANDOMIZED CLINICAL-TRIAL; SUBSTANCE-ABUSE TREATMENT; PARTNER VIOLENCE; WOMEN; INVOLVEMENT; DEPENDENCE; ABSTINENCE AB Objective: This naturalistic study (conducted from 1992 to 1998) of behavioral couples therapy (BCT) compared female and male alcohol use disorder (AUD) patients on improvement and on drinking and relationship outcomes after BCT. We also evaluated gender differences on presenting clinical problems and extent of BCT participation. Method: Participants were 103 female and 303 male AUD patients (98.5% alcohol dependence, 1.5% alcohol abuse) and their heterosexual partners, mostly White in their forties. Couples received 20-22 BCT sessions over 5-6 months. Drinking outcomes were percentage days abstinent (PDA) and alcohol-related problems. Relationship outcome was Dyadic Adjustment Scale. Outcome data were examined at baseline, post-treatment, and 6- and 12-month follow-up. Presenting problems were demographics, alcohol problem severity, illicit drug use, emotional distress, and relationship adjustment. BCT participation was BCT attendance and BCT-targeted behaviors. Results: We found few differences between female and male patients, who did not differ on improvement and outcomes after BCT. Both females and males showed significant large effect size improvements through 12-month follow-up on PDA and alcohol-related problems, and significant small to medium effect size improvements on relationship adjustment. Both females and males had high levels of BCT participation. Gender differences in presenting clinical problems (females being lower on age, years problem drinking, and baseline PDA, and higher on emotional distress) did not translate into gender differences in response to BCT. Conclusion: Results showed no support for the suggestion that BCT might lead to greater improvement and better outcomes for female than male AUD patients on drinking or on relationship outcomes. (C) 2015 Elsevier Ltd. All rights reserved. C1 [O'Farrell, Timothy J.; Schreiner, Amy; Murphy, Marie] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02401 USA. [Schumm, Jeremiah] Univ Cincinnati, Cincinnati VA Med Ctr, Cincinnati, OH USA. RP O'Farrell, TJ (reprint author), Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, VAMC 116B1,940 Belmont St, Brockton, MA 02301 USA. EM timothy_ofarrell@hms.harvard.edu FU National Institute on Alcohol Abuse and Alcoholism [R01AA08637, R01AA10356, K02AA0234]; U.S. Department of Veterans Affairs FX Funding for this study was provided by grants to the first author from the National Institute on Alcohol Abuse and Alcoholism (grants R01AA08637, R01AA10356, K02AA0234), and by the U.S. Department of Veterans Affairs. NIAAA and the VA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 29 TC 0 Z9 0 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD MAR PY 2016 VL 54 BP 46 EP 51 DI 10.1016/j.addbeh.2015.12.005 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DC1CJ UT WOS:000368954100008 PM 26709856 ER PT J AU Khan, SI Blumrosen, G Vecchio, D Golberg, A McCormack, MC Yarmush, ML Hamblin, MR Austen, WG AF Khan, Saiqa I. Blumrosen, Gaddi Vecchio, Daniela Golberg, Alexander McCormack, Michael C. Yarmush, Martin L. Hamblin, Michael R. Austen, William G., Jr. TI Eradication of multidrug-resistant pseudomonas biofilm with pulsed electric fields SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE biofilm; treatment of mesh infection; pulsed electric fields; medical device disinfection; eradication of multidrug resistant infections; irreversible electroporation ID IRREVERSIBLE ELECTROPORATION; PHOTODYNAMIC THERAPY; STAPHYLOCOCCUS-AUREUS; MICROBIAL BIOFILMS; SKIN ABRASION; IN-VIVO; MODEL; BLEOMYCIN; INFECTION; REMOVAL AB Biofilm formation is a significant problem, accounting for over eighty percent of microbial infections in the body. Biofilm eradication is problematic due to increased resistance to antibiotics and antimicrobials as compared to planktonic cells. The purpose of this study was to investigate the effect of Pulsed Electric Fields (PEF) on biofilm-infected mesh. Prolene mesh was infected with bioluminescent Pseudomonas aeruginosa and treated with PEF using a concentric electrode system to derive, in a single experiment, the critical electric field strength needed to kill bacteria. The effect of the electric field strength and the number of pulses (with a fixed pulse length duration and frequency) on bacterial eradication was investigated. For all experiments, biofilm formation and disruption were confirmed with bioluminescent imaging and Scanning Electron Microscopy (SEM). Computation and statistical methods were used to analyze treatment efficiency and to compare it to existing theoretical models. In all experiments 1500V are applied through a central electrode, with pulse duration of 50s, and pulse delivery frequency of 2Hz. We found that the critical electric field strength (Ecr) needed to eradicate 100-80% of bacteria in the treated area was 121 +/- 14V/mm when 300 pulses were applied, and 235 +/- 6.1V/mm when 150 pulses were applied. The area at which 100-80% of bacteria were eradicated was 50.5 +/- 9.9mm(2) for 300 pulses, and 13.4 +/- 0.65mm(2) for 150 pulses. 80% threshold eradication was not achieved with 100 pulses. The results indicate that increased efficacy of treatment is due to increased number of pulses delivered. In addition, we that showed the bacterial death rate as a function of the electrical field follows the statistical Weibull model for 150 and 300pulses. We hypothesize that in the clinical setting, combining systemic antibacterial therapy with PEF will yield a synergistic effect leading to improved eradication of mesh infections. Biotechnol. Bioeng. 2016;113: 643-650. (c) 2015 Wiley Periodicals, Inc. C1 [Khan, Saiqa I.; McCormack, Michael C.; Austen, William G., Jr.] Harvard Univ, Div Plast & Reconstruct Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Blumrosen, Gaddi] Tel Aviv Univ, Dept Comp Sci, IL-69978 Tel Aviv, Israel. [Vecchio, Daniela; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Vecchio, Daniela; Hamblin, Michael R.] Harvard Univ, Dept Dermatol, Sch Med, Boston, MA 02115 USA. [Golberg, Alexander; Yarmush, Martin L.] Harvard Univ, Ctr Engn Med, Dept Surg, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. [Golberg, Alexander; Yarmush, Martin L.] Shriners Burns Hosp, Boston, MA 02114 USA. [Golberg, Alexander] Tel Aviv Univ, Porter Sch Environm Studies, IL-69978 Tel Aviv, Israel. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Khan, SI (reprint author), Harvard Univ, Div Plast & Reconstruct Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM sikhan@mgh.harvard.edu FU US NIH [R01AI050875] FX We thank Ann Tisdale, an expert at The Schepens Eye Research Institute, Massachusetts Eye and Ear SEM Core Facility, for her valuable Scanning Electron Microscopy knowledge, skill, and contributions. DV and MRH were supported by US NIH grant R01AI050875. NR 40 TC 1 Z9 1 U1 7 U2 41 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 EI 1097-0290 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD MAR PY 2016 VL 113 IS 3 BP 643 EP 650 DI 10.1002/bit.25818 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DC1YT UT WOS:000369015100019 PM 26332437 ER PT J AU Hirko, KA Chen, WY Willett, WC Rosner, BA Hankinson, SE Beck, AH Tamimi, RM Eliassen, AH AF Hirko, Kelly A. Chen, Wendy Y. Willett, Walter C. Rosner, Bernard A. Hankinson, Susan E. Beck, Andrew H. Tamimi, Rulla M. Eliassen, A. Heather TI Alcohol consumption and risk of breast cancer by molecular subtype: Prospective analysis of the nurses' health study after 26 years of follow-up SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; alcohol; molecular subtypes; luminal; basal ID PROGESTERONE-RECEPTOR STATUS; MAMMARY EPITHELIAL-CELLS; GENE-EXPRESSION PATTERNS; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; PROSPECTIVE COHORT; IN-SITU; ESTROGEN; ETHANOL; EPIDEMIOLOGY AB Alcohol consumption is a consistent risk factor for breast cancer, although it is unclear whether the association varies by breast cancer molecular subtype. We investigated associations between cumulative average alcohol intake and risk of breast cancer by molecular subtype among 105,972 women in the prospective Nurses' Health Study cohort, followed from 1980 to 2006. Breast cancer molecular subtypes were defined according to estrogen receptor (ER), progesterone receptor, human epidermal growth factor 2 (HER2), cytokeratin 5/6, and epidermal growth factor status from immunostained tumor microarrays in combination with histologic grade. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Competing risk analyses were used to assess heterogeneity by subtype. We observed suggestive heterogeneity in associations between alcohol and breast cancer by subtype (p(het)=0.06). Alcohol consumers had an increased risk of luminal A breast cancers [n=1,628 cases, per 10 g/day increment HR (95% CI) 51.10(1.05-1.15)], and an increased risk that was suggestively stronger for HER2-type breast cancer [n=160 cases, HR (95% CI) 51.16(1.02-1.33)]. We did not observe statistically significant associations between alcohol and risk of luminal B [n=631 cases, HR (95% CI) 51.08(0.99-1.16)], basal-like [n=254 cases, HR (95% CI) 50.90(0.77-1.04)], or unclassified [n=87 cases, HR (95% CI) 50.90(0.71-1.14)] breast cancer. Alcohol consumption was associated with increased risk of luminal A and HER2-type breast cancer, but not significantly associated with other subtypes. Given that ERs are expressed in luminal A but not in HER2-type tumors, our findings suggest that other mechanisms may play a role in the association between alcohol and breast cancer. C1 [Hirko, Kelly A.; Chen, Wendy Y.; Willett, Walter C.; Rosner, Bernard A.; Hankinson, Susan E.; Tamimi, Rulla M.; Eliassen, A. Heather] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Hirko, Kelly A.; Chen, Wendy Y.; Willett, Walter C.; Rosner, Bernard A.; Hankinson, Susan E.; Beck, Andrew H.; Tamimi, Rulla M.; Eliassen, A. Heather] Harvard Univ, Sch Med, 181 Longwood Ave, Boston, MA 02115 USA. [Hirko, Kelly A.; Willett, Walter C.; Hankinson, Susan E.; Tamimi, Rulla M.; Eliassen, A. Heather] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hankinson, Susan E.] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. RP Hirko, KA (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA.; Hirko, KA (reprint author), Harvard Univ, Sch Med, 181 Longwood Ave, Boston, MA 02115 USA.; Hirko, KA (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM kelly.hirko@channing.harvard.edu FU NIH [UM1 CA186107, P01 CA087969]; [R25T CA098566] FX Grant sponsors: NIH UM1 CA186107 (Meir Stampfer) and P01 CA087969 (Meir Stampfer); Grant sponsor: R25T CA098566 Training Grant NR 49 TC 1 Z9 1 U1 0 U2 15 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 MAR 1 PY 2016 VL 138 IS 5 BP 1094 EP 1101 DI 10.1002/ijc.29861 PG 8 WC Oncology SC Oncology GA DC4BL UT WOS:000369164700006 PM 26384849 ER PT J AU Shoultz-Henley, S Garden, AS Mohamed, ASR Sheu, T Kroll, MH Rosenthal, DI Gunn, GB Hayes, AJ French, C Eichelberger, H Kalpathy-Cramer, J Smith, BD Phan, J Ayoub, Z Lai, SY Pham, B Kies, M Gold, KA Sturgis, E Fuller, CD AF Shoultz-Henley, Sara Garden, Adam S. Mohamed, Abdallah S. R. Sheu, Tommy Kroll, Michael H. Rosenthal, David I. Gunn, G. Brandon Hayes, Amos J. French, Chloe Eichelberger, Hillary Kalpathy-Cramer, Jayashree Smith, Blaine D. Phan, Jack Ayoub, Zeina Lai, Stephen Y. Pham, Brian Kies, Merrill Gold, Kathryn A. Sturgis, Erich Fuller, Clifton D. TI Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE platelet; oropharyngeal cancer; chemoradiation; prognosis; survival ID MODULATED RADIATION-THERAPY; SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; POOR-PROGNOSIS; NECK-CANCER; STAGE-III; HEAD; THROMBOCYTOSIS; SURVIVAL; OUTCOMES AB The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLTpre-chemoRT, Hgb(pre-chemoRT)) before start of treatment were identified. Patients were risk-stratified using Dahlstrom-Sturgis criteria and were tested for association with survival and disease-control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLTpre-chemoRT value of >= 350 3 10(9) /L. Actuarial 5-year locoregional control (LRC) and FDM were 83 and 85% for non-thrombocythemic patients while patient with high platelets had 5-year LRC and FDM of 73 and 74%, respectively. Likewise, 5-year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLTpre-chemoRT was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3-, 5-and 10-year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients. C1 [Shoultz-Henley, Sara; Garden, Adam S.; Mohamed, Abdallah S. R.; Sheu, Tommy; Rosenthal, David I.; Gunn, G. Brandon; Hayes, Amos J.; French, Chloe; Eichelberger, Hillary; Smith, Blaine D.; Phan, Jack; Fuller, Clifton D.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Box 0097,1515 Holcombe Blvd, Houston, TX 77030 USA. [Shoultz-Henley, Sara; French, Chloe; Eichelberger, Hillary; Smith, Blaine D.] Univ Texas Houston, Sch Med, Houston, TX USA. [Mohamed, Abdallah S. R.] Univ Alexandria, Fac Med, Dept Clin Oncol & Nucl Med, Alexandria, Egypt. [Kroll, Michael H.] Univ Texas MD Anderson Canc Ctr, Dept Internal Med, Box 0097,1515 Holcombe Blvd, Houston, TX 77030 USA. [Hayes, Amos J.] Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Denton, TX 76203 USA. [Kalpathy-Cramer, Jayashree] MIT, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Div Hlth Sci & Technol, Charlestown, MA USA. [Ayoub, Zeina] Amer Univ Beirut, Med Ctr, Dept Radiat Oncol, Beirut, Lebanon. [Lai, Stephen Y.; Sturgis, Erich] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Box 0097,1515 Holcombe Blvd, Houston, TX 77030 USA. [Pham, Brian] Rosalind Franklin Univ Med & Sci, Chicago, IL USA. [Kies, Merrill; Gold, Kathryn A.] Univ Texas MD Anderson Canc Ctr, Dept Med Oncol, Box 0097,1515 Holcombe Blvd, Houston, TX 77030 USA. [Fuller, Clifton D.] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA. RP Mohamed, ASR; Fuller, CD (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Box 0097,1515 Holcombe Blvd, Houston, TX 77030 USA.; Mohamed, ASR (reprint author), Univ Alexandria, Fac Med, Dept Clin Oncol & Nucl Med, Alexandria, Egypt.; Fuller, CD (reprint author), Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA.; Mohamed, ASR; Fuller, CD (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Head & Neck Sect, Box 0097,1515 Holcombe Blvd, Houston, TX 77030 USA. EM asmohamed@mdanderson.org; cdfuller@mdanderson.org OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Fuller, Clifton/0000-0002-5264-3994; Mohamed, Abdallah/0000-0003-2064-7613 FU National Science Foundation Division of Mathematical Sciences Proposals for Quantitative Approaches to Biomedical Big Data (QuBBD) Grant [1557559]; National Institutes of Health/National Cancer Institute's Paul Calabresi Clinical Oncology Award Program [K12 CA088084-06]; Clinician Scientist Loan Repayment Program [L30 CA136381-02]; SWOG/Hope Foundation Dr. Charles A. Coltman, Jr., Fellowship in Clinical Trials; General Electric Healthcare/MD Anderson Center for Advanced Biomedical Imaging In-Kind Award; Elekta AB/MD Anderson Department of Radiation Oncology Seed Grant; Center for Radiation Oncology Research at MD Anderson Cancer Center; MD Anderson Institutional Research Grant; Union for International Cancer Control/American Cancer Society International Fellowships for Beginning Investigators (UICC/ACSBI) FX Grant sponsor: National Science Foundation Division of Mathematical Sciences Proposals for Quantitative Approaches to Biomedical Big Data (QuBBD) Grant; Grant number: 1557559; Grant sponsor: National Institutes of Health/National Cancer Institute's Paul Calabresi Clinical Oncology Award Program; Grant number: K12 CA088084-06; Grant sponsor: Clinician Scientist Loan Repayment Program; Grant number: L30 CA136381-02; Grant sponsors: The SWOG/Hope Foundation Dr. Charles A. Coltman, Jr., Fellowship in Clinical Trials; A General Electric Healthcare/MD Anderson Center for Advanced Biomedical Imaging In-Kind Award; An Elekta AB/MD Anderson Department of Radiation Oncology Seed Grant; The Center for Radiation Oncology Research at MD Anderson Cancer Center; The MD Anderson Institutional Research Grant; Union for International Cancer Control/American Cancer Society International Fellowships for Beginning Investigators (UICC/ACSBI) NR 39 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2016 VL 138 IS 5 BP 1290 EP 1297 DI 10.1002/ijc.29870 PG 8 WC Oncology SC Oncology GA DC4BL UT WOS:000369164700025 PM 26414107 ER PT J AU Imran, TF Shah, R Ha, AS Thomas, R Joseph, J AF Imran, Tasnim F. Shah, Rashesh Ha, Albert S. Thomas, Renjit Joseph, Jacob TI Heart failure associated with small molecule tyrosine kinase inhibitors SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter ID CELL-CARCINOMA; SORAFENIB; SUNITINIB; PHASE C1 [Imran, Tasnim F.; Ha, Albert S.; Joseph, Jacob] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brigham & Womens Hosp, Boston, MA 02120 USA. [Shah, Rashesh; Thomas, Renjit] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07103 USA. RP Imran, TF (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, 1620 Tremont St, Boston, MA 02120 USA. EM TFImran@partners.org NR 10 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 1 PY 2016 VL 206 BP 110 EP + DI 10.1016/j.ijcard.2016.01.059 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DC0HD UT WOS:000368896900030 PM 26785036 ER PT J AU Gruber, J Siegel, EH Purcell, AL Earls, HA Cooper, G Barrett, LF AF Gruber, June Siegel, Erika H. Purcell, Amanda L. Earls, Holly A. Cooper, Gaia Barrett, Lisa Feldman TI Unseen positive and negative affective information influences social perception in bipolar I disorder and healthy adults SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Affect; Social perception; Implicit emotion; Unconscious processing; Continuous flash suppression ID TOP-DOWN FACILITATION; DEPRESSIVE SYMPTOMATOLOGY; BACKWARD-MASKING; MOOD DISORDERS; MANIA; EMOTION; RECOGNITION; SCHIZOPHRENIA; REACTIVITY; INVENTORY AB Bipolar disorder is fundamentally a disorder of emotion regulation, and associated with explicit processing biases for socially relevant emotional information in human faces. Less is known, however, about whether implicit processing of this type of emotional information directly influences social perception. We thus investigated group-related differences in the influence of unconscious emotional processing on conscious person perception judgments using a continuous flash suppression task among 22 individuals with remitted bipolar I disorder (BD; Age(M)=30.82, Age(SD)= 7.04; 68.2% female) compared with 22 healthy adults (CTL; Age(M)=20.86, Age(SD)=9.91; 72.2% female). Across both groups, participants rated neutral faces as more trustworthy, warm, and competent when paired with unseen happy faces as compared to unseen angry and neutral faces; participants rated neutral faces as less trustworthy, warm, and competent when paired with unseen angry as compared to neutral faces. These findings suggest that emotion-related disturbances are not explained by early automatic processing stages, and that activity in the dorsal visual stream underlying implicit emotion processing is intact in bipolar disorder. Implications for understanding the etiology of emotion disturbance in BD are discussed. (C) 2015 Elsevier B.V. All rights reserved. C1 [Gruber, June; Earls, Holly A.; Cooper, Gaia] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Siegel, Erika H.; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA USA. [Purcell, Amanda L.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Gruber, J (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. FU NIMH NIH HHS [T32 MH019391] NR 51 TC 0 Z9 0 U1 6 U2 11 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 MAR 1 PY 2016 VL 192 BP 191 EP 198 DI 10.1016/j.jad.2015.12.037 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DB8UG UT WOS:000368791600027 PM 26745436 ER PT J AU Reilly-Harrington, NA Shelton, RC Kamali, M Rabideau, DJ Shesler, LW Trivedi, MH McElroy, SL Sylvia, LG Bowden, CL Ketter, TA Calabrese, JR Thase, ME Bobo, WV Deckersbach, T Tohen, M McInnis, MG Kocsis, JH Gold, AK Singh, V Finkelstein, DM Kinrys, G Nierenberg, AA AF Reilly-Harrington, Noreen A. Shelton, Richard C. Kamali, Masoud Rabideau, Dustin J. Shesler, Leah W. Trivedi, Madhukar H. McElroy, Susan L. Sylvia, Louisa G. Bowden, Charles L. Ketter, Terence A. Calabrese, Joseph R. Thase, Michael E. Bobo, William V. Deckersbach, Thilo Tohen, Mauricio McInnis, Melvin G. Kocsis, James H. Gold, Alexandra K. Singh, Vivek Finkelstein, Daniel M. Kinrys, Gustavo Nierenberg, Andrew A. TI A tool to predict suicidal ideation and behavior in bipolar disorder: The Concise Health Risk Tracking Self-Report SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Suicide; Psychometrics; Self-report; Risk ID SEVERITY RATING-SCALE; PRIMARY-CARE; PSYCHIATRIC OUTPATIENTS; CLINICAL PREDICTORS; SYMPTOMS SCALE; DEPRESSION; QUESTIONNAIRE; HOPELESSNESS; MANAGEMENT; INVENTORY AB Background: Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality. Methods: The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions-Bipolar Version) were conducted at baseline and follow-up. Results: The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs. Limitations: The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up. Conclusions: The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice. (C) 2015 Elsevier B.V. All rights reserved. C1 [Reilly-Harrington, Noreen A.; Shesler, Leah W.; Sylvia, Louisa G.; Deckersbach, Thilo; Gold, Alexandra K.; Kinrys, Gustavo; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Reilly-Harrington, Noreen A.; Sylvia, Louisa G.; Deckersbach, Thilo; Kinrys, Gustavo; Nierenberg, Andrew A.] Harvard Univ, Sch Med, Boston, MA USA. [Shelton, Richard C.] Univ Alabama Birmingham, Dept Psychiat, Birmingham, AL USA. [Kamali, Masoud; McInnis, Melvin G.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Rabideau, Dustin J.; Finkelstein, Daniel M.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [McElroy, Susan L.] Lindner Ctr HOPE, Mason, OH USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45221 USA. [Bowden, Charles L.; Singh, Vivek] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Ketter, Terence A.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Bipolar Disorders Res Ctr, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Thase, Michael E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Bobo, William V.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Tohen, Mauricio] Univ New Mexico, Dept Psychiat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Kocsis, James H.] Cornell Univ, Dept Psychiat, Weill Cornell Med Coll, New York, NY 10021 USA. RP Reilly-Harrington, NA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Bipolar Clin, 50 Staniford St,Suite 580, Boston, MA 02114 USA.; Reilly-Harrington, NA (reprint author), Massachusetts Gen Hosp, Res Program, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM nharrington11@mgh.harvard.edu NR 38 TC 1 Z9 1 U1 6 U2 11 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 MAR 1 PY 2016 VL 192 BP 212 EP 218 DI 10.1016/j.jad.2015.12.036 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DB8UG UT WOS:000368791600029 PM 26748736 ER PT J AU Haynes, PL Kelly, M Warner, L Quan, SF Krakow, B Bootzin, RR AF Haynes, Patricia L. Kelly, Monica Warner, Lesley Quan, Stuart F. Krakow, Barry Bootzin, Richard R. TI Cognitive Behavioral Social Rhythm Group Therapy for Veterans with posttraumatic stress disorder, depression, and sleep disturbance: Results from an open trial SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Veterans; Post-traumatic stress disorder; Depression; Insomnia; Cognitive behavioral therapy ID ADMINISTERED PTSD SCALE; RANDOMIZED CONTROLLED-TRIAL; CIRCADIAN-RHYTHMS; MAJOR DEPRESSION; PSYCHOLOGICAL TREATMENTS; COMORBID INSOMNIA; IMAGERY REHEARSAL; MENTAL-DISORDERS; VIETNAM VETERANS; COMBAT VETERANS AB Introduction: Cognitive Behavioral Social Rhythm Therapy (CBSRT) is a group psychotherapy tailored for Veterans with Posttraumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD), and sleep disturbances. The aims of this study were to introduce and present initial outcomes of Cognitive Behavioral Social Rhythm Therapy (CBSRT), a 12-week skills group therapy designed to improve sleep and mood by reducing chaotic or isolated lifestyles in Veterans with PTSD. Methods: Twenty-four male Veterans with at least moderate PTSD and MDD participated in this open trial. Main outcomes were the daily sleep diary for sleep disturbances, the Clinician-Administered PTSD Scale (CAPS) for PTSD, and the Hamilton Depression Rating scale for MDD. Results: Veterans improved on all measures (a) with large within subject effects on PTSD symptoms, MDD symptoms, and sleep quality, and (b) with 46-58% of the sample receiving clinically significant benefits on MDD and PTSD symptoms respectively. The consistency of social rhythms was associated with the average reduction in global CAPS scores over time. Only 13% of participants dropped-out of the group therapy prematurely suggesting that this new group therapy is relatively well-tolerated by Veterans. Limitations: Future research that employs a control condition is necessary to establish efficacy of CBSRT. Conclusions: Data from this initial pilot study demonstrate that CBSRT may be an effective group treatment option for Veterans presenting with all three symptom complaints. These data also suggest that daily routine may be an important mechanism to consider in the treatment of PTSD symptoms comorbid with depression. (C) 2015 Elsevier B.V. All rights reserved. C1 [Haynes, Patricia L.] Univ Arizona, Dept Hlth Promot Sci, 1295 N Martin Ave,POB 245209, Tucson, AZ 85724 USA. [Haynes, Patricia L.; Kelly, Monica; Warner, Lesley; Bootzin, Richard R.] Univ Arizona, Dept Psychiat, 1501 N Campbell Ave, Tucson, AZ 85724 USA. [Haynes, Patricia L.; Kelly, Monica; Warner, Lesley] Southern Arizona VA Hlth Care Syst, 3601 S 6th Ave,116B, Tucson, AZ 85723 USA. [Haynes, Patricia L.; Kelly, Monica; Bootzin, Richard R.] Univ Arizona, Dept Psychol, 1503 E Univ Blvd, Tucson, AZ 85721 USA. [Quan, Stuart F.] Univ Arizona, Dept Med, 1501 N Campbell Ave, Tucson, AZ 85724 USA. [Quan, Stuart F.] Harvard Univ, Div Sleep Med, Sch Med, 164 Longwood Ave, Boston, MA 02115 USA. [Krakow, Barry] Maimonides Sleep Arts & Sci, 6739 Acad Rd NE Suite 380, Albuquerque, NM 87109 USA. [Warner, Lesley] VA Puget Sound Hlth Care Syst, 1660 South Columbian Way, Seattle, WA 98108 USA. RP Haynes, PL (reprint author), Univ Arizona, Dept Hlth Promot Sci, 1295 N Martin Ave,POB 245209, Tucson, AZ 85724 USA. EM thaynes@email.arizona.edu FU American Sleep Medicine Foundation Career Development Grant [37-CA-06]; Institute for Mental Health Research Pilot Award FX This project was supported by the American Sleep Medicine Foundation Career Development Grant (Grant #37-CA-06) and the Institute for Mental Health Research Pilot Award. The authors gratefully acknowledge the assistance of Marta Williamson, Valerie Scheller, Sacha Brown, and Suzanne Perkins. Dr. Haynes, Ms. Kelly, and Ms. Warner are no longer affiliated with the Southern Arizona VA Health Care System. NR 94 TC 2 Z9 2 U1 15 U2 33 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 MAR 1 PY 2016 VL 192 BP 234 EP 243 DI 10.1016/j.jad.2015.12.012 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DB8UG UT WOS:000368791600032 PM 26748739 ER PT J AU Garcia, HA McGeary, CA Finley, EP McGeary, DD Ketchum, NS Peterson, AL AF Garcia, Hector A. McGeary, Cindy A. Finley, Erin P. McGeary, Donald D. Ketchum, Norma S. Peterson, Alan L. TI The influence of trauma and patient characteristics on provider burnout in VA post-traumatic stress disorder specialty programmes SO PSYCHOLOGY AND PSYCHOTHERAPY-THEORY RESEARCH AND PRACTICE LA English DT Article DE burnout; Veterans Health Administration; post-traumatic stress disorder; malingering; personality disorders ID COGNITIVE PROCESSING THERAPY; MENTAL-HEALTH PROVIDERS; COMPASSION SATISFACTION; BEHAVIORAL THERAPY; JOB BURNOUT; VETERANS; RECOMMENDATIONS; DISSEMINATION; PROFESSIONALS; FATIGUE AB ObjectiveProlonged exposure (PE) and cognitive processing therapy (CPT) - post-traumatic stress disorder (PTSD) treatments now available at the Veterans Health Administration (VHA) - expose the provider to graphic traumatic material. Little is known about the impact of traumatic material on VHA providers. The purpose of this study was to examine the relationship between trauma content, patient characteristics, and burnout among VHA PTSD Clinical Team (PCT) providers. It was hypothesized that trauma content and patient characteristics would significantly predict burnout in this population. DesignThis cross-sectional study consisted of 137 participants. The sample was mostly female (67%), Caucasian (non-Hispanic; 81%), and married (70%) with a mean age of 44.3years (SD=11.3). MethodsParticipants completed an electronic survey that assessed demographics, patient characteristics (i.e., anger, personality disorder, malingering), trauma content characteristics (e.g., killing of women and children) as well as burnout as measured by the Maslach Burnout Inventory-General Survey (MBI-GS; Maslach etal., 1996, Burnout inventory manual. Palo Alto: Consulting Psychologist Press). ResultsOver half of the study population reported being bothered by trauma content; however, trauma content did not predict burnout. Treating patients with personality disorders and suspected malingering predicted burnout in PCT providers. High numbers (77%) reported perceiving that emotional exhaustion impacted the quality of care they provided. ConclusionThese findings suggest an important role of burnout assessment, prevention, and treatment strategies at the VHA. C1 [Garcia, Hector A.; Finley, Erin P.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Garcia, Hector A.; McGeary, Cindy A.; McGeary, Donald D.; Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Finley, Erin P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ketchum, Norma S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. RP Garcia, HA (reprint author), Frank Tejeda Outpatient Clin, 5788 Eckhert Rd, San Antonio, TX 78240 USA. EM Hector.Garcia2@va.gov OI Finley, Erin/0000-0003-4497-7721 FU Practice Based Research Network, The University of Texas Health Science Center at San Antonio FX The research was supported in part by the Practice Based Research Network, The University of Texas Health Science Center at San Antonio. NR 43 TC 2 Z9 2 U1 4 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1476-0835 EI 2044-8341 J9 PSYCHOL PSYCHOTHER-T JI Psychol. Psychother.-Theory Res. Pract. PD MAR PY 2016 VL 89 IS 1 BP 66 EP 81 DI 10.1111/papt.12057 PG 16 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DB9KE UT WOS:000368834000005 PM 25643839 ER PT J AU Rasmussen, J Siev, J Abramovitch, A Wilhelm, S AF Rasmussen, Jessica Siev, Jedidiah Abramovitch, Amitai Wilhelm, Sabine TI Scrupulosity and contamination OCD are not associated with deficits in response inhibition SO JOURNAL OF BEHAVIOR THERAPY AND EXPERIMENTAL PSYCHIATRY LA English DT Article DE Scrupulosity; Obsessive-compulsive disorder; Response inhibition ID OBSESSIVE-COMPULSIVE DISORDER; ANXIETY STRESS SCALES; SYMPTOM DIMENSIONS; NEUROPSYCHOLOGICAL PERFORMANCE; PSYCHOMETRIC PROPERTIES; EXECUTIVE FUNCTION; MEMORY; CHECKING; DEPRESSION; TASK AB Background and objectives: Prior research has indicated a number of neuropsychological deficits in patients with OCD consistent with the cortico-striato-thalamo-cortical model of the disorder. Response inhibition (RI), defined as the inability to inhibit a prepotent response, has been identified as a possible candidate endophenotype for OCD. However, the results from previous studies of RI in OCD patients have been mixed, suggesting the possibility that some OCD dimensions may be associated with deficits in RI while others may not. The present study aimed to examine RI using a Go/No-Go (GNG) task in two OCD symptom dimensions, one of which, scrupulosity, has never been subject to neuropsychological investigation. Methods: A total of 63 individuals, consisting of scrupulous OCD (n = 26), contamination OCD (n = 18) and non-psychiatric controls (n = 19) completed study measures. Controlling for depression symptoms, no significant performance differences were found between the groups on the GNG test, indicating no deficits in RI among contamination or scrupulous OCD. Results: Results are consistent with several prior studies of RI in OCD that found no differences as compared to non-psychiatric controls, especially on GNG tests, and with more recent suggestions that RI may not constitute a clinical significant impaired domain in OCD. Limitations: Limitations included a primarily highly educated and Causasian sample. Conclusions: Additional conclusions include careful consideration of the RI measures selected for future studies, as well as the need for further investigation into the neuropsychological and neurobiological nature of scrupulous OCD. (c) 2015 Elsevier Ltd. All rights reserved. C1 [Rasmussen, Jessica; Abramovitch, Amitai; Wilhelm, Sabine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rasmussen, Jessica; Abramovitch, Amitai; Wilhelm, Sabine] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Siev, Jedidiah] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Abramovitch, Amitai] Texas State Univ, San Marcos, TX USA. RP Rasmussen, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jrasmussen@mgh.harvard.edu OI Abramovitch, Amitai/0000-0001-9640-0970 FU International OCD Foundation FX This research was supported by a grant from the International OCD Foundation to the second author. NR 58 TC 1 Z9 1 U1 4 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7916 EI 1873-7943 J9 J BEHAV THER EXP PSY JI J. Behav. Ther. Exp. Psychiatry PD MAR PY 2016 VL 50 BP 120 EP 126 DI 10.1016/j.jbtep.2015.06.004 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CZ6LQ UT WOS:000367213200016 PM 26183654 ER PT J AU Gaullier, G Miron, S Pisano, S Buisson, R Le Bihan, YV Tellier-Lebegue, C Messaoud, W Roblin, P Guimaraes, BG Thai, R Giraud-Panis, MJ Gilson, E Le Du, MH AF Gaullier, Guillaume Miron, Simona Pisano, Sabrina Buisson, Remi Le Bihan, Yann-Vai Tellier-Lebegue, Carine Messaoud, Wala Roblin, Pierre Guimaraes, Beatriz G. Thai, Robert Giraud-Panis, Marie-Josephe Gilson, Eric Le Du, Marie-Helene TI A higher-order entity formed by the flexible assembly of RAP1 with TRF2 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TELOMERIC PROTEINS TRF1; GENE-EXPRESSION; S-PHASE; DNA; PROTECTION; BINDING; SHELTERIN; DOMAINS; COMPLEX; MOTIF AB Telomere integrity is essential to maintain genome stability, and telomeric dysfunctions are associated with cancer and aging pathologies. In human, the shelterin complex binds TTAGGG DNA repeats and provides capping to chromosome ends. Within shelterin, RAP1 is recruited through its interaction with TRF2, and TRF2 is required for telomere protection through a network of nucleic acid and protein interactions. RAP1 is one of the most conserved shelterin proteins although one unresolved question is how its interaction may influence TRF2 properties and regulate its capacity to bind multiple proteins. Through a combination of biochemical, biophysical and structural approaches, we unveiled a unique mode of assembly between RAP1 and TRF2. The complete interaction scheme between the full-length proteins involves a complex biphasic interaction of RAP1 that directly affects the binding properties of the assembly. These results reveal how a non-DNA binding protein can influence the properties of a DNA-binding partner by mutual conformational adjustments. C1 [Gaullier, Guillaume; Miron, Simona; Le Bihan, Yann-Vai; Tellier-Lebegue, Carine; Messaoud, Wala; Le Du, Marie-Helene] Univ Paris 11, Dept Biochem Biophys & Struct Biol, Inst Integrat Biol Cell, CEA,UMR CNRS 9198,CEA Saclay, Batiment 144, F-91191 Gif Sur Yvette, France. [Pisano, Sabrina; Buisson, Remi; Giraud-Panis, Marie-Josephe; Gilson, Eric] Inst Res Canc & Aging Nice, F-06107 Nice, France. [Pisano, Sabrina; Buisson, Remi; Giraud-Panis, Marie-Josephe; Gilson, Eric] CNRS, UMR7284, INSERM, U1081, F-06107 Nice, France. [Pisano, Sabrina; Buisson, Remi; Giraud-Panis, Marie-Josephe; Gilson, Eric] Fac Med, F-06107 Nice, France. [Roblin, Pierre; Guimaraes, Beatriz G.] Synchrotron SOLEIL, St Aubin BP 48, F-91192 Gif Sur Yvette, France. [Roblin, Pierre] INRA, Unite Biopolymeres Interact Assemblages, F-44026 Nantes, France. [Thai, Robert] CEA, iBiTecS, F-91191 Gif Sur Yvette, France. [Gilson, Eric] CHU Nice, Dept Genet, F-06107 Nice, France. [Buisson, Remi] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02129 USA. [Le Bihan, Yann-Vai] Inst Canc Res, Div Canc Therapeut, London SW3 6JB, England. RP Le Du, MH (reprint author), Univ Paris 11, Dept Biochem Biophys & Struct Biol, Inst Integrat Biol Cell, CEA,UMR CNRS 9198,CEA Saclay, Batiment 144, F-91191 Gif Sur Yvette, France. EM marie-helene.ledu@cea.fr OI Gaullier, Guillaume/0000-0003-3405-6021 FU Agence Nationale de la Recherche (TELOLOOP grant) [ANR-1582-30020690]; Ligue contre cancer (EG equipe labellisee); INCa (TELOCHROM grant); Essonne committee of the Ligue contre le cancer [M18756, M22897]; Foundation ARC pour la Recherche sur le Cancer [SFI20121205503]; Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA); French Infrastructure for Integrated Structural Biology (FRISBI); Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (INSERM); CEA; ANR FX Agence Nationale de la Recherche (TELOLOOP grant) [ANR-1582-30020690]; Ligue contre cancer (EG equipe labellisee); INCa (TELOCHROM grant); Essonne committee of the Ligue contre le cancer (grant M18756 and M22897); Foundation ARC pour la Recherche sur le Cancer (grant SFI20121205503); Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA); French Infrastructure for Integrated Structural Biology (FRISBI); Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (INSERM). Funding for open access charge: CEA; ANR. NR 55 TC 4 Z9 4 U1 4 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 29 PY 2016 VL 44 IS 4 BP 1962 EP 1976 DI 10.1093/nar/gkv1531 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF7ED UT WOS:000371519700048 PM 26748096 ER PT J AU Tarnoki, AD Tarnoki, DL Littvay, L Garami, Z Molnar, AA Berczi, V Karlinger, K Baffy, G AF Tarnoki, Adam D. Tarnoki, David L. Littvay, Levente Garami, Zsolt Molnar, Andrea Agnes Berczi, Viktor Karlinger, Kinga Baffy, Gyorgy TI Environmental Factors Responsible for Variability of Hepatic Vein Flow: A Doppler Assessment in Healthy Twins SO CHINESE JOURNAL OF PHYSIOLOGY LA English DT Article DE blood flow; hepatocellular function; liver; physical activity; velocity ID FATTY LIVER-DISEASE; WAVE-FORM; PORTAL-HYPERTENSION; ULTRASONOGRAPHY; ULTRASOUND; SEVERITY; CHILDREN; SPLEEN; ARTERY; RATS AB Doppler interrogation studies of the liver blood flow indicate altered hepatic vein waveforms in association with impaired hepatocellular function. However, little is known about the mechanisms responsible for variations of these parameters in the absence of disease. We aimed to investigate the contribution of heritable and environmental factors to the physiological variability of hepatic vein flow in a twin cohort. Two hundred twenty-eight healthy adult Hungarian twins (69 monozygotic, 45 same-sex dizygotic pairs) underwent Doppler sonography of the hepatic vein. Age- and sex-adjusted heritability of the highest velocity (amplitude of S wave) of hepatic vein flow was negligible. Shared environment contributed to 33% (95% CI, 16%-51%), and unshared environment was responsible for the largest portion (67%; 95% CI, 49%-84%) of the variance. Duration of sports activities was significantly (P < 0.05) related to the magnitude of hepatic vein flow, while other risk factors and lifestyle characteristics had no significant influence. The data suggest that genetic factors have little impact on the parameters of hepatic venous blood flow. The variability observed in healthy twins by the Doppler interrogation can be explained by the effect of unshared environmental components primarily related to regular physical activity. These findings underscore the importance of unique environments in physiological variations of hepatic venous blood flow. C1 [Tarnoki, Adam D.; Tarnoki, David L.; Berczi, Viktor; Karlinger, Kinga] Semmelweis Univ, Dept Radiol & Oncotherapy, 78-A Ulloi St, H-1082 Budapest, Hungary. [Littvay, Levente] Cent European Univ, H-1051 Budapest, Hungary. [Garami, Zsolt] Houston Methodist Hosp, Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Molnar, Andrea Agnes] Mil Hosp, Dept Cardiol, H-1134 Budapest, Hungary. [Baffy, Gyorgy] Harvard Univ, Sch Med, Dept Med, VA Boston Healthcare Syst, Boston, MA 02130 USA. [Baffy, Gyorgy] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02130 USA. RP Tarnoki, AD (reprint author), Semmelweis Univ, Dept Radiol & Oncotherapy, 78-A Ulloi St, H-1082 Budapest, Hungary. EM tarnoki2@gmail.com NR 29 TC 0 Z9 0 U1 0 U2 3 PU CHINESE PHYSIOLOGICAL SOC PI TAIPEI PA NATL YANG-MING UNIV, TAIPEI, TAIWAN SN 0304-4920 J9 CHINESE J PHYSIOL JI Chin. J. Physiol. PD FEB 29 PY 2016 VL 59 IS 1 BP 33 EP 38 DI 10.4077/CJP.2016.BAE360 PG 6 WC Physiology SC Physiology GA DF5EO UT WOS:000371374800004 PM 26875560 ER PT J AU Schwieler, L Samuelsson, M Frye, MA Bhat, M Schuppe-Koistinen, I Jungholm, O Johansson, AG Landen, M Sellgren, CM Erhardt, S AF Schwieler, Lilly Samuelsson, Martin Frye, Mark A. Bhat, Maria Schuppe-Koistinen, Ina Jungholm, Oscar Johansson, Anette G. Landen, Mikael Sellgren, Carl M. Erhardt, Sophie TI Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE NMDA receptor; Cytokines; ECT; Quinolinic acid; Inflammation; IL-6; Kynurenic acid; Treatment-resistant depression ID CEREBROSPINAL-FLUID; MAJOR DEPRESSION; INDOLEAMINE 2,3-DIOXYGENASE; TRYPTOPHAN CATABOLISM; ENDOGENOUS-DEPRESSION; IMMUNE ACTIVATION; QUINOLINIC ACID; ELEVATED LEVELS; AMINO-ACIDS; DISORDER AB Background: Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression. Methods: Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22). Results: Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002). Conclusions: This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT. C1 [Schwieler, Lilly; Samuelsson, Martin; Schuppe-Koistinen, Ina; Jungholm, Oscar; Sellgren, Carl M.; Erhardt, Sophie] Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden. [Samuelsson, Martin] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Sect Psychiat, Linkoping, Sweden. [Frye, Mark A.] Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN USA. [Bhat, Maria] AstraZeneca, Personalized Healthcare & Biomarker Labs, Prot Biomarkers, Innovat Med, Gothenburg, Sweden. [Bhat, Maria; Johansson, Anette G.] Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden. [Schuppe-Koistinen, Ina] Karolinska Inst, Prote & Nanobiotechn, Sci Life Lab, SE-17177 Stockholm, Sweden. [Landen, Mikael] Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden. [Landen, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Sellgren, Carl M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Sellgren, Carl M.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Schwieler, L (reprint author), Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden. EM lilly.schwieler@ki.se OI samuelsson, martin/0000-0003-2576-0543 FU Swedish Medical Research Council [2009-7053; 2013-2838, K2014-62X-14647-12-51]; Swedish Brain Foundation; Svenska Lakaresallskapet; Petrus och Augusta Hedlunds Stiftelse; Ostergotland County Council; AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science; Karolinska Institutet (KID); Swedish Federal Government under the LUA/ALF [ALF 20130032]; Linkoping University Hospital; Karolinska Institutet FX This work was supported by grants from the Swedish Medical Research Council (2009-7053; 2013-2838), the Swedish Brain Foundation, Svenska Lakaresallskapet, Petrus och Augusta Hedlunds Stiftelse, Ostergotland County Council, the AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science, and the Karolinska Institutet (KID). The collection of population-based controls was funded by the Swedish Medical Research Council (K2014-62X-14647-12-51) and the Swedish Federal Government under the LUA/ALF agreement (ALF 20130032). We thank the patients, healthy volunteers, and healthy controls for their participation and express our gratitude toward the health professionals who facilitated our work; in particular, we would like to thank the research nurses. There are no commercial associations that might pose a conflict of interest in connection with the manuscript. The clinical research study was sponsored by Linkoping University Hospital and Karolinska Institutet with an AstraZeneca in-kind contribution to the sample analysis for the present paper. NR 57 TC 3 Z9 4 U1 7 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD FEB 29 PY 2016 VL 13 AR 51 DI 10.1186/s12974-016-0517-7 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DE9JI UT WOS:000370952400001 PM 26925576 ER PT J AU Han, SJ Jang, HS Kim, JI Lipschutz, JH Park, KM AF Han, Sang Jun Jang, Hee-Seong Kim, Jee In Lipschutz, Joshua H. Park, Kwon Moo TI Unilateral nephrectomy elongates primary cilia in the remaining kidney via reactive oxygen species SO SCIENTIFIC REPORTS LA English DT Article ID INDUCED FUNCTIONAL INJURY; HEPATOCYTE GROWTH-FACTOR; MAPK KINASE ACTIVATION; ISCHEMIA/REPERFUSION INJURY; OXIDATIVE STRESS; EPITHELIAL-CELLS; ISCHEMIC-INJURY; CILIOGENESIS; CYSTOGENESIS; HYPERTROPHY AB The length of primary cilia is associated with normal cell and organ function. In the kidney, the change of functional cilia length/mass is associated with various diseases such as ischemia/reperfusion injury, polycystic kidney disease, and congenital solitary kidney. Here, we investigate whether renal mass reduction affects primary cilia length and function. To induce renal mass reduction, mice were subjected to unilateral nephrectomy (UNx). UNx increased kidney weight and superoxide formation in the remaining kidney. Primary cilia were elongated in proximal tubule cells, collecting duct cells and parietal cells of the remaining kidney. Mn(III) Tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP), an antioxidant, reduced superoxide formation in UNx-mice and prevented the elongation of primary cilia. UNx increased the expression of phosphorylated ERK, p21, and exocyst complex members Sec8 and Sec10, in the remaining kidney, and these increases were prevented by MnTMPyP. In MDCK, a kidney tubular epithelial cell line, cells, low concentrations of H2O2 treatment elongated primary cilia. This H2O2-induced elongation of primary cilia was also prevented by MnTMPyP treatment. Taken together, these data demonstrate that kidney compensation, induced by a reduction of renal mass, results in primary cilia elongation, and this elongation is associated with an increased production of reactive oxygen species (ROS). C1 [Han, Sang Jun; Jang, Hee-Seong; Park, Kwon Moo] Kyungpook Natl Univ, Sch Med, Dept Anat, Daegu 700422, South Korea. [Han, Sang Jun; Jang, Hee-Seong; Park, Kwon Moo] Kyungpook Natl Univ, Sch Med, BK Project 21, Daegu 700422, South Korea. [Kim, Jee In] Keimyung Univ, Sch Med, Dept Mol Med, Daegu 705717, South Korea. [Kim, Jee In] Keimyung Univ, Sch Med, MRC, Daegu 705717, South Korea. [Lipschutz, Joshua H.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Lipschutz, Joshua H.] Ralph H Johnson Vet Affairs Med Ctr, Dept Med, Charleston, SC USA. RP Park, KM (reprint author), Kyungpook Natl Univ, Sch Med, Dept Anat, Daegu 700422, South Korea.; Park, KM (reprint author), Kyungpook Natl Univ, Sch Med, BK Project 21, Daegu 700422, South Korea. EM kmpark@knu.ac.kr FU National Research Foundation of Korea (NRF) - Korea government (MEST) [NRF-2014R1A11049549]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI14C2011] FX This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2014R1A11049549) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HI14C2011), Republic of Korea. NR 31 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 29 PY 2016 VL 6 AR 22281 DI 10.1038/srep22281 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF1OO UT WOS:000371109300002 PM 26923764 ER PT J AU Dekel, S Mamon, D Solomon, Z Lanman, O Dishy, G AF Dekel, Sharon Mamon, Dania Solomon, Zahava Lanman, Olivia Dishy, Gabriella TI Can guilt lead to psychological growth following trauma exposure? SO PSYCHIATRY RESEARCH LA English DT Article DE Posttraumatic growth; Posttraumatic stress disorder; Guilt ID COGNITIVE-PROCESSING THERAPY; POSTTRAUMATIC-STRESS-DISORDER; FEMALE RAPE VICTIMS; INVENTORY; PTSD; VALIDATION AB With the growing interest in posttraumatic growth (PTG) and its predictors, this study examined the relationship between trauma-related guilt and PTG in a sample of veterans over time. Self-reported guilt, PTG, and posttraumatic stress disorder (PTSD) symptoms were measured in combat veterans and prisoners of war (POWs). Positive correlations were found between guilt, PTSD, and PTG levels. Hierarchical regression revealed that initial guilt levels predicted subsequent PTG controlling for initial PTSD in combat veterans but not in POWs. The findings suggest that posttraumatic growth can be facilitated by trauma-related guilt, underscoring the complex relationship between positive and negative trauma outcomes. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Dekel, Sharon; Lanman, Olivia; Dishy, Gabriella] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Dekel, Sharon] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Mamon, Dania] William James Coll, Newton, MA USA. [Solomon, Zahava] Tel Aviv Univ, Sch Social Work, IL-69978 Tel Aviv, Israel. [Solomon, Zahava] I Core Res Ctr Mass Trauma, Tel Aviv, Israel. [Lanman, Olivia] Boston Univ, Boston, MA 02215 USA. [Dishy, Gabriella] Northeastern Univ, Boston, MA 02115 USA. RP Dekel, S (reprint author), Massachusetts Gen Hosp East, PTSD Res Lab, 120 S Ave, Charlestown, MA 02129 USA. EM sdekel@mgh.harvard.edu FU Executive Committee on Research (ECOR) of Massachusetts General Hospital [22442] FX This study was supported by the Claflin Distinguished Scholar Award awarded to Sharon Dekel from the Executive Committee on Research (ECOR) (#22442) of Massachusetts General Hospital. NR 22 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD FEB 28 PY 2016 VL 236 BP 196 EP 198 DI 10.1016/j.psychres.2016.01.011 PG 3 WC Psychiatry SC Psychiatry GA DE8VD UT WOS:000370913900033 PM 26795127 ER PT J AU Wang, ML Spiegelman, D Kuchiba, A Lochhead, P Kim, S Chan, AT Poole, EM Tamimi, R Tworoger, SS Giovannucci, E Rosner, B Ogino, S AF Wang, Molin Spiegelman, Donna Kuchiba, Aya Lochhead, Paul Kim, Sehee Chan, Andrew T. Poole, Elizabeth M. Tamimi, Rulla Tworoger, Shelley S. Giovannucci, Edward Rosner, Bernard Ogino, Shuji TI Statistical methods for studying disease subtype heterogeneity SO STATISTICS IN MEDICINE LA English DT Article DE heterogeneity test; molecular pathologic epidemiology; omics; pathogenesis; pathology ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; COLORECTAL-CANCER RISK; LIFE-STYLE FACTORS; TUMOR MICROSATELLITE INSTABILITY; MLH1-93G-GREATER-THAN-A PROMOTER POLYMORPHISM; ISLAND METHYLATOR PHENOTYPE; EPITHELIAL OVARIAN-CANCER; BODY-MASS INDEX; COLON-CANCER; ETIOLOGIC HETEROGENEITY AB A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Wang, Molin; Spiegelman, Donna; Rosner, Bernard] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. [Wang, Molin; Spiegelman, Donna; Tamimi, Rulla; Tworoger, Shelley S.; Giovannucci, Edward; Ogino, Shuji] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. [Spiegelman, Donna; Giovannucci, Edward] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard Univ, TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Wang, Molin; Chan, Andrew T.; Poole, Elizabeth M.; Tamimi, Rulla; Tworoger, Shelley S.; Giovannucci, Edward; Rosner, Bernard] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Wang, Molin; Chan, Andrew T.; Poole, Elizabeth M.; Tamimi, Rulla; Tworoger, Shelley S.; Giovannucci, Edward; Rosner, Bernard; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kuchiba, Aya] Natl Canc Ctr, Dept Biostat, Tokyo 104, Japan. [Kim, Sehee] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Lochhead, Paul; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02115 USA. RP Wang, ML (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA.; Wang, ML; Ogino, S (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA.; Ogino, S (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02115 USA.; Wang, ML (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, 677 Huntington Ave, Boston, MA 02115 USA.; Ogino, S (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM stmow@channing.harvard.edu; shuji_ogino@dfci.harvard.edu FU NIH [R01 CA151993, UM1 CA167552, P01 CA55075, P01 CA87969, UM1 CA186107, R01 CA137178, R35 CA197735] FX We thank the Associate Editor and two referees for their helpful comments in improving this paper. We also thank Dr. Meir Stampfer for reviewing this paper and providing helpful comments. This research was supported by the NIH grants R01 CA151993, UM1 CA167552, P01 CA55075, P01 CA87969, UM1 CA186107, R01 CA137178 and R35 CA197735. NR 99 TC 12 Z9 12 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2016 VL 35 IS 5 BP 782 EP 800 DI 10.1002/sim.6793 PG 19 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DC0YW UT WOS:000368945000010 PM 26619806 ER PT J AU Nadarajan, S Mohideen, F Tzur, YB Ferrandiz, N Crawley, O Montoya, A Faull, P Snijders, AP Cutillas, PR Jambhekar, A Blower, MD Martinez-Perez, E Herper, JW Colaiacovo, MP AF Nadarajan, Saravanapriah Mohideen, Firaz Tzur, Yonatan B. Ferrandiz, Nuria Crawley, Oliver Montoya, Alex Faull, Peter Snijders, Ambrosius P. Cutillas, Pedro R. Jambhekar, Ashwini Blower, Michael D. Martinez-Perez, Enrique Herper, J. Wade Colaiacovo, Monica P. TI The MAP kinase pathway coordinates crossover designation with disassembly of synaptonemal complex proteins during meiosis SO ELIFE LA English DT Article ID CAENORHABDITIS-ELEGANS GERMLINE; CELL-CYCLE PROGRESSION; BUDDING YEAST MEIOSIS; POLO-LIKE KINASE; C. ELEGANS; MOUSE SPERMATOCYTES; MEIOTIC PROPHASE; REGULATES CYTOKINESIS; PHOSPHORYLATION SITES; CRISPR-CAS9 SYSTEM AB Asymmetric disassembly of the synaptonemal complex (SC) is crucial for proper meiotic chromosome segregation. However, the signaling mechanisms that directly regulate this process are poorly understood. Here we show that the mammalian Rho GEF homolog, ECT-2, functions through the conserved RAS/ERK MAP kinase signaling pathway in the C. elegans germline to regulate the disassembly of SC proteins. We find that SYP-2, a SC central region component, is a potential target for MPK-1-mediated phosphorylation and that constitutively phosphorylated SYP-2 impairs the disassembly of SC proteins from chromosomal domains referred to as the long arms of the bivalents. Inactivation of MAP kinase at late pachytene is critical for timely disassembly of the SC proteins from the long arms, and is dependent on the crossover (CO) promoting factors ZHP-3/RNF212/Zip3 and COSA-1/CNTD1. We propose that the conserved MAP kinase pathway coordinates CO designation with the disassembly of SC proteins to ensure accurate chromosome segregation. C1 [Nadarajan, Saravanapriah; Tzur, Yonatan B.; Jambhekar, Ashwini; Blower, Michael D.; Colaiacovo, Monica P.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Mohideen, Firaz; Herper, J. Wade] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Ferrandiz, Nuria; Crawley, Oliver; Martinez-Perez, Enrique] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London, England. [Montoya, Alex; Faull, Peter; Snijders, Ambrosius P.; Cutillas, Pedro R.] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, Prote Facil, London, England. [Jambhekar, Ashwini; Blower, Michael D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tzur, Yonatan B.] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Genet, Jerusalem, Israel. [Snijders, Ambrosius P.] London Res Inst, S Mimms, Herts, England. [Cutillas, Pedro R.] Barts Canc Inst, London, England. RP Colaiacovo, MP (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. EM mcolaiacovo@genetics.med.harvard.edu OI Snijders, Bram/0000-0002-5416-8592 FU Lalor Foundation; Human Frontier Science Program; National Institutes of Health [R01GM086434, AG011085, R01GM072551]; MRC FX The Lalor Foundation Saravanapriah Nadarajan; Human Frontier Science Program Yonatan B Tzur; National Institutes of Health R01GM086434 Michael D Blower; MRC-Core funding Enrique Martinez-Perez; National Institutes of Health AG011085 J Wade Harper; National Institutes of Health R01GM072551 Monica P Colaiacovo NR 78 TC 2 Z9 2 U1 0 U2 8 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 27 PY 2016 VL 5 AR e12039 DI 10.7554/eLife.12039 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG2HS UT WOS:000371888500001 PM 26920220 ER PT J AU Shifren, J AF Shifren, Jan TI From vulvovaginal atrophy to the genitourinary syndrome of menopause: what's in a name? SO GYNECOLOGICAL ENDOCRINOLOGY LA English DT Meeting Abstract C1 [Shifren, Jan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0951-3590 EI 1473-0766 J9 GYNECOL ENDOCRINOL JI Gynecol. Endocrinol. PD FEB 26 PY 2016 VL 32 SU 1 BP 36 EP 36 PG 1 WC Endocrinology & Metabolism; Obstetrics & Gynecology SC Endocrinology & Metabolism; Obstetrics & Gynecology GA DG6FZ UT WOS:000372180000039 ER PT J AU Curie, A Brun, A Cheylus, A Reboul, A Nazir, T Bussy, G Delange, K Paulignan, Y Mercier, S David, A Marignier, S Merle, L de Freminville, B Prieur, F Till, M Mortemousque, I Toutain, A Bieth, E Touraine, R Sanlaville, D Chelly, J Kong, J Ott, D Kassai, B Hadjikhani, N Gollub, RL des Portes, V AF Curie, Aurore Brun, Amandine Cheylus, Anne Reboul, Anne Nazir, Tatjana Bussy, Gerald Delange, Karine Paulignan, Yves Mercier, Sandra David, Albert Marignier, Stephanie Merle, Lydie de Freminville, Benedicte Prieur, Fabienne Till, Michel Mortemousque, Isabelle Toutain, Annick Bieth, Eric Touraine, Renaud Sanlaville, Damien Chelly, Jamel Kong, Jian Ott, Daniel Kassai, Behrouz Hadjikhani, Nouchine Gollub, Randy L. des Portes, Vincent TI A Novel Analog Reasoning Paradigm: New Insights in Intellectually Disabled Patients SO PLOS ONE LA English DT Article ID FRAGILE-X-SYNDROME; RAVEN PROGRESSIVE MATRICES; LINKED MENTAL-RETARDATION; DOWN-SYNDROME; DEVELOPMENTAL DISORDERS; RESPONSE-INHIBITION; EXECUTIVE FUNCTIONS; YOUNG MALES; TERM-MEMORY; CHILDREN AB Background Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. Objective We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. Methods We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). Results Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. Conclusion We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations. C1 [Curie, Aurore; Brun, Amandine; Bussy, Gerald; Delange, Karine; Marignier, Stephanie; des Portes, Vincent] Hosp Civils Lyon, Hop Femme Mere Enfant, Deficiences Intellectuelles Causes Rares, Ctr Reference, Bron, France. [Curie, Aurore; Brun, Amandine; Cheylus, Anne; Reboul, Anne; Nazir, Tatjana; Bussy, Gerald; Delange, Karine; Paulignan, Yves; des Portes, Vincent] CNRS, UMR 5304, L2C2, Inst Cognit Sci, Bron, France. [Curie, Aurore; des Portes, Vincent] Univ Lyon, Fac Med Lyon Sud Charles Merieux, Lyon, France. [Curie, Aurore; Kong, Jian; Ott, Daniel; Hadjikhani, Nouchine; Gollub, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Curie, Aurore; Kassai, Behrouz] Univ Lyon, LBBE, UMR5558, INSERM,EPICIME CIC 1407, Lyon, France. [Mercier, Sandra; David, Albert] CHU Nantes, Genet, F-44035 Nantes 01, France. [Merle, Lydie] CH Ie Vinatier, Ctr Rech Neurosci Lyon, INSERM, U1028,CNRS,UMR5292, Lyon, France. [de Freminville, Benedicte; Prieur, Fabienne; Touraine, Renaud] Ctr Hosp Univ, Genet, St Etienne, France. [Till, Michel] Hop St Luc St Joseph, Med Interne, Lyon, France. [Mortemousque, Isabelle; Toutain, Annick] CHU Tours, Genet, Tours, France. [Bieth, Eric] Ctr Hosp Univ, Genet, Toulouse, France. [Sanlaville, Damien] Univ Lyon 1, Hop Femme Mere Enfant, Hosp Civils Lyon, Serv Genet,CRNL,CNRS,UMR5292,INSERM,U1028, F-69365 Lyon, France. [Chelly, Jamel] Univ Strasbourg, Hop Univ Strasbourg, IGBMC, Strasbourg, France. [Hadjikhani, Nouchine] Gillberg Neuropsychiatr Ctr, Gothenburg, Sweden. RP Curie, A (reprint author), Hosp Civils Lyon, Hop Femme Mere Enfant, Deficiences Intellectuelles Causes Rares, Ctr Reference, Bron, France.; Curie, A (reprint author), CNRS, UMR 5304, L2C2, Inst Cognit Sci, Bron, France.; Curie, A (reprint author), Univ Lyon, Fac Med Lyon Sud Charles Merieux, Lyon, France.; Curie, A (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA.; Curie, A (reprint author), Univ Lyon, LBBE, UMR5558, INSERM,EPICIME CIC 1407, Lyon, France. EM aurorecurie@yahoo.fr OI Hadjikhani, Nouchine/0000-0003-4075-3106 FU French Ministry of Health; CNRS / Hospice Civils de Lyon; Fondation Jerome-Lejeune; Xtraordinaire Association; Novartis Pharmaceuticals; ARRENNE association; French XLMR parents' association "Xtraordinaire"; French Fragile X parents' association "Le Goeland"; association "Xtraordinaire" FX Financial support was provided from the French Ministry of Health (grant PHRC 2008, VDP), the CNRS / Hospice Civils de Lyon (research fellow post-graduate grant for AC), the Fondation Jerome-Lejeune (grant for AC), the Xtraordinaire Association (grant for AC), Novartis Pharmaceuticals and the ARRENNE association (grant for AC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors received funding from Novartis Pharmaceuticals. But Novartis was not involved in the study design, collection, analysis, and interpretation of data, writing of the paper nor decision to submit for publication.; Authors are indebted to patients and their families and caregivers. Special thanks for the support of the French XLMR parents' association "Xtraordinaire" and of the French Fragile X parents' association "Le Goeland". Financial support was provided from the French Ministry of Health (grant PHRC 2008, VDP), the CNRS / Hospice Civils de Lyon (research fellow postgraduate grant for AC), the Fondation Jerome-Lejeune (grant for AC), the association "Xtraordinaire" (grant for AC), Novartis Pharmaceuticals and the ARRENNE association (grant for AC). NR 42 TC 1 Z9 1 U1 5 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 26 PY 2016 VL 11 IS 2 AR e0149717 DI 10.1371/journal.pone.0149717 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3UU UT WOS:000371274400040 PM 26918704 ER PT J AU Bashari, MH Fan, FJ Vallet, S Sattler, M Arn, M Luckner-Minden, C Schulze-Bergkamen, H Zornig, I Marme, F Schneeweiss, A Cardone, MH Opferman, JT Jager, D Podar, K AF Bashari, Muhammad Hasan Fan, Fengjuan Vallet, Sonia Sattler, Martin Arn, Melissa Luckner-Minden, Claudia Schulze-Bergkamen, Henning Zoernig, Inka Marme, Frederik Schneeweiss, Andreas Cardone, Michael H. Opferman, Joseph T. Jaeger, Dirk Podar, Klaus TI Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications SO BREAST CANCER RESEARCH LA English DT Article DE Breast cancer; Myeloid cell leukemia-1; Hypoxia; Apoptosis ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NERVOUS-SYSTEM METASTASES; BH3 MIMETIC ABT-737; BCL-2 FAMILY; MOLECULAR PORTRAITS; BRAIN METASTASES; ANTIAPOPTOTIC MCL-1; TARGETING MCL-1; OVARIAN-CANCER; UP-REGULATION AB Background: Molecular mechanisms leading to the adaptation of breast cancer (BC) cells to hypoxia are largely unknown. The anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) is frequently amplified in BC; and elevated Mcl-1 levels have been correlated with poor prognosis. Here we investigated the pathophysiologic role of Mcl-1 in Her2-positive BC cells under hypoxic conditions. Methods: RNA interference and a novel small molecule inhibitor, EU-5346, were used to examine the role of Mcl-1 in Her2-positive BC cell lines and primary BC cells (sensitive or intrinsically resistant to Her2 inhibitors) under hypoxic conditions (using a hypoxic incubation chamber). Mechanisms-of-action were investigated by RT-PCR, mitochondrial isolation, as well as immunoprecipitation/blotting analysis, and microscopy. The specificity against Mcl-1 of the novel small molecule inhibitor EU5346 was verified in Mcl-1(Delta/null) versus Mcl-1(wt/wt) Murine Embryonic Fibroblasts (MEFs). Proliferation, survival, and spheroid formation were assessed in response to Mcl-1 and Her2 inhibition. Results: We demonstrate for a strong correlation between high Mcl-1 protein levels and hypoxia, predominantly in Her2-positive BC cells. Surprisingly, genetic depletion of Mcl-1 decreased Her2 and Hif-1 alpha levels followed by inhibition of BC cell survival. In contrast, Mcl-1 protein levels were not downregulated after genetic depletion of Her2 indicating a regulatory role of Mcl-1 upstream of Her2. Indeed, Mcl-1 and Her2 co-localize within the mitochondrial fraction and form a Mcl-1/Her2-protein complex. Similar to genetically targeting Mcl-1 the novel small molecule Mcl-1 inhibitor EU-5346 induced cell death and decreased spheroid formation in Her2-positive BC cells. Of interest, EU-5346 induced ubiquitination of Mcl-1-bound Her2 demonstrating a previously unknown role for Mcl-1 to stabilize Her2 protein levels. Importantly, targeting Mcl-1 was also active in Her2-positive BC cells resistant to Her2 inhibitors, including a brain-primed Her2-positive cell line. Conclusion: Our data demonstrate a critical role of Mcl-1 in Her2-positive BC cell survival under hypoxic conditions and provide the preclinical framework for the therapeutic use of novel Mcl-1-targeting agents to improve patient outcome in BC. C1 [Bashari, Muhammad Hasan; Fan, Fengjuan; Vallet, Sonia; Luckner-Minden, Claudia; Schulze-Bergkamen, Henning; Zoernig, Inka; Marme, Frederik; Schneeweiss, Andreas; Jaeger, Dirk; Podar, Klaus] Heidelberg Univ, Dept Med Oncol, Natl Ctr Tumor Dis NCT, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. [Bashari, Muhammad Hasan] Padjadjaran State Univ, Fac Med, Dept Pharmacol & Therapy, Jl Eijkman 38, Bandung, Indonesia. [Sattler, Martin] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Arn, Melissa; Cardone, Michael H.] Futrop Inc, 767C Concord Ave, Cambridge, MA 02138 USA. [Luckner-Minden, Claudia; Zoernig, Inka; Jaeger, Dirk] German Canc Res Ctr, Nenheimer Feld 460, D-69120 Heidelberg, Germany. [Opferman, Joseph T.] St Jude Childrens Res Hosp, 262 Danny Thomas Pl, Memphis, TN 38105 USA. RP Podar, K (reprint author), Heidelberg Univ, Dept Med Oncol, Natl Ctr Tumor Dis NCT, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. EM klaus.podar@nct-heidelberg.de RI Bashari, Muhammad Hasan/H-7079-2016 OI Bashari, Muhammad Hasan/0000-0001-7298-0317 FU DAAD-Indonesian German Scholarship Programme (IGSP); B. Braun Stiftungs-Grant FX The authors thank M Bucur (DKFZ) for technical advice and S Malvestiti for technical assistance. JIMT-1-BR3 cells (brain metastatic BC cell line) were a kind gift from Dr Patricia Steeg (Laboratory of Molecular Pharmacology, NCI's Women's Malignancies Branch, National Cancer Institute/National Institutes of Health, Bethesda MD, USA). The authors thank Dr Frank Winkler (DKFZ) for helpful discussions. MHB is supported by the DAAD-Indonesian German Scholarship Programme (IGSP) for doctoral fellowship. KP is the recipient of a B. Braun Stiftungs-Grant. NR 63 TC 2 Z9 2 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. 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CA CDF Collaboration TI Measurement of the single top quark production cross section and vertical bar V-tb vertical bar in 1.96 TeV p(p)over-bar collisions with missing transverse energy and jets and final CDF combination SO PHYSICAL REVIEW D LA English DT Article AB An updated measurement of the single top quark production cross section is presented using the full data set collected by the Collider Detector at Fermilab (CDF), corresponding to 9.5 fb(-1) of integrated luminosity from proton-antiproton collisions at 1.96 TeV center-of-mass energy. The events selected contain an imbalance in the total transverse momentum, jets identified as containing b quarks, and no identified leptons. The sum of the s- and t-channel single top quark cross sections is measured to be 3.53(-1.16)(+1.25) pb and a lower limit on the magnitude of the top-to-bottom quark coupling, vertical bar V-tb vertical bar of 0.63, is obtained at the 95% credibility level. 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RP Aaltonen, T (reprint author), Univ Helsinki, Dept Phys, Div High Energy Phys, FIN-00014 Helsinki, Finland.; Aaltonen, T (reprint author), Helsinki Inst Phys, FIN-00014 Helsinki, Finland. RI Gorelov, Igor/J-9010-2015; Prokoshin, Fedor/E-2795-2012; Canelli, Florencia/O-9693-2016; Ruiz, Alberto/E-4473-2011; Paulini, Manfred/N-7794-2014; OI Gorelov, Igor/0000-0001-5570-0133; Prokoshin, Fedor/0000-0001-6389-5399; Canelli, Florencia/0000-0001-6361-2117; Ruiz, Alberto/0000-0002-3639-0368; Paulini, Manfred/0000-0002-6714-5787; Simonenko, Alexander/0000-0001-6580-3638 FU U.S. Department of Energy; National Science Foundation; Italian Istituto Nazionale di Fisica Nucleare; Ministry of Education, Culture, Sports, Science and Technology of Japan; Natural Sciences and Engineering Research Council of Canada; National Science Council of the Republic of China; Swiss National Science Foundation; A.P. Sloan Foundation; Bundesministerium fur Bildung und Forschung, Germany; Korean World Class University Program, the National Research Foundation of Korea; Science and Technology Facilities Council; Royal Society, United Kingdom; Russian Foundation for Basic Research; Ministerio de Ciencia e Innovacion; Programa Consolider-Ingenio, Spain; Slovak RD Agency; Academy of Finland; Australian Research Council (ARC); EU community Marie Curie Fellowship [302103] FX We thank the Fermilab staff and the technical staffs of the participating institutions for their vital contributions. This work was supported by the U.S. Department of Energy and National Science Foundation; the Italian Istituto Nazionale di Fisica Nucleare; the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Natural Sciences and Engineering Research Council of Canada; the National Science Council of the Republic of China; the Swiss National Science Foundation; the A.P. Sloan Foundation; the Bundesministerium fur Bildung und Forschung, Germany; the Korean World Class University Program, the National Research Foundation of Korea; the Science and Technology Facilities Council and the Royal Society, United Kingdom; the Russian Foundation for Basic Research; the Ministerio de Ciencia e Innovacion, and Programa Consolider-Ingenio 2010, Spain; the Slovak R&D Agency; the Academy of Finland; the Australian Research Council (ARC); and the EU community Marie Curie Fellowship Contract No. 302103. NR 29 TC 1 Z9 1 U1 2 U2 4 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0010 EI 2470-0029 J9 PHYS REV D JI Phys. Rev. D PD FEB 26 PY 2016 VL 93 IS 3 AR 032011 DI 10.1103/PhysRevD.93.032011 PG 9 WC Astronomy & Astrophysics; Physics, Particles & Fields SC Astronomy & Astrophysics; Physics GA DE7VU UT WOS:000370845600002 ER PT J AU Liu, Y Fei, T Zheng, XQ Brown, M Zhang, P Liu, XS Wang, HY AF Liu, Yin Fei, Teng Zheng, Xiaoqi Brown, Myles Zhang, Peng Liu, X. Shirley Wang, Haiyun TI An Integrative Pharmacogenomic Approach Identifies Two-drug Combination Therapies for Personalized Cancer Medicine SO SCIENTIFIC REPORTS LA English DT Article ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; ACQUIRED-RESISTANCE; DRUG-SENSITIVITY; GEFITINIB RESISTANCE; IMPROVED SURVIVAL; KRAS MUTATIONS; MEK INHIBITION; EGFR; MELANOMA AB An individual tumor harbors multiple molecular alterations that promote cell proliferation and prevent apoptosis and differentiation. Drugs that target specific molecular alterations have been introduced into personalized cancer medicine, but their effects can be modulated by the activities of other genes or molecules. Previous studies aiming to identify multiple molecular alterations for combination therapies are limited by available data. Given the recent large scale of available pharmacogenomic data, it is possible to systematically identify multiple biomarkers that contribute jointly to drug sensitivity, and to identify combination therapies for personalized cancer medicine. In this study, we used pharmacogenomic profiling data provided from two independent cohorts in a systematic in silico investigation of perturbed genes cooperatively associated with drug sensitivity. Our study predicted many pairs of molecular biomarkers that may benefit from the use of combination therapies. One of our predicted biomarker pairs, a mutation in the BRAF gene and upregulated expression of the PIM1 gene, was experimentally validated to benefit from a therapy combining BRAF inhibitor and PIM1 inhibitor in lung cancer. This study demonstrates how pharmacogenomic data can be used to systematically identify potentially cooperative genes and provide novel insights to combination therapies in personalized cancer medicine. C1 [Liu, Yin; Wang, Haiyun] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China. [Liu, Yin] Shanghai Pulm Hosp, Shanghai Key Lab TB, Shanghai 200433, Peoples R China. [Liu, Yin; Liu, X. Shirley; Wang, Haiyun] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Liu, Yin; Liu, X. Shirley; Wang, Haiyun] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Fei, Teng; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fei, Teng; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Fei, Teng; Brown, Myles; Liu, X. Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Zheng, Xiaoqi] Shanghai Normal Univ, Dept Math, Shanghai 200234, Peoples R China. [Zhang, Peng] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai 200433, Peoples R China. RP Wang, HY (reprint author), Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China.; Liu, XS; Wang, HY (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.; Liu, XS; Wang, HY (reprint author), Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA.; Liu, XS (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA.; Zhang, P (reprint author), Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai 200433, Peoples R China. EM Zhangpeng1121@163.com; xsliu@jimmy.harvard.edu; wanghaiyun@tongji.edu.cn OI Brown, Myles/0000-0002-8213-1658 FU National Natural Science Foundation of China [31571363, 31100912, 81573023, 31329003, 31100953]; National Institute of Health of USA [1U01 CA180980] FX This work was supported by grants from National Natural Science Foundation of China (31571363, 31100912 and 81573023 to HW; 31329003 to XSL; 31100953 to XZ), and National Institute of Health of USA (1U01 CA180980 to XSL). The authors would like to acknowledge Drs. William Hahn and David Fisher for generously sharing their cancer cell lines for experimental validation, and H. Hansen He for helpful discussions on this study. NR 55 TC 1 Z9 1 U1 5 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 26 PY 2016 VL 6 AR 22120 DI 10.1038/srep22120 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE8CM UT WOS:000370863400001 PM 26916442 ER PT J AU Yang, Z Liu, SW Zhu, MG Zhang, H Wang, J Xu, Q Lin, KS Zhou, XM Tao, M Li, C Zhu, H AF Yang, Zhao Liu, Shengwu Zhu, Mingao Zhang, Hong Wang, Ji Xu, Qian Lin, Kaisu Zhou, Xiumin Tao, Min Li, Chong Zhu, Hong TI PS341 inhibits hepatocellular and colorectal cancer cells through the FOXO3/CTNNB1 signaling pathway SO SCIENTIFIC REPORTS LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; UBIQUITIN-PROTEASOME SYSTEM; PHASE-II TRIAL; TUMOR-SUPPRESSOR; BORTEZOMIB; CARCINOMA; BETA; METASTASIS; EXPRESSION; SORAFENIB AB Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Particularly, a large number of patients with CRC also have liver metastasis. Currently, there are just a few targeted drugs against these two kinds of tumors which can only benefit a very small population of patients. Therefore, the need of more effective therapeutic drugs or strategies for these two types of cancers is urgent. PS341 (Bortezomib) is the first proteasome inhibitor drug which has been approved in clinical treatment for multiple myeloma. Here we demonstrated that PS341 negatively regulated HCC and CRC both in vitro and in vivo, including the inhibition of cell proliferation, epithelial-mesenchymal transition (EMT), the expression of stemness-related genes, cell migration and invasiveness. Mechanically, PS341 upregulated the expression of FOXO3, which inhibited the transcriptional activation of CTNNB1. The downregualtion of CTNNB1 led to apoptosis, cell cycle arrest, and the inhibition of migration, invasion, self-renewal and tumor formation of these two cancer types. In sum, our findings shed light on the PS341 mediated targeted therapy against both HCC and CRC in the future. C1 [Yang, Zhao; Zhou, Xiumin; Tao, Min; Li, Chong; Zhu, Hong] Suzhou Univ, Affiliated Hosp 1, Dept Oncol, Suzhou 215006, Peoples R China. [Yang, Zhao] Chinese Acad Sci, CAS Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Beijing 100101, Peoples R China. [Liu, Shengwu] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Liu, Shengwu] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Zhu, Mingao; Zhang, Hong; Wang, Ji; Xu, Qian; Lin, Kaisu] Soochow Univ, Affiliated Hosp 2, Dept Oncol, Suzhou 215000, Peoples R China. [Li, Chong] Chinese Acad Sci, Lab Anim Ctr, Inst Biophys, Beijing 100101, Peoples R China. [Yang, Zhao] Chinese Acad Sci, Inst Biophys, CAS Key Lab Infect & Immun, Beijing 100101, Peoples R China. RP Li, C; Zhu, H (reprint author), Suzhou Univ, Affiliated Hosp 1, Dept Oncol, Suzhou 215006, Peoples R China.; Li, C (reprint author), Chinese Acad Sci, Lab Anim Ctr, Inst Biophys, Beijing 100101, Peoples R China. EM lichong@moon.ibp.ac.cn; zhuhong_jasmine@suda.edu.cn FU National Natural Science Foundation of China [81472413, 81000944, 81572345, 81572992]; Shenzhen Science and Technology development Funds Program [CXZZ20130516153248144]; Shenzhen Strategic Emerging Industry Development Special Funds Program [JSGG20130411091246833]; Natural Science Foundation of the Jiangsu Higher Education Institutions of China [10KJB320020]; Tianqing Liver Disease Research Foundation [20120024]; Priority Academic Program Development of Jiangsu Higher Education Institutions FX The authors thank all the faculties and staffs of Institute of Microbiology, Harvard Medical School, the First Affiliated Hospital of Soochow University, the Second Affiliated Hospital of Soochow University and Institute of Biophysics whose names were not included in the author list, but who contributed to this work. This work was supported by the National Natural Science Foundation of China (81472413, 81000944, 81572345, 81572992), Shenzhen Science and Technology development Funds Program CXZZ20130516153248144), Shenzhen Strategic Emerging Industry Development Special Funds Program (JSGG20130411091246833), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 10KJB320020), Tianqing Liver Disease Research Foundation (No. 20120024) and Priority Academic Program Development of Jiangsu Higher Education Institutions. NR 48 TC 6 Z9 6 U1 3 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 FEB 26 PY 2016 VL 6 AR 22090 DI 10.1038/srep22090 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE8ZV UT WOS:000370926100001 PM 26915315 ER PT J AU Wilkins, K Hassan, M Francescatto, M Jespersen, J Parra, RG Cuypers, B DeBlasio, D Junge, A Jigisha, A Rahman, F AF Wilkins, Katie Hassan, Mehedi Francescatto, Margherita Jespersen, Jakob Gonzalo Parra, R. Cuypers, Bart DeBlasio, Dan Junge, Alexander Jigisha, Anupama Rahman, Farzana TI Highlights from the eleventh ISCB Student Council Symposium 2015 SO BMC BIOINFORMATICS LA English DT Meeting Abstract CT 11th ISCB-Student-Council Symposium held in conjunction with the Intelligent Systems for Molecular Biology (ISMB) Conference / European Conference on Computational Biology (ECCB) CY JUL 10, 2015 CL Dublin, IRELAND SP Int Soc Computat Biol, Student Council C1 [Wilkins, Katie] Cornell Univ, Sch Integrat Plant Sci, Plant Pathol & Plant Microbe Biol Sect, Ithaca, NY USA. [Wilkins, Katie] Cornell Univ, Grad Field Computat Biol, Ithaca, NY USA. [Hassan, Mehedi; Rahman, Farzana] Univ South Wales, Sch Comp & Math, Cardiff, S Glam, Wales. [Francescatto, Margherita] Helmholtz Assoc, German Ctr Neurodegenerat Dis DZNE, Dept Genome Biol Neurodegenerat Dis, Berlin, Germany. [Jespersen, Jakob] Broad Inst MIT & Harvard, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Jespersen, Jakob] Tech Univ Denmark, Dept Syst Biol, Kemitorvet, Denmark. [Gonzalo Parra, R.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Prot Physiol Lab, Buenos Aires, DF, Argentina. [Cuypers, Bart] Inst Trop Med, MPU, Natl Str 155, B-2000 Antwerp, Belgium. [Cuypers, Bart] Univ Antwerp, Adv Database Res & Modeling ADReM Res Grp, Middelheimlaan 1, B-2020 Antwerp, Belgium. [DeBlasio, Dan] Univ Arizona, Dept Comp Sci, Tucson, AZ 84721 USA. [Junge, Alexander] Univ Copenhagen, Dept Vet Clin & Anim Sci, Ctr Noncoding RNA Technol & Hlth, Copenhagen, Denmark. [Jigisha, Anupama] Univ Coll Dublin, Dublin 2, Ireland. EM frahman@iscb.org NR 15 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 25 PY 2016 VL 17 SU 3 MA A1 BP 203 EP 205 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DG2HC UT WOS:000371886800002 ER PT J AU Knight, EM Ruiz, HH Kim, SH Harte, JC Hsieh, W Glabe, C Klein, WL Attie, AD Buettner, C Ehrlich, ME Gandy, S AF Knight, Elysse M. Ruiz, Henry H. Kim, Soong Ho Harte, Jessica C. Hsieh, Wilson Glabe, Charles Klein, William L. Attie, Alan D. Buettner, Christoph Ehrlich, Michelle E. Gandy, Sam TI Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer's APP/PSEN1 mice by gene targeting of diabetes/Alzheimer's-related Sorcs1 SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE Alzheimer's disease; Amyloid beta; Metabolic; Insulin; Glucose; Transgenic model ID AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN-E RECEPTOR; QUANTITATIVE TRAIT LOCUS; TRANSGENIC MOUSE MODEL; INSULIN-RESISTANCE; A-BETA; DIABETES-MELLITUS; LR11/SORLA EXPRESSION; RETROMER COMPLEX; DISEASE AB Introduction: Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer's disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice. Results: Male mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (A beta) peptide. Conclusions: In general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease. C1 [Knight, Elysse M.; Kim, Soong Ho; Harte, Jessica C.; Ehrlich, Michelle E.; Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Knight, Elysse M.; Kim, Soong Ho; Harte, Jessica C.; Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Knight, Elysse M.; Kim, Soong Ho; Harte, Jessica C.; Gandy, Sam] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Ruiz, Henry H.; Hsieh, Wilson; Buettner, Christoph] Icahn Sch Med Mt Sinai, Dept Med, Diabet Obes & Metab Inst, New York, NY 10029 USA. [Glabe, Charles] Univ Calif Irvine, Irvine, CA 92697 USA. [Klein, William L.] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA. [Attie, Alan D.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Ehrlich, Michelle E.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Gandy, Sam] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Glabe, Charles] King Abdulaziz Univ, Fac Sci, Dept Biochem, Jeddah, Saudi Arabia. [Glabe, Charles] King Abdulaziz Univ, King Fahd Med Res Ctr, Expt Biochem Unit, Jeddah 21413, Saudi Arabia. RP Gandy, S (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA.; Gandy, S (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Gandy, S (reprint author), Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, New York, NY 10029 USA.; Gandy, S (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. EM samuel.gandy@mssm.edu RI Faculty of, Sciences, KAU/E-7305-2017 FU BLRD VA [I01 BX000348]; NIA NIH HHS [P50 AG005138, R34 AG049649, U01 AG046170]; NIAAA NIH HHS [AA023416, R01 AA023416]; NIDDK NIH HHS [DK074873, DK082724, DK083568, K08 DK074873, R03 DK082724]; NINDS NIH HHS [NS075685, R01 NS075685]; RRD VA [I01 RX000684] NR 70 TC 2 Z9 2 U1 1 U2 5 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 FEB 25 PY 2016 VL 4 AR 16 DI 10.1186/s40478-016-0282-y PG 15 WC Neurosciences SC Neurosciences & Neurology GA DE7SE UT WOS:000370836200001 PM 26916443 ER PT J AU Olenchock, BA Moslehi, J Baik, AH Davidson, SM Williams, J Gibson, WJ Pierce, KA Miller, CM Hanse, EA Kelekar, A Sullivan, LB Wagers, AJ Clish, CB Vander Heiden, MG Kaelin, WG AF Olenchock, Benjamin A. Moslehi, Javid Baik, Alan H. Davidson, Shawn M. Williams, Jeremy Gibson, William J. Pierce, Kerry A. Miller, Christine M. Hanse, Eric A. Kelekar, Ameeta Sullivan, Lucas B. Wagers, Amy J. Clish, Clary B. Vander Heiden, Matthew G. Kaelin, William G., Jr. TI EGLN1 Inhibition and Rerouting of alpha-Ketoglutarate Suffice for Remote Ischemic Protection SO CELL LA English DT Article ID REDUCTIVE GLUTAMINE-METABOLISM; PROLYL HYDROXYLASE-ACTIVITY; MYOCARDIAL-INFARCTION; REPERFUSION INJURY; IN-VIVO; HYPOXIA; HEART; SURGERY; TRIAL; 4-HYDROXYLASE AB Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (alpha KG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating alpha KG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting. C1 [Olenchock, Benjamin A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Olenchock, Benjamin A.; Gibson, William J.; Kaelin, William G., Jr.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Olenchock, Benjamin A.; Davidson, Shawn M.; Sullivan, Lucas B.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Moslehi, Javid] Vanderbilt Univ Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37235 USA. [Baik, Alan H.] Univ San Francisco, Dept Med, San Francisco, CA 94117 USA. [Williams, Jeremy; Gibson, William J.; Vander Heiden, Matthew G.; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Pierce, Kerry A.; Clish, Clary B.] Broad Inst, Metabol Platform, Cambridge, MA 02142 USA. [Miller, Christine M.; Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Miller, Christine M.; Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Hanse, Eric A.; Kelekar, Ameeta] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Hanse, Eric A.; Kelekar, Ameeta] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA.; Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Kaelin, WG (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM william_kaelin@dfci.harvard.edu FU NIH [K08 HL119355, K08 HL097031, UO1 HL100402, R01 CA157971]; Gilead Sciences Research Scholars Program in Cardiovascular Disease; Heart Failure Society of America Research Fellowship; Watkins Cardiovascular Discovery Award; Sarnoff Cardiovascular Research Foundation; Broad Institute SPARC program; Burrough's Wellcome Fund; F31 award [CA177119]; Fibrogen, Inc. FX We thank Gerald Wogan, Laura Trudel, and Luiz Godoy for measuring nitrite, Rongli Lao and Souen Ngoy (Brigham and Women's Hospital, BWH) for help with cardiac I/R injury studies, Tom Cooper (Baylor College of Medicine) for the HSA-CreER mice and Lee Flippin and Michael Arend (Fibrogen) for FG-4497. B.A.O. was supported by NIH K08 HL119355 and the Gilead Sciences Research Scholars Program in Cardiovascular Disease. J.M. was supported by NIH K08 HL097031, Heart Failure Society of America Research Fellowship, and the Watkins Cardiovascular Discovery Award (BWH). A.H.B. was supported by a grant from the Sarnoff Cardiovascular Research Foundation. A.J.W. received grant support from NIH UO1 HL100402. M.G.V.H. was supported by the Broad Institute SPARC program and the Burrough's Wellcome Fund. A.J.W. was supported by a grant from the NIH. A.K. was funded by NIH R01 CA157971, E.A.H. by F31 award (CA177119). W.G.K. was supported by grants from the NIH and is an HHMI Investigator. W.G.K. has a financial interest in Fibrogen, Inc., which is developing EGLN inhibitors for treating anemia and ischemic diseases. NR 57 TC 14 Z9 14 U1 11 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 25 PY 2016 VL 164 IS 5 BP 884 EP 895 DI 10.1016/j.cell.2016.02.006 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DE8DZ UT WOS:000370867300013 PM 26919427 ER PT J AU David, CJ Huang, YH Chen, M Su, J Zou, YL Bardeesy, N Iacobuzio-Donahue, CA Massague, J AF David, Charles J. Huang, Yun-Han Chen, Mo Su, Jie Zou, Yilong Bardeesy, Nabeel Iacobuzio-Donahue, Christine A. Massague, Joan TI TGF-beta Tumor Suppression through a Lethal EMT SO CELL LA English DT Article ID GROWTH-FACTOR-BETA; EPITHELIAL-MESENCHYMAL TRANSITION; PANCREATIC DUCTAL ADENOCARCINOMA; LINEAGE-SURVIVAL ONCOGENES; ACUTE MYELOID-LEUKEMIA; TRANSCRIPTION FACTOR; STEM-CELLS; ENHANCED EXPRESSION; DECREASED SURVIVAL; SELF-RENEWAL AB TGF-beta signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-beta mediator Smad4. We show that TGF-beta induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-beta-sensitive PDA cells, EMT becomes lethal by converting TGF-beta-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-beta. TGF-beta-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-beta tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network. C1 [David, Charles J.; Huang, Yun-Han; Su, Jie; Zou, Yilong; Massague, Joan] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Iacobuzio-Donahue, Christine A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Chen, Mo] Rockefeller Univ, New York, NY 10065 USA. [Bardeesy, Nabeel] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA. RP Massague, J (reprint author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. EM j-massague@ski.mskcc.org FU NIH [R01-CA34610, P30-CA008748]; MSKCC Translational Research Oncology Training Program; NIH Medical Scientist Training Program [T32GM007739] FX We thank S. Lowe, A. Lujambio, J. Ahn, R. Garippa, and Q. Xiang for help and advice with shRNA screening. We thank C. Huang for the tandem shRNA vector and K. Xu, M. Overholtzer, and S.E. Kim for help with time-lapse videos. This work was supported by NIH grants R01-CA34610 (J.M.) and P30-CA008748 (MSKCC) and MSKCC Translational Research Oncology Training Program (C.J.D.). Y.-H.H. was supported by NIH Medical Scientist Training Program grant T32GM007739 to the Tri-Institutional MD/PhD Program. NR 59 TC 34 Z9 34 U1 15 U2 38 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 25 PY 2016 VL 164 IS 5 BP 1015 EP 1030 DI 10.1016/j.cell.2016.01.009 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DE8DZ UT WOS:000370867300023 PM 26898331 ER PT J AU Pott, GB Tsurudome, M Bamfo, N Goalstone, ML AF Pott, Gregory B. Tsurudome, Mark Bamfo, Nadia Goalstone, Marc L. TI ERK2 and Akt are negative regulators of insulin and Tumor Necrosis Factor-alpha stimulated VCAM-1 expression in rat aorta endothelial cells SO JOURNAL OF INFLAMMATION-LONDON LA English DT Article DE Atherosclerosis; Inflammation; ERK2; Akt; RNAi; Insulin; TNF alpha; VCAM-1 ID ADHESION MOLECULE-1 EXPRESSION; ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; NF-KAPPA-B; CARDIOVASCULAR-DISEASE; SURFACE EXPRESSION; RESISTANCE; DIFFERENTIATION; INFLAMMATION; MONOCYTE AB Background: Diabetes is quickly becoming the most widespread disorder in the Western world. Among the most prevalent effects of diabetes is atherosclerosis, which in turn is driven in part by inflammation. Both insulin and Tumor Necrosis Factor-alpha (TNF alpha) increase the presence of Vascular Cellular Adhesion Molecule-1 (VCAM-1) expression. The aim of this study is to determine the effects of downregulating Extracellular signal-Regulated Kinase-2 (ERK2) and Akt on insulin and TNF alpha-stimulated VCAM-1 expression. Methods: Here we begin to define the relationships between ERK2 and Akt regulation of insulin and TNF alpha-stimulated VCAM-1 expression in Rat Arterial Endothelial Cells (RAEC) by transfecting RAEC with ERK2 and Akt RNA interference (RNAi) and then treating these cells with insulin (10 nM) or TNF alpha (10 ng/mL) alone or in combination. Results: Western blot analyses, flow cytometry and confocal microscopy were used to determine changes in VCAM-1 expression within the above-stated parameters. Cells transfected with ERK2 or Akt RNAi plasmids increased insulin and TNF alpha-stimulated VCAM-1 total protein expression significantly (P < 0.05) greater than that seen in mock transfected cells and expressed cell surface VCAM-1 greater than that seen in mock transfected cells as indicated by flow cytometry and confocal microscopy. Nevertheless, the decrease of both kinases did not increase insulin or TNF alpha-stimulated VCAM-1 expression above that seen when one or the other RNAi was present. Conclusions: Taken together, our results demonstrate that ERK2 and Akt may be negative regulators of insulin and TNF-alpha stimulated VCAM-1 and that their loss or down regulation might upregulate VCAM-1 expression and contribute to vascular disease. C1 [Pott, Gregory B.; Tsurudome, Mark; Bamfo, Nadia; Goalstone, Marc L.] Univ Colorado Anschutz Med Campus, Div Endocrinol Metab & Diabet, 12801 East 17th Ave Mail Stop 8106, Aurora, CO 80045 USA. [Goalstone, Marc L.] Eastern Colorado Hlth Care Syst, Denver VA Med Ctr, 1055 Clermont St Mail Stop 151, Denver, CO 80220 USA. RP Goalstone, ML (reprint author), Univ Colorado Anschutz Med Campus, Div Endocrinol Metab & Diabet, 12801 East 17th Ave Mail Stop 8106, Aurora, CO 80045 USA.; Goalstone, ML (reprint author), Eastern Colorado Hlth Care Syst, Denver VA Med Ctr, 1055 Clermont St Mail Stop 151, Denver, CO 80220 USA. EM Marc.Goalstone@va.gov FU Research Service of the Department of Veterans Affairs FX This work was supported by the Research Service of the Department of Veterans Affairs (to M.L.G.), in which Dr. Goalstone is a recipient of a VA Merit Review Award. We would like to thank Ron Bouchard for his excellent work in confocal microscopy and Harsh Pratap for his beneficial assistance with our flow cytometry measurements. The flow cytometer is equipment associated with the Mucosal and Vaccine Research Colorado (MAVRC). NR 25 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 1476-9255 J9 J INFLAMM-LOND JI J. Inflamm.-Lond. PD FEB 25 PY 2016 VL 13 AR 6 DI 10.1186/s12950-016-0115-6 PG 9 WC Immunology SC Immunology GA DF1WR UT WOS:000371130600001 PM 26917991 ER PT J AU Albrecht, BK Gehling, VS Hewitt, MC Vaswani, RG Cote, A Leblanc, Y Nasveschuk, CG Bellon, S Bergeron, L Campbell, R Cantone, N Cooper, MR Cummings, RT Jayaram, H Joshi, S Mertz, JA Neiss, A Normant, E O'Meara, M Pardo, E Poy, F Sandy, P Supko, J Sims, RJ Harmange, JC Taylor, AM Audia, JE AF Albrecht, Brian K. Gehling, Victor S. Hewitt, Michael C. Vaswani, Rishi G. Cote, Alexandre Leblanc, Yves Nasveschuk, Christopher G. Bellon, Steve Bergeron, Louise Campbell, Robert Cantone, Nico Cooper, Michael R. Cummings, Richard T. Jayaram, Hariharan Joshi, Shivangi Mertz, Jennifer A. Neiss, Adrianne Normant, Emmanuel O'Meara, Michael Pardo, Eneida Poy, Florence Sandy, Peter Supko, Jeffrey Sims, Robert J., III Harmange, Jean-Christophe Taylor, Alexander M. Audia, James E. TI Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; C-MYC; BRD4; TARGET; CANCER; CELLS AB In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-kappa B. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610). C1 [Albrecht, Brian K.; Gehling, Victor S.; Hewitt, Michael C.; Vaswani, Rishi G.; Cote, Alexandre; Leblanc, Yves; Nasveschuk, Christopher G.; Bellon, Steve; Bergeron, Louise; Campbell, Robert; Cantone, Nico; Cooper, Michael R.; Cummings, Richard T.; Jayaram, Hariharan; Joshi, Shivangi; Mertz, Jennifer A.; Neiss, Adrianne; Normant, Emmanuel; O'Meara, Michael; Pardo, Eneida; Poy, Florence; Sandy, Peter; Supko, Jeffrey; Sims, Robert J., III; Harmange, Jean-Christophe; Taylor, Alexander M.; Audia, James E.] Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA. [Albrecht, Brian K.; Harmange, Jean-Christophe] Third Rock Ventures, 29 Newbury St 301, Boston, MA 02116 USA. [Leblanc, Yves] Paraza Pharma Inc, 7171 Frederick Banting, Montreal, PQ H4S 1Z9, Canada. [Nasveschuk, Christopher G.] Broad Inst, 415 Main St, Cambridge, MA 02142 USA. [Bergeron, Louise] Bergeron Drug Discovery, Rome, Italy. [Campbell, Robert] Blueprint Med, 38 Sidney St 200, Cambridge, MA 02139 USA. [Jayaram, Hariharan; Joshi, Shivangi] Editas Med, 300 Third St, Cambridge, MA 02142 USA. [Neiss, Adrianne] Huntsman Canc Inst, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA. [Normant, Emmanuel] Surface Oncol, 215 First St,Suite 400-S, Cambridge, MA 02142 USA. [Pardo, Eneida] Forma Therapeut, 500 Arsenal St, Watertown, MA 02472 USA. [Sandy, Peter] Evelo Therapeut, 620 Mem Dr,Suite 200 West, Cambridge, MA 02139 USA. [Supko, Jeffrey] Massachusetts Gen Hosp, Dana Farber Harvard Canc Ctr, 55 Fruit St,GRJ1025, Boston, MA 02114 USA. RP Taylor, AM; Audia, JE (reprint author), Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA. EM Alex.Taylor@constellationpharma.com; Jim.Audia@constellationpharma.com OI Neiss, Adrianne/0000-0001-5329-782X NR 28 TC 11 Z9 11 U1 4 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 25 PY 2016 VL 59 IS 4 SI SI BP 1330 EP 1339 DI 10.1021/acs.jmedchem.5b01882 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DF1MJ UT WOS:000371103600006 PM 26815195 ER PT J AU Clemente-Casares, X Blanco, J Ambalavanan, P Yamanouchi, J Singha, S Fandos, C Tsai, S Wang, JG Garabatos, N Izquierdo, C Agrawal, S Keough, MB Yong, VW James, E Moore, A Yang, Y Stratmann, T Serra, P Santamaria, P AF Clemente-Casares, Xavier Blanco, Jesus Ambalavanan, Poornima Yamanouchi, Jun Singha, Santiswarup Fandos, Cesar Tsai, Sue Wang, Jinguo Garabatos, Nahir Izquierdo, Cristina Agrawal, Smriti Keough, Michael B. Yong, V. Wee James, Eddie Moore, Anna Yang, Yang Stratmann, Thomas Serra, Pau Santamaria, Pere TI Expanding antigen-specific regulatory networks to treat autoimmunity SO NATURE LA English DT Article ID SUBUNIT-RELATED PROTEIN; CD8(+) T-CELLS; C-MAF; TOLERANCE; DIFFERENTIATION; AUTOANTIGEN; INSTABILITY; ACTIVATION; GENERATION; ARTHRITIS AB Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (T(R)1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into T(R)1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner. C1 [Clemente-Casares, Xavier; Ambalavanan, Poornima; Yamanouchi, Jun; Singha, Santiswarup; Tsai, Sue; Yang, Yang; Santamaria, Pere] Univ Calgary, Snyder Inst Chron Dis & Hotchkiss Brain Inst, Cumming Sch Med, JMDRC, Calgary, AB T2N 4N1, Canada. [Clemente-Casares, Xavier; Ambalavanan, Poornima; Yamanouchi, Jun; Singha, Santiswarup; Tsai, Sue; Wang, Jinguo; Yang, Yang; Santamaria, Pere] Univ Calgary, Snyder Inst Chron Dis & Hotchkiss Brain Inst, Cumming Sch Med, Dept Microbiol Immunol & Infect Dis, Calgary, AB T2N 4N1, Canada. [Blanco, Jesus; Fandos, Cesar; Serra, Pau; Santamaria, Pere] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain. [Blanco, Jesus] Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedades, Metab Asociadas CIBERDEM, Madrid 28029, Spain. [Garabatos, Nahir; Izquierdo, Cristina; Stratmann, Thomas] Univ Barcelona, Fac Biol, Dept Physiol & Immunol, E-08028 Barcelona, Spain. [Agrawal, Smriti; Keough, Michael B.; Yong, V. Wee] Univ Calgary, Fac Med, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada. [Agrawal, Smriti; Keough, Michael B.; Yong, V. Wee] Univ Calgary, Fac Med, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. [James, Eddie] Virginia Mason, Benaroya Res Inst, Seattle, WA 98101 USA. [Moore, Anna] Massachusetts Gen Hosp, Dept Radiol, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Yang, Yang] Univ Calgary, Cumming Sch Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. RP Santamaria, P (reprint author), Univ Calgary, Snyder Inst Chron Dis & Hotchkiss Brain Inst, Cumming Sch Med, JMDRC, Calgary, AB T2N 4N1, Canada.; Santamaria, P (reprint author), Univ Calgary, Snyder Inst Chron Dis & Hotchkiss Brain Inst, Cumming Sch Med, Dept Microbiol Immunol & Infect Dis, Calgary, AB T2N 4N1, Canada.; Santamaria, P (reprint author), Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain. EM psantama@ucalgary.ca RI Blanco Carrasco, Antonio Jesus/H-8938-2015 OI Blanco Carrasco, Antonio Jesus/0000-0001-5903-430X FU Canadian Institutes of Health Research (CIHR); Diabetes Research Foundation; Juvenile Diabetes Research Foundation (JDRF); Canadian Diabetes Association (CDA); Multiple Sclerosis Society of Canada (MSSC); Brawn Family Foundation; National Research Council of Canada-Industrial Research Assistance Program (NRC-IRAP); Instituto de Investigaciones Sanitarias Carlos III (ISCIII) Integrated Project of Excellence; Instituto de Investigaciones Sanitarias Carlos III (ISCIII) Integrated Project of FEDER; Ministerio de Economia y Competitividad of Spain (MINECO); European Association for the study of diabetes (EASD); Sarda Farriol Research Programme; European Community; AXA Research Fund; endMS network; Rio Hortega fellowship; Spanish Society for Diabetes; Alberta Heritage Foundation of Medical Research (AHFMR); CDA; JDRF Career Development Award; Diabetes Association (Foothills) FX We thank S. Thiessen, J. DeLongchamp, J. Erickson, J. Luces, R. Barasi and K. Umeshappa for technical contributions; L. Kennedy, L. Robertson and Y. Liu for flow cytometry; F. Jirik for help with histological analyses of arthritic mice; J. Elliott and K. Suzuki for Meso Scale measurements; M. Fritzler for Luminex; and P. Colarusso for assistance with microscopy. This work was funded by the Canadian Institutes of Health Research (CIHR), the Diabetes Research Foundation, the Juvenile Diabetes Research Foundation (JDRF), the Canadian Diabetes Association (CDA), the Multiple Sclerosis Society of Canada (MSSC), the Brawn Family Foundation, National Research Council of Canada-Industrial Research Assistance Program (NRC-IRAP), Instituto de Investigaciones Sanitarias Carlos III (ISCIII) Integrated Projects of Excellence and FEDER, the Ministerio de Economia y Competitividad of Spain (MINECO), the European Association for the study of diabetes (EASD), the Sarda Farriol Research Programme, and the European Community's Seventh Framework Programme. X. C. C. was supported by studentships from the AXA Research Fund and the endMS network. P. A. was supported by the endMS network. J. B. was suported by a Rio Hortega fellowship and by a grant from the Spanish Society for Diabetes. S. T. was supported by a studentship from the Alberta Heritage Foundation of Medical Research (AHFMR). J. W. was funded by a fellowship from the CDA. P. Se. is an investigator of the Ramon y Cajal reintegration program and is supported by a JDRF Career Development Award. P. Sa. is a Scientist of the Alberta Innovates-Health Solutions and a scholar of ISCIII. The JMDRC is supported by the Diabetes Association (Foothills) and the CDA. NR 31 TC 35 Z9 36 U1 11 U2 40 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 FEB 25 PY 2016 VL 530 IS 7591 BP 434 EP + DI 10.1038/nature16962 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE5RW UT WOS:000370690800026 PM 26886799 ER PT J AU Nishikawa, JL Boeszoermenyi, A Vale-Silva, LA Torelli, R Posteraro, B Sohn, YJ Ji, F Gelev, V Sanglard, D Sanguinetti, M Sadreyev, RI Mukherjee, G Bhyravabhotla, J Buhrlage, SJ Gray, NS Wagner, G Naar, AM Arthanari, H AF Nishikawa, Joy L. Boeszoermenyi, Andras Vale-Silva, Luis A. Torelli, Riccardo Posteraro, Brunella Sohn, Yoo-Jin Ji, Fei Gelev, Vladimir Sanglard, Dominique Sanguinetti, Maurizio Sadreyev, Ruslan I. Mukherjee, Goutam Bhyravabhotla, Jayaram Buhrlage, Sara J. Gray, Nathanael S. Wagner, Gerhard Naeaer, Anders M. Arthanari, Haribabu TI Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction SO NATURE LA English DT Article ID AZOLE ANTIFUNGAL AGENTS; CANDIDA-GLABRATA; PROTEIN; EXPRESSION; INFECTION; PDR1 AB Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex(1,2). Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi(3,4). The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata(5,6). The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent(7,8). Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active(9-14), suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a transcription factor-binding site in Mediator as a novel therapeutic strategy in fungal infectious disease. C1 [Nishikawa, Joy L.; Sohn, Yoo-Jin; Naeaer, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Nishikawa, Joy L.; Sohn, Yoo-Jin; Naeaer, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Boeszoermenyi, Andras; Buhrlage, Sara J.; Gray, Nathanael S.; Wagner, Gerhard; Arthanari, Haribabu] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Vale-Silva, Luis A.; Sanglard, Dominique] Univ Lausanne Hosp, Inst Microbiol, CH-1011 Lausanne, Switzerland. [Vale-Silva, Luis A.; Sanglard, Dominique] Univ Hosp Ctr, CH-1011 Lausanne, Switzerland. [Torelli, Riccardo; Sanguinetti, Maurizio] Univ Cattolica Sacro Cuore, Inst Microbiol, I-00168 Rome, Italy. [Posteraro, Brunella] Univ Cattolica Sacro Cuore, Inst Publ Hlth, I-00168 Rome, Italy. [Ji, Fei; Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Ji, Fei] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Gelev, Vladimir] Univ Sofia, Fac Chem & Pharm, Sofia 1164, Bulgaria. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mukherjee, Goutam; Bhyravabhotla, Jayaram] Indian Inst Technol Delhi, Dept Chem, New Delhi 110016, India. [Mukherjee, Goutam; Bhyravabhotla, Jayaram] Indian Inst Technol Delhi, Supercomp Facil Bioinformat & Computat Biol, New Delhi 110016, India. [Bhyravabhotla, Jayaram] Indian Inst Technol Delhi, Kusuma Sch Biol Sci, New Delhi 110016, India. [Buhrlage, Sara J.; Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Naar, AM (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.; Wagner, G; Arthanari, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM gerhard_wagner@hms.harvard.edu; naar@helix.mgh.harvard.edu; hari_arthanari@hms.harvard.edu RI Mukherjee, G/B-2622-2017; Mukherjee, Goutam/B-6478-2017; OI Mukherjee, G/0000-0003-2422-1601; Mukherjee, Goutam/0000-0002-4620-2770; Boeszoermenyi, Andras/0000-0001-9810-7241; Sanguinetti, Maurizio/0000-0002-9780-7059; Sanglard, Dominique/0000-0002-5244-4178 FU National Institute of Health [GM047467, EB002026]; NSERC fellowship FX We are grateful to P. Coote, E. Papadopoulos, R. Oh and R. E. Luna for helpful discussions and advice with data analysis and manuscript preparation. We acknowledge the ICCB-Longwood Screening Facility at Harvard Medical School for assistance with the high-throughput screens and access to the compound libraries, and the MGH Next Gen sequencing core for RNA-seq library construction. Mouse plasma and microsomal stability experiments were carried out at the Scripps Research Institute and iKIX1 pharmacokinetic parameters were assessed by Sai Life Sciences Limited. We acknowledge support from the National Institute of Health (grants GM047467 to G.W. and A.M.N. and EB002026 to G.W.). J.L.N. was supported by an NSERC fellowship. NR 26 TC 9 Z9 9 U1 12 U2 29 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 FEB 25 PY 2016 VL 530 IS 7591 BP 485 EP + DI 10.1038/nature16963 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE5RW UT WOS:000370690800037 PM 26886795 ER PT J AU Paul-Emile, K Smith, AK Lo, B Fernandez, A AF Paul-Emile, Kimani Smith, Alexander K. Lo, Bernard Fernandez, Alicia TI Dealing with Racist Patients SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Paul-Emile, Kimani] Fordham Univ, Sch Law, New York, NY 10023 USA. [Lo, Bernard] Greenwall Fdn, New York, NY USA. [Smith, Alexander K.] Univ Calif San Francisco, Div Geriatr, Dept Med, San Francisco, CA 94143 USA. [Fernandez, Alicia] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Smith, Alexander K.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Paul-Emile, K (reprint author), Fordham Univ, Sch Law, New York, NY 10023 USA. NR 3 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 FEB 25 PY 2016 VL 374 IS 8 BP 708 EP 711 DI 10.1056/NEJMp1514939 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DE6BB UT WOS:000370716600004 PM 26933847 ER PT J AU Chan, JK Brady, MF Penson, RT Huang, H Birrer, MJ Walker, JL DiSilvestro, PA Rubin, SC Martin, LP Davidson, SA Huh, WK O'Malley, DM Boente, MP Michael, H Monk, BJ AF Chan, J. K. Brady, M. F. Penson, R. T. Huang, H. Birrer, M. J. Walker, J. L. DiSilvestro, P. A. Rubin, S. C. Martin, L. P. Davidson, S. A. Huh, W. K. O'Malley, D. M. Boente, M. P. Michael, H. Monk, B. J. TI Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC BREAST-CANCER; PHASE-III TRIAL; EVERY 3 WEEKS; EPITHELIAL OVARIAN; OPEN-LABEL; ADJUVANT TREATMENT; PRIMARY PERITONEAL; FALLOPIAN-TUBE; SOLID TUMORS; BEVACIZUMAB AB BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.) C1 [Chan, J. K.] Calif Pacific Palo Alto Med Fdn, Sutter Canc Res Inst, 3838 Calif St,Unit 410, San Francisco, CA 94118 USA. [Brady, M. F.; Huang, H.] Roswell Pk Canc Inst, Stat & Data Ctr, NRG Oncol Gynecol Oncol Grp, Buffalo, NY 14263 USA. [Penson, R. T.; Birrer, M. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, J. L.] Univ Oklahoma, Oklahoma City, OK USA. [DiSilvestro, P. A.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Rubin, S. C.] Univ Penn, Philadelphia, PA 19104 USA. [Martin, L. P.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Davidson, S. A.] Univ Colorado, Ctr Canc, Aurora, CO USA. [Huh, W. K.] Univ Alabama Birmingham, Birmingham, AL USA. [O'Malley, D. M.] Ohio State Univ, James Canc Ctr, Columbus, OH 43210 USA. [Boente, M. P.] Minnesota Oncol Hematol Oncol Serv, Edina, MN USA. [Michael, H.] Indiana Univ Sch Med, Carmel, IN USA. [Monk, B. J.] Univ Arizona, Ctr Canc, Phoenix, AZ USA. [Monk, B. J.] Creighton Univ, Sch Med, Phoenix, AZ USA. [Monk, B. J.] St Josephs Hosp, Phoenix, AZ USA. RP Chan, JK (reprint author), Calif Pacific Palo Alto Med Fdn, Sutter Canc Res Inst, 3838 Calif St,Unit 410, San Francisco, CA 94118 USA. EM chanjohn@sutterhealth.org RI OMalley, David/E-3789-2011 FU National Cancer Institute; Genentech FX Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712. NR 36 TC 22 Z9 23 U1 8 U2 12 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 FEB 25 PY 2016 VL 374 IS 8 BP 738 EP 748 DI 10.1056/NEJMoa1505067 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DE6BB UT WOS:000370716600007 PM 26933849 ER PT J AU Zhang, YQ Niu, JB Choi, HK AF Zhang, Yuqing Niu, Jingbo Choi, Hyon K. TI Excess Mortality among Persons with Type 2 Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Zhang, Yuqing; Niu, Jingbo] Boston Univ, Sch Med, Boston, MA 02118 USA. [Choi, Hyon K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zhang, YQ (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM yuqing@bu.edu NR 4 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 25 PY 2016 VL 374 IS 8 BP 788 EP 788 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DE6BB UT WOS:000370716600016 PM 26933855 ER PT J AU Khamis, RY Woollard, KJ Hyde, GD Boyle, JJ Bicknell, C Chang, SH Malik, TH Hara, T Mauskapf, A Granger, DW Johnson, JL Ntziachristos, V Matthews, PM Jaffer, FA Haskard, DO AF Khamis, Ramzi Y. Woollard, Kevin J. Hyde, Gareth D. Boyle, Joseph J. Bicknell, Colin Chang, Shang-Hung Malik, Talat H. Hara, Tetsuya Mauskapf, Adam Granger, David W. Johnson, Jason L. Ntziachristos, Vasilis Matthews, Paul M. Jaffer, Farouc A. Haskard, Dorian O. TI Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis SO SCIENTIFIC REPORTS LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; OXIDATION-SPECIFIC EPITOPES; RECEPTOR-DEFICIENT MICE; IN-VIVO; LESIONS; PLAQUE; CORONARY; STABILIZATION; INFLAMMATION; EXPRESSION AB We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis. LO1, a well-characterized monoclonal autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions. Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr(-/-) mice led to specific focal localization within the aortic arch and its branches, as detected by fluorescence molecular tomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocal microscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites of atherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMP activity (MMPSense-645-FAST), both probes produced statistically significant increases in NIRF signal in the Ldlr(-/-)model in relation to duration of HF diet. Upon withdrawing the HF diet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less marked than the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization was successfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detection catheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parent antibody in murine atheroma showing promise for future translation. C1 [Khamis, Ramzi Y.; Hyde, Gareth D.; Boyle, Joseph J.; Chang, Shang-Hung; Haskard, Dorian O.] Univ London Imperial Coll Sci Technol & Med, Vasc Sci Sect, Natl Heart & Lung Inst, London, England. [Woollard, Kevin J.; Malik, Talat H.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Bicknell, Colin] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Hara, Tetsuya; Mauskapf, Adam; Ntziachristos, Vasilis; Jaffer, Farouc A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Cambridge, MA 02138 USA. [Hara, Tetsuya; Mauskapf, Adam; Ntziachristos, Vasilis; Jaffer, Farouc A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Cambridge, MA 02138 USA. [Granger, David W.] GlaxoSmithKline, Biopharm R&D, Stevenage, Herts, England. [Johnson, Jason L.] Univ Bristol, Sch Clin Sci, Bristol BS8 1TH, Avon, England. [Matthews, Paul M.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Brain Sci, London, England. RP Haskard, DO (reprint author), Univ London Imperial Coll Sci Technol & Med, Vasc Sci Sect, Natl Heart & Lung Inst, London, England. EM d.haskard@imperial.ac.uk OI Khamis, Ramzi /0000-0003-4119-5193 FU Wellcome Trust Clinical Research Fellowship, as part of the Wellcome Trust/GSK Fellowship programme [095034/Z/10/Z]; British Atherosclerosis Society Binks Trust Travel Award [BASBT/13/001]; NIH [HL R01 108229]; British Heart Foundation (BHF); BHF; Imperial College Healthcare Trust Biomedical Research Centre FX We thank Professors Martin Wilkins and Michael Schneider at Imperial College for their help in making the resources available. We also thank and acknowledge Lisa Wells and Nicholas Keat at Imanova, Jordi Lopez Tremoleda and Willy Gsell at the Biological Imaging Centre, Martin Spitaler in Facility for Imaging by Light Microscopy (FILM), all at Imperial College for their technical support. We also acknowledge Cecilia Reid in Biopharm R&D, GSK for confirmatory mass spectrometry. RK received a Wellcome Trust Clinical Research Fellowship (095034/Z/10/Z) (as part of the Wellcome Trust/GSK Fellowship programme), and a British Atherosclerosis Society Binks Trust Travel Award (BASBT/13/001). Rabbit studies were supported by NIH HL R01 108229 (FAJ). DH receives professorial chair funding from the British Heart Foundation (BHF). The FMT equipment was purchased by an infrastructure grant from the BHF. PMM's research and supply of human carotid tissue was supported by the Imperial College Healthcare Trust Biomedical Research Centre. NR 33 TC 2 Z9 2 U1 3 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 FEB 25 PY 2016 VL 6 AR 21785 DI 10.1038/srep21785 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE7BZ UT WOS:000370790300001 PM 26911995 ER PT J AU Li, X Chatterjee, N Spirohn, K Boutros, M Bohmann, D AF Li, Xuan Chatterjee, Nirmalya Spirohn, Kerstin Boutros, Michael Bohmann, Dirk TI Cdk12 Is A Gene-Selective RNA Polymerase II Kinase That Regulates a Subset of the Transcriptome, Including Nrf2 Target Genes SO SCIENTIFIC REPORTS LA English DT Article ID GLUTATHIONE-S-TRANSFERASES; TERMINAL REPEAT DOMAIN; PROTEIN-KINASE; ANTIOXIDANT RESPONSE; ADAPTIVE RESPONSE; OXIDATIVE STRESS; CELL-SURVIVAL; PHOSPHORYLATION; ACTIVATION; DEGRADATION AB The Nrf2 transcription factor is well conserved throughout metazoan evolution and serves as a central regulator of adaptive cellular responses to oxidative stress. We carried out an RNAi screen in Drosophila S2 cells to better understand the regulatory mechanisms governing Nrf2 target gene expression. This paper describes the identification and characterization of the RNA polymerase II (Pol II) kinase Cdk12 as a factor that is required for Nrf2 target gene expression in cell culture and in vivo. Cdk12 is, however, not essential for bulk mRNA transcription and cells lacking CDK12 function are viable and able to proliferate. Consistent with previous findings on the DNA damage and heat shock responses, it emerges that Cdk12 may be specifically required for stress activated gene expression. Transcriptome analysis revealed that antioxidant gene expression is compromised in flies with reduced Cdk12 function, which makes them oxidative stress sensitive. In addition to supporting Reactive Oxygen Species (ROS) induced gene activation, Cdk12 suppresses genes that support metabolic functions in stressed conditions. We suggest that Cdk12 acts as a gene-selective Pol II kinase that engages a global shift in gene expression to switch cells from a metabolically active state to "stress-defence mode" when challenged by external stress. C1 [Li, Xuan; Chatterjee, Nirmalya; Bohmann, Dirk] Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. [Spirohn, Kerstin; Boutros, Michael] Heidelberg Univ, Div Signaling & Funct Genom, German Canc Res Ctr DKFZ, Med Fac Mannheim, Heidelberg, Germany. [Spirohn, Kerstin; Boutros, Michael] Heidelberg Univ, Dept Cell & Mol Biol, Med Fac Mannheim, Heidelberg, Germany. [Spirohn, Kerstin] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RP Bohmann, D (reprint author), Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. EM dirk_bohmann@urmc.rochester.edu FU NIH [R01 GM100196, R01 AG039753]; DFG FX We would like to thank Helene McMurray, PhD. for her help with analyses of the RNA-seq data. We thank Christine Sommers for lab management and maintaining fly room infrastructure. This work was supported by NIH grants R01 GM100196 and R01 AG039753 to DB. Work in the lab of M.B. has been supported by a DFG infrastructure grant 'DRiC. NR 56 TC 2 Z9 2 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 FEB 25 PY 2016 VL 6 AR 21455 DI 10.1038/srep21455 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE6ZW UT WOS:000370784600001 PM 26911346 ER PT J AU Biller, JA Butros, SR Chan-Smutko, G Abrams, AN Chung, DC Hagen, CE AF Biller, Jeffrey A. Butros, S. Reha Chan-Smutko, Gayun Abrams, Annah N. Chung, Daniel C. Hagen, Catherine E. TI Case 6-2016: A 10-Year-Old Boy with Abdominal Cramping and Fevers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EUROPEAN CONSORTIUM CARE; EARLY-ONSET; MICROSATELLITE INSTABILITY; COLORECTAL-CARCINOMA; LYNCH-SYNDROME; CHILDREN; NEUROFIBROMATOSIS; CANCERS; INTUSSUSCEPTION; TUBERCULOSIS C1 [Biller, Jeffrey A.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Butros, S. Reha] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Abrams, Annah N.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Chung, Daniel C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hagen, Catherine E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chan-Smutko, Gayun; Chung, Daniel C.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Biller, Jeffrey A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Butros, S. Reha] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Abrams, Annah N.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Chung, Daniel C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hagen, Catherine E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Biller, JA (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 26 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 25 PY 2016 VL 374 IS 8 BP 772 EP 781 DI 10.1056/NEJMcpc1408597 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DE6BB UT WOS:000370716600012 PM 26933852 ER PT J AU Krieg, E Bastings, MMC Besenius, P Rybtchinski, B AF Krieg, Elisha Bastings, Maartje M. C. Besenius, Pol Rybtchinski, Boris TI Supramolecular Polymers in Aqueous Media SO CHEMICAL REVIEWS LA English DT Review ID HELICAL ROSETTE NANOTUBES; DYNAMIC COMBINATORIAL LIBRARIES; PEPTIDE-AMPHIPHILE NANOFIBERS; HYBRIDIZATION CHAIN-REACTION; ARTIFICIAL BETA-BARRELS; PERYLENE BISIMIDE DYES; TOBACCO-MOSAIC-VIRUS; THERMORESPONSIVE CYCLIC PEPTIDE; STRUCTURAL DNA NANOTECHNOLOGY; ASSEMBLING ORGANIC NANOTUBES AB This review discusses one-dimensional supramolecular polymers that form in aqueous media. First, naturally occurring supramolecular polymers are described, in particular, amyloid fibrils, actin filaments, and microtubules. Their structural, thermodynamic, kinetic, and nanomechanical properties are highlighted, as well as their importance for the advancement of biologically inspired supramolecular polymer materials. Second, five classes of synthetic supramolecular polymers are described: systems based on (1) hydrogen-bond motifs, (2) large pi-conjugated surfaces, (3) host guest interactions, (4) peptides, and (5) DNA. We focus on recent studies that address key challenges in the field, providing mechanistic understanding, rational polymer design, important functionality, robustness, or unusual thermodynamic and kinetic properties. C1 [Krieg, Elisha; Bastings, Maartje M. C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Krieg, Elisha; Bastings, Maartje M. C.] Harvard Univ, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Krieg, Elisha; Bastings, Maartje M. C.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Besenius, Pol] Johannes Gutenberg Univ Mainz, Inst Organ Chem, D-55128 Mainz, Germany. [Rybtchinski, Boris] Weizmann Inst Sci, Dept Organ Chem, IL-76100 Rehovot, Israel. RP Krieg, E (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Krieg, E (reprint author), Harvard Univ, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Krieg, E (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.; Besenius, P (reprint author), Johannes Gutenberg Univ Mainz, Inst Organ Chem, D-55128 Mainz, Germany.; Rybtchinski, B (reprint author), Weizmann Inst Sci, Dept Organ Chem, IL-76100 Rehovot, Israel. EM elisha.krieg@wyss.harvard.edu; besenius@uni-mainz.de; boris.rybtchinski@weizmann.ac.il RI Besenius, Pol/C-1207-2009; Krieg, Elisha/J-4591-2014 OI Besenius, Pol/0000-0001-7478-4459; Krieg, Elisha/0000-0002-2989-9879 FU Human Frontier Science Program; Israel Science Foundation; Minerva Foundation; US Israel Binational Science Foundation; Gerhardt M. J. Schmidt Minerva Center of Supramolecular Architectures; Helen and Martin Kimmel Center for Molecular Design FX E.K. and M.M.C.B. gratefully acknowledge support of the Human Frontier Science Program. B.R. acknowledges support from the Israel Science Foundation, Minerva Foundation, US Israel Binational Science Foundation, Gerhardt M. J. Schmidt Minerva Center of Supramolecular Architectures, and the Helen and Martin Kimmel Center for Molecular Design. NR 600 TC 35 Z9 35 U1 102 U2 241 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD FEB 24 PY 2016 VL 116 IS 4 SI SI BP 2414 EP 2477 DI 10.1021/acs.chemrev.5b00369 PG 64 WC Chemistry, Multidisciplinary SC Chemistry GA DF1NH UT WOS:000371106000017 PM 26727633 ER PT J AU Chu, YH Hsu, YC Keil, B Kuo, WJ Lin, FH AF Chu, Ying-Hua Hsu, Yi-Cheng Keil, Boris Kuo, Wen-Jui Lin, Fa-Hsuan TI A 32-Channel Head Coil Array with Circularly Symmetric Geometry for Accelerated Human Brain Imaging SO PLOS ONE LA English DT Article ID TO-NOISE RATIO; 3 TESLA; PHASED-ARRAY; PARALLEL MRI; DESIGN; ACQUISITION; RECONSTRUCTION; GRADIENTS; FIELDS; SENSE AB The goal of this study is to optimize a 32-channel head coil array for accelerated 3T human brain proton MRI using either a Cartesian or a radial k-space trajectory. Coils had curved trapezoidal shapes and were arranged in a circular symmetry (CS) geometry. Coils were optimally overlapped to reduce mutual inductance. Low-noise pre-amplifiers were used to further decouple between coils. The SNR and noise amplification in accelerated imaging were compared to results from a head coil array with a soccer-ball (SB) geometry. The maximal SNR in the CS array was about 120% (1070 vs. 892) and 62% (303 vs. 488) of the SB array at the periphery and the center of the FOV on a transverse plane, respectively. In onedimensional 4-fold acceleration, the CS array has higher averaged SNR than the SB array across the whole FOV. Compared to the SB array, the CS array has a smaller g-factor at head periphery in all accelerated acquisitions. Reconstructed images using a radial k-space trajectory show that the CS array has a smaller error than the SB array in 2- to 5-fold accelerations. C1 [Chu, Ying-Hua; Hsu, Yi-Cheng; Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. [Keil, Boris] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Keil, Boris] Mittelhessen Univ Appl Sci, Dept Life Sci Engn, Inst Med Phys & Radiat Safety, Giessen, Germany. [Kuo, Wen-Jui] Natl Yang Ming Univ, Inst Neurosci, Taipei 112, Taiwan. RP Lin, FH (reprint author), Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. EM fhlin@ntu.edu.tw RI Lin, Fa-Hsuan/G-6988-2012 OI Lin, Fa-Hsuan/0000-0002-9539-1731 FU National Science Council, Taiwan [NSC 101-2628-B-002-005-MY3, NSC 100-2325-B-002-046]; Academy of Finland (the FiDiPro program); Ministry of Science and Technology, Taiwan [MOST 103-2628-B-002-002-MY3, MOST 104-2314-B-002 -238, MOST 102-2410-H-010-004 -MY2]; Ministry of Economic Affairs, Taiwan [100-EC-17-A-19-S1-175]; National Health Research Institute, Taiwan [NHRI-EX103-10247EI] FX This work was supported by NSC 101-2628-B-002-005-MY3, NSC 100-2325-B-002-046 (National Science Council, Taiwan), and Academy of Finland (the FiDiPro program). This work was also partially supported by MOST 103-2628-B-002-002-MY3, MOST 104-2314-B-002 -238, MOST 102-2410-H-010-004 -MY2 (Ministry of Science and Technology, Taiwan), 100-EC-17-A-19-S1-175 (Ministry of Economic Affairs, Taiwan), and NHRI-EX103-10247EI (National Health Research Institute, Taiwan). The funders had no role in study design, NR 33 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 24 PY 2016 VL 11 IS 2 AR e0149446 DI 10.1371/journal.pone.0149446 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2IA UT WOS:000371164700034 PM 26909652 ER PT J AU Yang, N Friedl, A AF Yang, Ning Friedl, Andreas TI Syndecan-1-Induced ECM Fiber Alignment Requires Integrin alpha v beta 3 and Syndecan-1 Ectodomain and Heparan Sulfate Chains SO PLOS ONE LA English DT Article ID CELL-SURFACE PROTEOGLYCAN; BREAST-CARCINOMA CELLS; EXTRACELLULAR-MATRIX; FIBRONECTIN MATRIX; CANCER CELLS; 3-DIMENSIONAL MATRICES; BETA-3 INTEGRINS; ACTIN-FILAMENTS; NUCLEAR SHAPE; BINDING-SITE AB Expression of the cell surface proteoglycan syndecan-1 (Sdc1) is frequently induced in stromal fibroblasts of invasive breast carcinomas. We have recently identified a correlation between stromal Sdc1 expression and extracellular matrix (ECM) fiber alignment, both in vitro and in vivo. ECMs derived from Sdc1-positive human mammary fibroblasts (HMF) showed an aligned fiber architecture, which contrasted markedly with the more random fiber arrangement in the ECM produced by Sdc1-negative HMFs. We further demonstrated that aligned fiber architecture promotes the directional migration and invasion of breast carcinoma cells. To decipher the molecular mechanisms governing the formation of an aligned, invasion-permissive ECM, a series of Sdc1 mutants was introduced into HMF. We found that both the ectodomain and heparan sulfate chains of Sdc1 were required for full activity of Sdc1 in regulating ECM alignment, while transmembrane and cytoplasmic domains were dispensable. Sdc1 regulates the activities of several integrins via its ectodomain. Integrins are key players in the assembly of fibronectin-rich ECM. In addition, integrins are capable of regulating cell morphology and cell shape and orientation may affect ECM architecture. Therefore, we investigated the role of integrins in Sdc1-mediated ECM fiber alignment. Sdc1-overexpressing HMF gained an enhanced spindle-shaped morphology when cultured in an overconfluent state under conditions permissive for ECM production, which was partially reversed by siRNA-mediated silencing of beta 3 integrin expression. Moreover, suppression of alpha v beta 3 integrin activity by a function-blocking antibody or beta 3 knockdown largely abolished the aligned ECM fiber architecture and consequently the invasion-permissive properties of the ECM induced by Sdc1. The results suggest that Sdc1 may modulate fibronectin fibrillogenesis and/or alter cell morphology during ECM production through alpha v beta 3 integrin, thereby mediating ECM fiber alignment. Understanding the mechanisms governing ECM organization may lead to the development of novel stroma-targeted therapy for breast cancer, aiming at converting an invasion-permissive to an invasion-restrictive microenvironment. C1 [Yang, Ning; Friedl, Andreas] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Friedl, Andreas] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. [Friedl, Andreas] UW Carbone Canc Ctr, Madison, WI USA. RP Friedl, A (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA.; Friedl, A (reprint author), William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA.; Friedl, A (reprint author), UW Carbone Canc Ctr, Madison, WI USA. EM afriedl@wisc.edu FU National Cancer Institute [R01 CA107012-06]; NIH/NCI [R01 CA107012] FX This work was supported by the National Cancer Institute, R01 CA107012-06 (http://www.cancer.gov). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by NIH/NCI grant R01 CA107012. The authors are grateful to other members of the Friedl lab, especially Kristy Key Meyer, for help with experiments. The authors also thank the University of Wisconsin Carbone Cancer Center (P30 CA014520 40) for use of its facilities and Flow Cytometry Laboratory. The contents do not represent the views of the Dept. of Veterans Affairs or the United States Government. NR 81 TC 1 Z9 1 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 24 PY 2016 VL 11 IS 2 AR e0150132 DI 10.1371/journal.pone.0150132 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2IA UT WOS:000371164700069 PM 26909794 ER PT J AU Chen, JS Sprague, BL Klabunde, CN Tosteson, ANA Bitton, A Onega, T MacLean, CD Harris, K Schapira, MM Haas, JS AF Chen, Jane S. Sprague, Brian L. Klabunde, Carrie N. Tosteson, Anna N. A. Bitton, Asaf Onega, Tracy MacLean, Charles D. Harris, Kimberly Schapira, Marilyn M. Haas, Jennifer S. CA PROSPR Population-Based Res Optim TI Take the money and run? Redemption of a gift card incentive in a clinician survey SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Survey methods; Provider surveys ID SURVEY RESPONSE RATES; PHYSICIANS; BREAST AB Background: Clinician surveys provide critical information about many facets of health care, but are often challenging to implement. Our objective was to assess use by participants and non-participants of a prepaid gift card incentive that could be later reclaimed by the researchers if unused. Methods: Clinicians were recruited to participate in a mailed or online survey as part of a study to characterize women's primary health care provider attitudes towards breast and cervical cancer screening guidelines and practices (n = 177). An up-front incentive of a $50 gift card to a popular online retailer was included with the study invitation. Clinicians were informed that the gift card would expire if it went unused after 4 months. Outcome measures included use of gift cards by participants and non-participants and comparison of hypothetical costs of different incentive strategies. Results: 63.5 % of clinicians who responded to the survey used the gift card, and only one provider who didn't participate used the gift card (1.6 %). Many of those who participated did not redeem their gift cards (36.5 % of respondents). The price of the incentives actually claimed totaled $3700, which was less than half of the initial outlay. Since some of the respondents did not redeem their gift cards, the cost of incentives was less than it might have been if we had provided a conditional incentive of $50 to responders after they had completed the survey. Conclusions: Redeemable online gift card codes may provide an effective way to motivate clinicians to participate in surveys. C1 [Chen, Jane S.; Bitton, Asaf; Harris, Kimberly; Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. [Bitton, Asaf; Haas, Jennifer S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sprague, Brian L.; MacLean, Charles D.] Univ Vermont, Burlington, VT USA. [Tosteson, Anna N. A.; Onega, Tracy] Dartmouth & Norris Cotton Canc Ctr, Geisel Sch Med, Lebanon, NH USA. [Klabunde, Carrie N.] NIH, Off Director, Off Dis Prevent, Bethesda, MD USA. [Haas, Jennifer S.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Schapira, Marilyn M.] Univ Penn, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Chen, Jane S.] Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA.; Haas, JS (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM jhaas@partners.org FU [U54 CA163307]; [U54 CA 163313]; [U54 CA163303] FX The authors thank the participating PROSPR Research Centers for the data they have provided for this study. A list of the PROSPR investigators and contributing research staff are provided at: http://healthcaredelivery.cancer.gov/prospr/. (Grant numbers U54 CA163307, U54 CA 163313, U54 CA163303). NR 9 TC 1 Z9 1 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD FEB 24 PY 2016 VL 16 AR 25 DI 10.1186/s12874-016-0126-2 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DE7SH UT WOS:000370836500002 PM 26911445 ER PT J AU Helfrich, CD Sylling, PW Gale, RC Mohr, DC Stockdale, SE Joos, S Brown, EJ Grembowski, D Asch, SM Fihn, SD Nelson, KM Meredith, LS AF Helfrich, Christian D. Sylling, Philip W. Gale, Randall C. Mohr, David C. Stockdale, Susan E. Joos, Sandra Brown, Elizabeth J. Grembowski, David Asch, Steven M. Fihn, Stephan D. Nelson, Karin M. Meredith, Lisa S. TI The facilitators and barriers associated with implementation of a patient-centered medical home in VHA SO IMPLEMENTATION SCIENCE LA English DT Article ID CARE; PROVIDERS; BURNOUT AB Background: The patient-centered medical home (PCMH) is a team-based, comprehensive model of primary care. When effectively implemented, PCMH is associated with higher patient satisfaction, lower staff burnout, and lower hospitalization for ambulatory care-sensitive conditions. However, less is known about what factors contribute to (or hinder) PCMH implementation. We explored the associations of specific facilitators and barriers reported by primary care employees with a previously validated, clinic-level measure of PCMH implementation, the Patient Aligned Care Team Implementation Progress Index (Pi(2)). Methods: We used a 2012 survey of primary care employees in the Veterans Health Administration to perform cross-sectional, respondent-level multinomial regressions. The dependent variable was the Pi2 categorized as high implementation (top decile, 54 clinics, 235 respondents), medium implementation (middle eight deciles, 547 clinics, 4537 respondents), and low implementation (lowest decile, 42 clinics, 297 respondents) among primary care clinics. The independent variables were ordinal survey items rating 19 barriers to patient-centered care and 10 facilitators of PCMH implementation. For facilitators, we explored clinic Pi(2) score decile both as a function of respondent-reported availability of facilitators and of rating of facilitator helpfulness. Results: The availability of five facilitators was associated with higher odds of a respondent's clinic's Pi(2) scores being in the highest versus lowest decile: teamlet huddles (OR = 3.91), measurement tools (OR = 3.47), regular team meetings (OR = 2.88), information systems (OR = 2.42), and disease registries (OR = 2.01). The helpfulness of four facilitators was associated with higher odds of a respondent's clinic's Pi(2) scores being in the highest versus lowest decile. Six barriers were associated with significantly higher odds of a respondent's clinic's Pi(2) scores being in the lowest versus highest decile, with the strongest associations for the difficulty recruiting and retaining providers (OR = 2.37) and non-provider clinicians (OR = 2.17). Results for medium versus low Pi(2) score clinics were similar, with fewer, smaller significant associations, all in the expected direction. Conclusions: A number of specific barriers and facilitators were associated with PCMH implementation, notably recruitment and retention of clinicians, team huddles, and local education. These findings can guide future research, and may help healthcare policy makers and leaders decide where to focus attention and limited resources. C1 [Helfrich, Christian D.; Fihn, Stephan D.; Nelson, Karin M.] US Dept Vet Affairs, Seattle Denver Ctr Innovat Vet Ctr & Value Driven, VA Puget Sound, 1660 Columbian Way S-152, Seattle, WA 98108 USA. [Helfrich, Christian D.; Grembowski, David] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Sylling, Philip W.; Fihn, Stephan D.] US Dept Vet Affairs, Off Analyt & Business Intelligence, Seattle, WA USA. [Gale, Randall C.; Asch, Steven M.] VHA Palo Alto Healthcare Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Mohr, David C.] VA Boston Healthcare Syst, CHOIR, Boston, MA USA. [Mohr, David C.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Stockdale, Susan E.] VHA Greater Los Angeles Hlth Care Syst, HSR&D Ctr Study Healthcare Innovat Implementat &, North Hills, CA USA. [Stockdale, Susan E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Joos, Sandra] US Dept Vet Affairs, VISN Patient Aligned Care Team PACT Demonstrat La, Portland, OR USA. [Brown, Elizabeth J.] Philadelphia Vet Affairs Med Ctr, CEPACT, Philadelphia, PA USA. [Brown, Elizabeth J.] Univ Penn, Perelman Sch Med, Robert Wood Johnson Fdn Clin Scholars Program, Philadelphia, PA 19104 USA. [Brown, Elizabeth J.] Univ Penn, Perelman Sch Med, Dept Family & Community Med, Philadelphia, PA 19104 USA. [Asch, Steven M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Fihn, Stephan D.; Nelson, Karin M.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Meredith, Lisa S.] RAND Corp, Santa Monica, CA USA. [Meredith, Lisa S.] VA HSR&D Ctr Study Healthcare Innovat Implementat, Los Angeles, CA USA. RP Helfrich, CD (reprint author), US Dept Vet Affairs, Seattle Denver Ctr Innovat Vet Ctr & Value Driven, VA Puget Sound, 1660 Columbian Way S-152, Seattle, WA 98108 USA.; Helfrich, CD (reprint author), Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. EM christian.helfrich@va.gov FU Patient Centered Medical Home Demonstration Laboratory Coordination Center from the United States (U.S.) Department of Veterans Affairs [XVA-61-041]; VA Office of Patient Care Services; Office of Clinical Operations FX This work was supported by the Patient Centered Medical Home Demonstration Laboratory Coordination Center (XVA-61-041) from the United States (U.S.) Department of Veterans Affairs. The survey was conducted by the VA Healthcare Analysis and Information Group, and sponsored by the VA Office of Patient Care Services and Office of Clinical Operations. We are grateful to Drs. Gordon Schectman and Richard Stark, and Ms. Julie Kurutz for their support fielding the survey. The content does not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 22 TC 0 Z9 0 U1 3 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD FEB 24 PY 2016 VL 11 AR 24 DI 10.1186/s13012-016-0386-6 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DE8ZC UT WOS:000370924200001 PM 26911135 ER PT J AU Montazerhodjat, V Weinstock, DM Lo, AW AF Montazerhodjat, Vahid Weinstock, David M. Lo, Andrew W. TI Buying cures versus renting health: Financing health care with consumer loans SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CHRONIC HEPATITIS-C; SUSTAINED VIROLOGICAL RESPONSE; VIRUS-INFECTION; MORTALITY; OUTCOMES AB A crisis is building over the prices of new transformative therapies for cancer, hepatitis C virus infection, and rare diseases. The clinical imperative is to offer these therapies as broadly and rapidly as possible. We propose a practical way to increase drug affordability through health care loans (HCLs)-the equivalent of mortgages for large health care expenses. HCLs allow patients in both multipayer and single-payer markets to access a broader set of therapeutics, including expensive short-duration treatments that are curative. HCLs also link payment to clinical benefit and should help lower per-patient cost while incentivizing the development of transformative therapies rather than those that offer small incremental advances. Moreover, we propose the use of securitization-a well-known financial engineering method-to finance a large diversified pool of HCLs through both debt and equity. Numerical simulations suggest that securitization is viable for a wide range of economic environments and cost parameters, allowing a much broader patient population to access transformative therapies while also aligning the interests of patients, payers, and the pharmaceutical industry. C1 [Montazerhodjat, Vahid; Lo, Andrew W.] MIT, Lab Financial Engn, Sloan Sch Management, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Montazerhodjat, Vahid; Lo, Andrew W.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Weinstock, David M.] Harvard Univ, Sch Med, Boston, MA USA. [Weinstock, David M.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Lo, Andrew W.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lo, Andrew W.] AlphaSimplex Grp LLC, Cambridge, MA USA. RP Lo, AW (reprint author), MIT, Lab Financial Engn, Sloan Sch Management, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Lo, AW (reprint author), MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA.; Weinstock, DM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Weinstock, DM (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Weinstock, DM (reprint author), Broad Inst Harvard & MIT, Cambridge, MA USA.; Lo, AW (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Lo, AW (reprint author), AlphaSimplex Grp LLC, Cambridge, MA USA. EM dweinstock@partners.org; alo-admin@mit.edu FU MIT Laboratory for Financial Engineering FX We gratefully acknowledge research support from the MIT Laboratory for Financial Engineering. NR 30 TC 2 Z9 2 U1 1 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 24 PY 2016 VL 8 IS 327 AR 327ps6 DI 10.1126/scitranslmed.aad6913 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DE9PQ UT WOS:000370970600002 PM 26912902 ER PT J AU Bauer, MS Miller, C Kim, B Lew, R Weaver, K Coldwell, C Henderson, K Holmes, S Seibert, MN Stolzmann, K Elwy, AR Kirchner, J AF Bauer, Mark S. Miller, Christopher Kim, Bo Lew, Robert Weaver, Kendra Coldwell, Craig Henderson, Kathy Holmes, Sally Seibert, Marjorie Nealon Stolzmann, Kelly Elwy, A. Rani Kirchner, JoAnn TI Partnering with health system operations leadership to develop a controlled implementation trial SO IMPLEMENTATION SCIENCE LA English DT Article DE Cooperative behavior; Health-care quality; access and evaluation; Health plan implementation; Mental disorders; Patient care management; Patient satisfaction; Randomized controlled trial; Self care ID REPLICATING EFFECTIVE PROGRAMS; IMPROVING PRIMARY-CARE; MENTAL-HEALTH; BIPOLAR DISORDER; COLLABORATIVE CARE; CHRONIC ILLNESS; QUALITY IMPROVEMENT; DEPRESSION; MANAGEMENT; DESIGNS AB Background: Outcome for mental health conditions is suboptimal, and care is fragmented. Evidence from controlled trials indicates that collaborative chronic care models (CCMs) can improve outcomes in a broad array of mental health conditions. US Department of Veterans Affairs leadership launched a nationwide initiative to establish multidisciplinary teams in general mental health clinics in all medical centers. As part of this effort, leadership partnered with implementation researchers to develop a program evaluation protocol to provide rigorous scientific data to address two implementation questions: (1) Can evidence-based CCMs be successfully implemented using existing staff in general mental health clinics supported by internal and external implementation facilitation? (2) What is the impact of CCM implementation efforts on patient health status and perceptions of care? Methods/design: Health system operation leaders and researchers partnered in an iterative process to design a protocol that balances operational priorities, scientific rigor, and feasibility. Joint design decisions addressed identification of study sites, patient population of interest, intervention design, and outcome assessment and analysis. Nine sites have been enrolled in the intervention-implementation hybrid type III stepped-wedge design. Using balanced randomization, sites have been assigned to receive implementation support in one of three waves beginning at 4-month intervals, with support lasting 12 months. Implementation support consists of US Center for Disease Control's Replicating Effective Programs strategy supplemented by external and internal implementation facilitation support and is compared to dissemination of materials plus technical assistance conference calls. Formative evaluation focuses on the recipients, context, innovation, and facilitation process. Summative evaluation combines quantitative and qualitative outcomes. Quantitative CCM fidelity measures (at the site level) plus health outcome measures (at the patient level; n = 765) are collected in a repeated measures design and analyzed with general linear modeling. Qualitative data from provider interviews at baseline and 1 year elaborate CCM fidelity data and provide insights into barriers and facilitators of implementation. Discussion: Conducting a jointly designed, highly controlled protocol in the context of health system operational priorities increases the likelihood that time-sensitive questions of operational importance will be answered rigorously and that the outcomes will result in sustainable change in the health-care system. C1 [Bauer, Mark S.; Miller, Christopher; Kim, Bo] Harvard Univ, Sch Med, VA Boston Healthcare Syst, 150 South Huntington Ave 152M, Boston, MA 02130 USA. [Lew, Robert] Boston Univ, Sch Med, VA Boston Healthcare Syst, 150 South Huntington Ave MAVERIC, Boston, MA 02130 USA. [Weaver, Kendra] James H Quillen VA Med Ctr Corner Lamont & Vet Wa, Mountain Home, TN 37684 USA. [Coldwell, Craig] Boston Univ, Sch Med, VA New England Healthcare Syst, 200 Springs Rd,Bldg 61 136G, Bedford, MA 01730 USA. [Henderson, Kathy; Kirchner, JoAnn] Univ Arkansas Med Sci, Cent Arkansas Vet Healthcare Syst, 2200 Ft Roots Dr,Bldg 58, North Little Rock, AR 72114 USA. [Holmes, Sally; Seibert, Marjorie Nealon; Stolzmann, Kelly; Elwy, A. Rani] VA Boston Healthcare Syst, 150 South Huntington Ave 152M, Boston, MA 02130 USA. RP Bauer, MS (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, 150 South Huntington Ave 152M, Boston, MA 02130 USA. EM mark.bauer@va.gov FU Department of Veterans Affairs Quality Enhancement Research Initiative (QUERI) [RRP-13-237, QUE-15-289] FX This work is supported by grants from the Department of Veterans Affairs Quality Enhancement Research Initiative (QUERI), #RRP-13-237 and QUE-15-289. The authors wish to gratefully acknowledge the assistance of Ms. Allyson Gittens in preparing this manuscript. NR 68 TC 1 Z9 1 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD FEB 24 PY 2016 VL 11 AR 22 DI 10.1186/s13012-016-0385-7 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DE5TY UT WOS:000370696500001 PM 26912342 ER PT J AU Kovar, H Amatruda, J Brunet, E Burdach, S Cidre-Aranaz, F de Alava, E Dirksen, U van der Ent, W Grohar, P Grunewald, TGP Helman, L Houghton, P Iljin, K Korsching, E Ladanyi, M Lawlor, E Lessnick, S Ludwig, J Meltzer, P Metzler, M Mora, J Moriggl, R Nakamura, T Papamarkou, T Sarikas, BR Redini, F Richter, GHS Rossig, C Schadler, K Schafer, BW Scotlandi, K Sheffield, NC Shelat, A Snaar-Jagalska, E Sorensen, P Stegmaier, K Stewart, E Sweet-Cordero, A Szuhai, K Tirado, OM Tirode, F Toretsky, J Tsafou, K Uren, A Zinovyev, A Delattre, O AF Kovar, Heinrich Amatruda, James Brunet, Erika Burdach, Stefan Cidre-Aranaz, Florencia de Alava, Enrique Dirksen, Uta van der Ent, Wietske Grohar, Patrick Grunewald, Thomas G. P. Helman, Lee Houghton, Peter Iljin, Kristiina Korsching, Eberhard Ladanyi, Marc Lawlor, Elizabeth Lessnick, Stephen Ludwig, Joseph Meltzer, Paul Metzler, Markus Mora, Jaume Moriggl, Richard Nakamura, Takuro Papamarkou, Theodore Sarikas, Branka Radic Redini, Francoise Richter, Guenther H. S. Rossig, Claudia Schadler, Keri Schaefer, Beat W. Scotlandi, Katia Sheffield, Nathan C. Shelat, Anang Snaar-Jagalska, Ewa Sorensen, Poul Stegmaier, Kimberly Stewart, Elizabeth Sweet-Cordero, Alejandro Szuhai, Karoly Tirado, Oscar M. Tirode, Franck Toretsky, Jeffrey Tsafou, Kalliopi Uren, Aykut Zinovyev, Andrei Delattre, Olivier TI The second European interdisciplinary Ewing sarcoma research summit - A joint effort to deconstructing the multiple layers of a complex disease SO ONCOTARGET LA English DT Article DE Ewing sarcoma; epigenetics; development; therapy; microenvironment ID GENOMIC LANDSCAPE; TUMOR; SENSITIVITY; INHIBITION; EWS-FLI1; TRABECTEDIN; GROWTH; CANCER; GENES AB Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second "European interdisciplinary Ewing sarcoma research summit" assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter-and intratumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits. C1 [Kovar, Heinrich] St Anna Kinderkrebsforsch, Childrens Canc Res Inst, Vienna, Austria. [Kovar, Heinrich] Med Univ Vienna, Dept Pediat, Vienna, Austria. [Amatruda, James] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Amatruda, James] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Amatruda, James] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Brunet, Erika] Museum Natl Hist Nat, INSERM, U1154, CNRS 7196, F-75231 Paris, France. [Burdach, Stefan; Richter, Guenther H. S.] Tech Univ Munich, Klinikum Rechts Isar, Childrens Canc Res Ctr, D-80290 Munich, Germany. [Burdach, Stefan; Richter, Guenther H. S.] Tech Univ Munich, Klinikum Rechts Isar, Dept Pediat, D-80290 Munich, Germany. [Burdach, Stefan; Richter, Guenther H. S.] Comprehens Canc Ctr Munich CCCM, Munich, Germany. [Cidre-Aranaz, Florencia] Inst Salud Carlos III, Unidad Tumores Solidos Infantiles, Area Genet Humana, Inst Invest Enfermedades Raras, Madrid, Spain. [de Alava, Enrique] Univ Seville, CSIC, Virgen del Rocio Univ Hosp, Inst Biomed Sevilla IBiS,Dept Pathol, Seville, Spain. [Dirksen, Uta; Rossig, Claudia] Univ Childrens Hosp Muenster, Pediat Hematol & Oncol, Munster, Germany. [van der Ent, Wietske; Tirode, Franck; Zinovyev, Andrei; Delattre, Olivier] Inst Curie, Lab Genet & Biol Canc, U830, INSERM, Paris, France. [van der Ent, Wietske; Snaar-Jagalska, Ewa] Leiden Univ, Inst Biol, Leiden, Netherlands. [Grohar, Patrick] Van Andel Inst, Ctr Canc & Cell Biol, Grand Rapids, MI USA. [Grohar, Patrick] Helen DeVos Childrens Hosp, Grand Rapids, MI USA. [Grunewald, Thomas G. P.] Univ Munich, Inst Pathol, Lab Pediat Sarcoma Biol, Thalkirchner Str 36, D-80539 Munich, Germany. [Helman, Lee] NCI, Ctr Canc Rearch, NIH, Bethesda, MA USA. [Houghton, Peter] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Iljin, Kristiina] VTT Tech Res Ctr Finland Ltd, Espoo, Finland. [Korsching, Eberhard] Univ Munster, Fac Med, Inst Bioinformat, D-48149 Munster, Germany. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol & Human Oncol, 1275 York Ave, New York, NY 10021 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Lawlor, Elizabeth] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Lawlor, Elizabeth] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Lessnick, Stephen] Ohio State Univ, Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Disorders, Columbus, OH 43210 USA. [Lessnick, Stephen] Ohio State Univ, Div Pediat Hematol Oncol BMT, Columbus, OH 43210 USA. [Ludwig, Joseph] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Meltzer, Paul] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Metzler, Markus] Univ Hosp Erlangen, Pediat Oncol & Hematol, Erlangen, Germany. [Mora, Jaume] Sant Joan de Deu Hosp, Dept Pediat Oncol, Barcelona, Spain. [Moriggl, Richard] Ludwig Boltzmann Inst Canc Res, Vienna, Austria. [Moriggl, Richard] Univ Vet Med & Med Univ, Inst Anim Breeding & Genet, Vienna, Austria. [Nakamura, Takuro] Japanese Fdn Canc Res, Inst Canc, Div Carcinogenesis, Tokyo 170, Japan. [Papamarkou, Theodore] Univ Glasgow, Sch Math & Stat, Glasgow, Lanark, Scotland. [Sarikas, Branka Radic; Sheffield, Nathan C.] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria. [Redini, Francoise] Univ Nantes, UMR957, INSERM, Nantes, France. [Schadler, Keri] Univ Texas MD Anderson Canc Ctr, Dept Pediat Res, Houston, TX 77030 USA. [Schaefer, Beat W.] Univ Childrens Hosp, Dept Oncol, Zurich, Switzerland. [Schaefer, Beat W.] Univ Childrens Hosp, Childrens Res Ctr, Zurich, Switzerland. [Scotlandi, Katia] Rizzoli Inst, Expt Oncol Lab, CRS Dev Biomol Therapies, Bologna, Italy. [Shelat, Anang] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 332 N Lauderdale St, Memphis, TN 38105 USA. [Sorensen, Poul] British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada. [Stegmaier, Kimberly; Stewart, Elizabeth] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Stegmaier, Kimberly; Stewart, Elizabeth] Boston Childrens Hosp, Boston, MA USA. St Jude Childrens Res Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Sweet-Cordero, Alejandro] Stanford Univ, Dept Pediat, Div Hematol & Oncol, Stanford, CA 94305 USA. [Szuhai, Karoly] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Leiden, Netherlands. [Tirado, Oscar M.] Bellvitge Biomed Res Inst IDIBELL, Mol Oncol Lab, Sarcoma Res Grp, Barcelona, Spain. [Toretsky, Jeffrey; Tsafou, Kalliopi; Uren, Aykut] Georgetown Univ, Sch Med, Dept Oncol, Washington, DC USA. [Zinovyev, Andrei] INSERM, U900, Paris, France. [Zinovyev, Andrei] Ecole Mines ParisTech, Fontainebleau, France. RP Kovar, H (reprint author), St Anna Kinderkrebsforsch, Childrens Canc Res Inst, Vienna, Austria.; Kovar, H (reprint author), Med Univ Vienna, Dept Pediat, Vienna, Austria. EM heinrich.kovar@ccri.at RI Papamarkou, Theodore/A-2958-2012; REDINI, Francoise/K-7981-2015; Grunewald, Thomas/O-2317-2013 OI Papamarkou, Theodore/0000-0002-9689-543X; Szuhai, Karoly/0000-0002-1228-4245; Grunewald, Thomas/0000-0003-0920-7377 FU European Union [261743, 259348] FX We thank Anirah Amber and Nuno Andrade for excellent organization of the meeting. The conference was supported by the European Union's Seventh Framework Programme grants 261743(ENCCA) and 259348 (ASSET). NR 35 TC 1 Z9 1 U1 7 U2 10 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 23 PY 2016 VL 7 IS 8 BP 8613 EP 8624 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL4OW UT WOS:000375618100014 PM 26802024 ER PT J AU Lau, KM Madden, E Neylan, TC Seal, KH Maguen, S AF Lau, Karen M. Madden, Erin Neylan, Thomas C. Seal, Karen H. Maguen, Shira TI Assessing for mild TBI among Iraq and Afghanistan veterans: Outcomes of injury severity and neurological factors SO BRAIN INJURY LA English DT Article DE veterans; injury severity markers; nausea; neurologic symptoms; Traumatic brain injury ID TRAUMATIC BRAIN-INJURY; NEUROBEHAVIORAL SYMPTOM INVENTORY; POSTCONCUSSION SYNDROME; CLINICAL MANAGEMENT; HEAD-INJURY; MILITARY; DIAGNOSIS; MANIFESTATIONS; CLASSIFICATION; PERFORMANCE AB Objective: To investigate injury severity markers and neurological symptoms associated with clinician-confirmed mild traumatic brain injury (TBI) among Iraq and Afghanistan veterans. Setting: Department of Veterans Affairs (VA) medical centre and five affiliated community-based outpatient clinics. Participants: Three hundred and fifty Iraq and Afghanistan veterans with positive initial VA TBI screens between 1 April 2007 and 1 June 2010 and clinician-confirmed TBI status by 1 December 2010. Methods: Retrospective-cohort study of medical record data. Main measures included clinician-confirmed TBI status, injury severity markers (e.g. loss of consciousness (LOC), post-traumatic amnesia (PTA) or confusion/disorientation) and neurological symptoms. Results: Among veterans who screened positive on the initial VA TBI and then received a clinician evaluation, 60% were confirmed to have a TBI diagnosis. Veterans reporting at least one LOC, confusion or PTA were almost 18-times more likely to receive a confirmed TBI diagnosis. Odds of clinician-confirmed TBI were 2.5-3-times greater among those who endorsed dizziness, poor coordination, headaches, nausea, vision problems and/or irritability, compared to those not endorsing these symptoms. Nausea had greatest utility for confirming a TBI. Conclusions: Identification of neurologic symptoms that most contribute to a clinician-confirmed diagnosis of TBI has potential for streamlining detection of TBI and symptoms needed for treatment. C1 [Lau, Karen M.; Madden, Erin; Neylan, Thomas C.; Seal, Karen H.; Maguen, Shira] San Francisco VA Med Ctr, 4150 Clement St 116-P, San Francisco, CA 94121 USA. [Neylan, Thomas C.; Seal, Karen H.; Maguen, Shira] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Seal, Karen H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Lau, KM (reprint author), San Francisco VA Med Ctr, 4150 Clement St 116-P, San Francisco, CA 94121 USA. EM karen.lau2@va.gov FU Department of Defense Psychological Health and Traumatic Brain Injury (PH/TBI) Research Program; VA Health Sciences Research and Development (HSR&D) Career Development 475 Award FX This research was supported by a Department of Defense Psychological Health and Traumatic Brain Injury (PH/TBI) Research Program (Maguen) and VA Health Sciences Research and Development (HSR&D) Career Development 475 Award (Maguen). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. NR 37 TC 0 Z9 0 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0269-9052 EI 1362-301X J9 BRAIN INJURY JI Brain Inj. PD FEB 23 PY 2016 VL 30 IS 3 BP 287 EP 294 DI 10.3109/02699052.2015.1089601 PG 8 WC Neurosciences; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA DG9QM UT WOS:000372418900006 PM 26910483 ER PT J AU Lemmens, R Hamilton, SA Liebeskind, DS Tomsick, TA Demchuk, AM Nogueira, RG Marks, MP Jahan, R Gralla, J Yoo, AJ Yeatts, SD Palesch, YY Saver, JL Pereira, VM Broderick, JP Albers, GW Lansberg, MG AF Lemmens, Robin Hamilton, Scott A. Liebeskind, David S. Tomsick, Tom A. Demchuk, Andrew M. Nogueira, Raul G. Marks, Michael P. Jahan, Reza Gralla, Jan Yoo, Albert J. Yeatts, Sharon D. Palesch, Yuko Y. Saver, Jeffrey L. Pereira, Vitor M. Broderick, Joseph P. Albers, Gregory W. Lansberg, Maarten G. CA DEFUSE 2 Trialist IMS III Trialist STAR Trialist SWIFT Trialist TI Effect of endovascular reperfusion in relation to site of arterial occlusion SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; M2 OCCLUSIONS; INTERVENTIONAL MANAGEMENT; II TRIAL; THERAPY; REVASCULARIZATION; RECANALIZATION; THROMBOLYSIS; OUTCOMES; MRI AB Objective: To assess whether the association between reperfusion and improved clinical outcomes after stroke differs depending on the site of the arterial occlusive lesion (AOL). Methods: We pooled data from Solitaire With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularisation (STAR), Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2), and Interventional Management of Stroke Trial (IMS III) to compare the strength of the associations between reperfusion and clinical outcomes in patients with internal carotid artery (ICA), proximal middle cerebral artery (MCA) (M1), and distal MCA (M2/3/4) occlusions. Results: Among 710 included patients, the site of the AOL was the ICA in 161, the proximal MCA in 389, and the distal MCA in 160 patients (M2 = 131, M3 = 23, and M4 = 6). Reperfusion was associated with an increase in the rate of good functional outcome (modified Rankin Scale [mRS] score 0-2) in patients with ICA (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.7-7.2) and proximal MCA occlusions (OR 6.2, 95% CI 3.8-10.2), but not in patients with distal MCA occlusions (OR 1.4, 95% CI 0.8-2.6). Among patients with M2 occlusions, a subset of the distal MCA cohort, reperfusion was associated with excellent functional outcome (mRS 0-1; OR 2.2, 95% CI 1.0-4.7). Conclusions: The association between endovascular reperfusion and better clinical outcomes is more profound in patients with ICA and proximal MCA occlusions compared to patients with distal MCA occlusions. Because there are limited data from randomized controlled trials on the effect of endovascular therapy in patients with distal MCA occlusions, these results underscore the need for inclusion of this subgroup in future endovascular therapy trials. C1 [Lemmens, Robin] Univ Leuven, KU Leuven, Dept Neurosci, Expt Neurol & Leuven Res Inst Neurosci & Dis, Leuven, Belgium. [Lemmens, Robin] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [Lemmens, Robin] Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium. [Hamilton, Scott A.; Marks, Michael P.; Albers, Gregory W.; Lansberg, Maarten G.] Stanford Univ, Stanford Stroke Ctr, Stanford, CA USA. [Liebeskind, David S.; Saver, Jeffrey L.] Univ Calif Los Angeles, Neurovasc Imaging Res Core, Los Angeles, CA USA. [Liebeskind, David S.; Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Liebeskind, David S.; Saver, Jeffrey L.] Univ Calif Los Angeles, Comprehens Stroke Ctr, Los Angeles, CA USA. [Jahan, Reza] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Div Intervent Neuroradiol, Los Angeles, CA 90095 USA. [Tomsick, Tom A.] Univ Cincinnati, Med Ctr, Dept Radiol, Cincinnati, OH 45221 USA. [Broderick, Joseph P.] Univ Cincinnati, Med Ctr, Dept Neurol, Cincinnati, OH 45221 USA. [Demchuk, Andrew M.] Univ Calgary, Fac Med, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB T2N 1N4, Canada. [Demchuk, Andrew M.] Univ Calgary, Fac Med, Hotchkiss Brain Inst, Dept Radiol, Calgary, AB T2N 1N4, Canada. [Nogueira, Raul G.] Emory Univ, Sch Med, Dept Neurol, Marcus Stroke & Neurosci Ctr,Grady Mem Hosp, Atlanta, GA 30322 USA. [Nogueira, Raul G.] Emory Univ, Sch Med, Dept Neurosurg, Marcus Stroke & Neurosci Ctr,Grady Mem Hosp, Atlanta, GA USA. [Nogueira, Raul G.] Emory Univ, Sch Med, Dept Radiol, Marcus Stroke & Neurosci Ctr,Grady Mem Hosp, Atlanta, GA 30322 USA. [Gralla, Jan] Univ Hosp Bern, Dept Diagnost & Intervent Neuroradiol, Bern, Switzerland. [Yoo, Albert J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Diagnost & Intervent Neuroradiol, Boston, MA USA. [Yeatts, Sharon D.; Palesch, Yuko Y.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Pereira, Vitor M.] Univ Hlth Network, Toronto Western Hosp, Div Neuroradiol, Dept Med Imaging, Toronto, ON, Canada. [Pereira, Vitor M.] Univ Hlth Network, Toronto Western Hosp, Div Neurosurg, Dept Surg, Toronto, ON, Canada. RP Lemmens, R (reprint author), Univ Leuven, KU Leuven, Dept Neurosci, Expt Neurol & Leuven Res Inst Neurosci & Dis, Leuven, Belgium.; Lemmens, R (reprint author), Univ Hosp Leuven, Dept Neurol, Leuven, Belgium.; Lemmens, R (reprint author), Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium. EM robin.lemmens@uzleuven.be FU National Institute for Neurological Disorders and Stroke [R01 NS03932505, R01 NS075209]; National Institute for Neurological Disorders and Stroke FX The DEFUSE 2 study was funded by grants from the National Institute for Neurological Disorders and Stroke (R01 NS03932505 to G.W.A. and R01 NS075209 to M.G.L.). The IMS III trial was funded by a grant from the National Institute for Neurological Disorders and Stroke. Dr. Lemmens is a Senior Clinical Investigator of FWO Flanders. NR 20 TC 4 Z9 4 U1 0 U2 0 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 FEB 23 PY 2016 VL 86 IS 8 BP 762 EP 770 DI 10.1212/WNL.0000000000002399 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DF6WM UT WOS:000371498400011 PM 26802090 ER PT J AU Olsen, AL Miller, JJ Bhattacharyya, S Voinescu, PE Klein, JP AF Olsen, Abby L. Miller, Julie J. Bhattacharyya, Shamik Voinescu, P. Emanuela Klein, Joshua P. TI Cerebral perfusion in stroke-like migraine attacks after radiation therapy syndrome SO NEUROLOGY LA English DT Editorial Material ID SMART SYNDROME; ENCEPHALOPATHY AB Stroke-like migraine attacks after radiation therapy (SMART) syndrome is characterized by transient, focal neurologic symptoms occurring years after radiation,(1) with focal or regional cortical thickening and gadolinium enhancement on MRI in the area of brain exposed to radiation. The pathophysiology of the syndrome is not well-understood. We present 2 patients with recurrent attacks of SMART syndrome with increased cerebral blood volume in affected regions and abnormal vascular reactivity on transcranial Doppler ultrasound, suggesting a potential mechanism. C1 [Olsen, Abby L.; Miller, Julie J.; Bhattacharyya, Shamik; Voinescu, P. Emanuela; Klein, Joshua P.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Olsen, Abby L.; Miller, Julie J.; Bhattacharyya, Shamik; Voinescu, P. Emanuela] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Olsen, Abby L.; Miller, Julie J.; Bhattacharyya, Shamik; Voinescu, P. Emanuela; Klein, Joshua P.] Harvard Univ, Sch Med, Boston, MA USA. RP Klein, JP (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.; Klein, JP (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM jpklein@partners.org OI Bhattacharyya, Shamik/0000-0001-8047-3622 NR 10 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 23 PY 2016 VL 86 IS 8 BP 787 EP 789 DI 10.1212/WNL.0000000000002400 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DF6WM UT WOS:000371498400014 PM 26819456 ER PT J AU Borzello, M Mateen, FJ AF Borzello, Mia Mateen, Farrah J. TI Time for a new March of Dimes SO NEUROLOGY LA English DT Article ID NEUROCYSTICERCOSIS AB Neurocysticercosis (NCC) is a leading cause of preventable epilepsy worldwide and is endemic in several continents. Despite the obvious mitigating factors of education and enhanced awareness, a surprising lack of investment has been made in cost-effective instructional initiatives at a community level. This needs to change. Because spread of the pathogen is largely a consequence of poor behavioral practices, it can be averted. We propose a disease awareness campaign as an important mechanism to achieve this, a crowd-sourcing strategy similar to the one championed decades earlier by the March of Dimes. C1 [Borzello, Mia; Mateen, Farrah J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Mateen, FJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM fmateen@partners.org FU World Federation of Neurology FX Funded by the World Federation of Neurology. NR 5 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 23 PY 2016 VL 86 IS 8 BP E85 EP E88 DI 10.1212/WNL.0000000000002347 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA DF6WP UT WOS:000371498800004 PM 26764031 ER PT J AU Passer, D van de Vrugt, A Atmanli, A Domian, IJ AF Passer, Derek van de Vrugt, Annebel Atmanli, Ayhan Domian, Ibrahim J. TI Atypical Protein Kinase C-Dependent Polarized Cell Division Is Required for Myocardial Trabeculation SO CELL REPORTS LA English DT Article ID SPINDLE ORIENTATION; CARDIAC MORPHOGENESIS; PAR COMPLEX; STEM-CELLS; IN-VIVO; HEART; LAMBDA; CARDIOMYOCYTES; ESTABLISHMENT; REVEALS AB A hallmark of cardiac development is the formation of myocardial trabeculations exclusively from the luminal surface of the primitive heart tube. Although a number of genetic defects in the endocardium and cardiac jelly disrupt myocardial trabeculation, the role of cell polarization remains unclear. Here, we demonstrate that atypical protein kinase C iota (Prkci) and its interacting partners are localized primarily to the luminal side of myocardial cells of early murine embryonic hearts. A subset of these cells undergoes polarized cell division with the cell division plane perpendicular to the heart's lumen. Disruption of the cell polarity complex by targeted gene mutations results in aberrant mitotic spindle alignment, loss of polarized cardiomyocyte division, and loss of normal myocardial trabeculation. Collectively, these results suggest that, in response to inductive signals, Prkci and its downstream partners direct polarized cell division of luminal myocardial cells to drive trabeculation in the nascent heart. C1 [Passer, Derek; van de Vrugt, Annebel; Atmanli, Ayhan; Domian, Ibrahim J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charles River Plaza CPZN 3200,185 Cambridge St, Boston, MA 02114 USA. [Passer, Derek; van de Vrugt, Annebel; Atmanli, Ayhan; Domian, Ibrahim J.] Harvard Univ, Sch Med, 250 Longwood Ave, Boston, MA 02115 USA. [Passer, Derek] Univ Nebraska Med Ctr, Dept Cellular & Integrat Physiol, Omaha, NE 68198 USA. [Domian, Ibrahim J.] Harvard Stem Cell Inst, 1350 Massachusetts Ave, Cambridge, MA 02138 USA. RP Domian, IJ (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charles River Plaza CPZN 3200,185 Cambridge St, Boston, MA 02114 USA.; Domian, IJ (reprint author), Harvard Univ, Sch Med, 250 Longwood Ave, Boston, MA 02115 USA.; Domian, IJ (reprint author), Harvard Stem Cell Inst, 1350 Massachusetts Ave, Cambridge, MA 02138 USA. EM domian@mgh.harvard.edu FU NIH/National Heart, Lung, and Blood Institute [NIH/NHLBI 1K08 HL091209] FX We gratefully acknowledge Drs. Irving Zucker and Mark Lindsay for critical review of the manuscript and Dr. Jeffery Hill for his continued support throughout the project. This work was supported by a grant from NIH/National Heart, Lung, and Blood Institute (NIH/NHLBI 1K08 HL091209). NR 47 TC 3 Z9 3 U1 1 U2 1 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 FEB 23 PY 2016 VL 14 IS 7 BP 1662 EP 1672 DI 10.1016/j.celrep.2016.01.030 PG 11 WC Cell Biology SC Cell Biology GA DE9PM UT WOS:000370970200011 PM 26876178 ER PT J AU Bellani, G Laffey, JG Pham, T Fan, E Brochard, L Esteban, A Gattinoni, L van Haren, F Larsson, A McAuley, DF Ranieri, M Rubenfeld, G Thompson, BT Wrigge, H Slutsky, AS Pesenti, A AF Bellani, Giacomo Laffey, John G. Pham, Tai Fan, Eddy Brochard, Laurent Esteban, Andres Gattinoni, Luciano van Haren, Frank Larsson, Anders McAuley, Daniel F. Ranieri, Marco Rubenfeld, Gordon Thompson, B. Taylor Wrigge, Hermann Slutsky, Arthur S. Pesenti, Antonio CA LUNG SAFE Investigators & ESICM TI Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE LUNG INJURY; BERLIN DEFINITION; VENTILATION; UNDERRECOGNITION; CLINICIAN; PRESSURE; UNDERUSE; COHORT; STATES AB IMPORTANCE Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS Of 29 144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0%(95% CI, 28.2%-31.9%); of moderate ARDS, 46.6%(95% CI, 44.5%-48.6%); and of severe ARDS, 23.4%(95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4%(95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5%(95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1%(95% CI, 38.2-42.1), whereas 82.6%(95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3%(95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9%(95% CI, 31.4%-38.5%) for those with mild, 40.3%(95% CI, 37.4%-43.3%) for those with moderate, and 46.1%(95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS. C1 [Bellani, Giacomo] Univ Milano Bicocca, Sch Med & Surg, Monza, Italy. [Bellani, Giacomo] San Gerardo Hosp, Dept Emergency & Intens Care, Monza, Italy. [Laffey, John G.] St Michaels Hosp, Dept Anesthesia & Crit Care Med, Keenan Res Ctr Biomed Sci, Toronto, ON, Canada. [Laffey, John G.] Univ Toronto, Dept Anesthesia, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Laffey, John G.] Univ Toronto, Dept Physiol, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Laffey, John G.; Fan, Eddy; Brochard, Laurent; Esteban, Andres; Rubenfeld, Gordon; Slutsky, Arthur S.] Univ Toronto, Interdept Div Crit Care Med, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Pham, Tai] Grp Hosp Hop Univ Est Parisien, Hop Tenon, AP HP, Unite Reanimat Med Chirurgicale,Pole Thorax Voies, Paris, France. [Pham, Tai] Univ Paris Diderot, Sorbonne Paris Cite, ECSTRA Team, UMR 1153,Inserm, Paris, France. [Pham, Tai] Univ Paris Est Creteil, UMR 915, INSERM, Creteil, France. [Fan, Eddy] Univ Hlth Network, Dept Med, Toronto, ON, Canada. [Fan, Eddy] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Fan, Eddy] Univ Toronto, Inst Hlth Policy Management & Evaluat, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Brochard, Laurent] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Esteban, Andres] Hosp Univ Getafe, CIBER Enfermedades Respiratorias, Madrid, Spain. [Gattinoni, Luciano; Pesenti, Antonio] Univ Milan, Ist Anestesia & Rianimaz, Osped Maggiore, Ist Ricovero & Cura Carattere Sci, Milan, Italy. [van Haren, Frank] Canberra Hosp, Intens Care Unit, Canberra, ACT, Australia. [van Haren, Frank] Australian Natl Univ, Canberra, ACT, Australia. [Larsson, Anders] Uppsala Univ, Sect Anesthesiol & Intens Care, Dept Surg Sci, Uppsala, Sweden. [McAuley, Daniel F.] Queens Univ Belfast, Ctr Med Expt, Belfast, Antrim, North Ireland. [McAuley, Daniel F.] Wellcome Wolfson Inst Expt Med, Belfast, Antrim, North Ireland. [McAuley, Daniel F.] Royal Victoria Hosp, Reg Intens Care Unit, Grosvenor Rd, Belfast BT12 6BA, Antrim, North Ireland. [Ranieri, Marco] Policlin Umberto 1, SAPIENZA Univ ROMA, Dipartimento Anestesia & Rianimaz, Viale Policlin 155, I-00161 Rome, Italy. [Rubenfeld, Gordon] Sunnybrook Hlth Sci Ctr, Program Trauma Emergency & Crit Care, Toronto, ON M4N 3M5, Canada. [Thompson, B. Taylor] Harvard Univ, Sch Med, Div Pulm, Boston, MA USA. [Thompson, B. Taylor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Crit Care Unit,Dept Med, Boston, MA USA. [Wrigge, Hermann] Univ Leipzig, Dept Anesthesiol & Intens Care Med, Liebigstr 20, D-04103 Leipzig, Germany. [Slutsky, Arthur S.] Univ Toronto, St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, 30 Bond St, Toronto, ON M5B 1W8, Canada. RP Laffey, JG (reprint author), Univ Toronto, Dept Anesthesia, 30 Bond St, Toronto, ON M5B 1W8, Canada.; Laffey, JG (reprint author), Univ Toronto, Dept Med, 30 Bond St, Toronto, ON M5B 1W8, Canada.; Laffey, JG (reprint author), Univ Toronto, Dept Crit Care Med, Keenan Res Ctr Biomed Sci, St Michaels Hosp, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM laffeyj@smh.ca RI Roux, Damien/L-3671-2014; Cortegiani, Andrea/H-4902-2016; Rialp, Gemma/I-3353-2016; Occhipinti, Giovanna/K-7307-2016; Brown, Samuel/E-6846-2015; Tomescu, Dana/J-9941-2013; Cinnella, Gilda/O-2987-2016; Reske, Andreas/E-8141-2010; OI Nichol, Alistair/0000-0002-4689-1238; HASHEMIAN, SEYED MOHAMMAD REZA/0000-0002-0768-9168; Aneman, Anders/0000-0003-2096-5304; Holzgraefe, Bernhard/0000-0002-5654-7764; Ferguson, Niall/0000-0002-6213-5264; foti, giuseppe/0000-0002-8698-2046; Van Haren, Frank/0000-0001-8037-4229; Roux, Damien/0000-0002-6103-6416; Volta, Carlo/0000-0003-3533-6121; Laffey, John/0000-0002-1246-9573; Cortegiani, Andrea/0000-0003-1416-9993; Rialp, Gemma/0000-0003-3614-3639; Occhipinti, Giovanna/0000-0003-3507-0036; Brown, Samuel/0000-0003-1206-6261; Tomescu, Dana/0000-0001-9673-5754; Cinnella, Gilda/0000-0001-9864-2893; Reske, Andreas/0000-0002-2759-0245; Szakmany, Tamas/0000-0003-3632-8844 FU European Society of Intensive Care Medicine (ESICM), Brussels, Belgium; St Michael's Hospital, Toronto, Canada; University of Milan-Bicocca, Monza, Italy FX This work was funded and supported by the European Society of Intensive Care Medicine (ESICM), Brussels, Belgium, by St Michael's Hospital, Toronto, Canada, and by the University of Milan-Bicocca, Monza, Italy. NR 27 TC 124 Z9 132 U1 9 U2 29 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 FEB 23 PY 2016 VL 315 IS 8 BP 788 EP 800 DI 10.1001/jama.2016.0291 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA DE5VH UT WOS:000370700500014 PM 26903337 ER PT J AU Anderson, RI Lopez, MF Becker, HC AF Anderson, Rachel I. Lopez, Marcelo F. Becker, Howard C. TI Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE ethanol; stress; kappa opioid receptor; dynorphin; mice ID CORTICOTROPIN-RELEASING-FACTOR; COCAINE PLACE PREFERENCE; ANXIETY-LIKE BEHAVIOR; CENTRAL AMYGDALA; ALCOHOL-DRINKING; INDUCED REINSTATEMENT; INDUCED INCREASES; CENTRAL NUCLEUS; SOCIAL STRESS; SALVINORIN-A AB Our laboratory has previously demonstrated that daily forced swim stress (FSS) prior to ethanol drinking sessions facilitates enhanced ethanol consumption in mice with a history of chronic intermittent ethanol (CIE) vapor exposure without altering ethanol intake in air -exposed controls. Because both stress and chronic ethanol exposure have been shown to activate the dynorphin/kappa opioid receptor (KOR) system, the present study was designed to explore a potential role for KORs in modulating stress effects on ethanol consumption in the CIE model of dependence and relapse drinking. After stable baseline ethanol intake was established in adult male C57BU6J mice, subjects received chronic intermittent exposure (16 h/day x 4 days/week) to ethanol vapor (CIE group) or air (CTL group). Weekly cycles of inhalation exposure were alternated with 5 -day limited access drinking tests (1 h access to 15% ethanol). Experiment 1 compared effects of daily FSS and KOR activation on ethanol consumption. CIE and CTL mice were either exposed to FSS (10 min), the KOR agonist U50,488 (5 mg/kg), or a vehicle injection (non stressedcondition) prior to each daily drinking session during test weeks. FSS selectively increased drinking in CIE mice. U50,488 mimicked this effect in CIE mice, but also increased drinking in CTL mice. Experiment 2 assessed effects of KOR blockade on stress induced drinking in CIE and CTL mice. Stressed and non stressed mice were administered the short -acting KOR antagonist LY2444296 (0 or 5 mg/kg) 30 min prior to each drinking session during test weeks. FSS selectively increased ethanol consumption in CIE mice, an effect that was abolished by LY2444296 pretreatment. In Experiment 3, CIE and CTL mice were administered one of four doses of U50,488 (0, 1.25, 2.5, 5.0 mg/kg) 1 h prior to each daily drinking test (in lieu of FSS). All doses of U50,488 increased ethanol consumption in both CIE and CTL mice. The U50,488 induced increase in drinking was blocked by LY2444296. Our results demonstrate that the KOR system contributes to the stress enhancement of ethanol intake in mice with a history of chronic ethanol exposure. C1 [Anderson, Rachel I.; Lopez, Marcelo F.; Becker, Howard C.] Med Univ S Carolina, Charleston, SC 29425 USA. [Anderson, Rachel I.; Lopez, Marcelo F.; Becker, Howard C.] Charleston Alcohol Res Ctr, Charleston, SC USA. [Becker, Howard C.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Anderson, RI (reprint author), Med Univ S Carolina, Charleston, SC 29425 USA.; Anderson, RI (reprint author), Charleston Alcohol Res Ctr, Charleston, SC USA. EM andersor@musc.edu OI Anderson, Rachel/0000-0002-6671-4810 FU NIH/NIAAA [U01 AA014095, P50 AA010761, U01 AA020929, T32 AA007474, F32 AA023700] FX This work was supported by NIH/NIAAA grants to HCB (U01 AA014095, P50 AA010761) and MFL (U01 AA020929). RIA was supported by NIH/NIAAA grants T32 AA007474 and F32 AA023700. Thanks to Chelsea Johnson, Rebecca Kritschil, and Anne Olsen for technical assistance. NR 60 TC 3 Z9 3 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD FEB 23 PY 2016 VL 10 AR 45 DI 10.3389/fncel.2016.00045 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DE5FH UT WOS:000370656100001 PM 26941607 ER PT J AU Nagae, LM Honce, JM Tanabe, J Shelton, E Sillau, SH Berman, BD AF Nagae, Lidia M. Honce, Justin M. Tanabe, Jody Shelton, Erika Sillau, Stefan H. Berman, Brian D. TI Microstructural Changes within the Basal Ganglia Differ between Parkinson Disease Subtypes SO FRONTIERS IN NEUROANATOMY LA English DT Article DE Parkinson disease; motor subtypes; diffusion tensor imaging; basal ganglia ID SUBSTANTIA-NIGRA; MOTOR SUBTYPES AB Diffusion tensor imaging (DTI) of the substantia nigra has shown promise in detecting and quantifying neurodegeneration in Parkinson disease (PD). It remains unknown, however, whether differences in microstructural changes within the basal ganglia underlie PD motor subtypes. We investigated microstructural changes within the basal ganglia of mild to moderately affected PD patients using DTI and sought to determine if microstructural changes differ between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes. Fractional anisotropy, mean diffusivity, radial, and axial diffusivity were obtained from bilateral caudate, putamen, globus pallidus, and substantia nigra of 21 PD patients (12 TD and 9 PIGD) and 20 age-matched healthy controls. T-tests and ANOVA methods were used to compare PD patients, subtypes, and controls, and Spearman correlations tested for relationships between DTI and clinical measures. We found our cohort of PD patients had reduced fractional anisotropy within the substantia nigra and increased mean and radial diffusivity within the substantia nigra and globus pallidus compared to controls, and that changes within those structures were largely driven by the PIGD subtype. Across all PD patients fractional anisotropy within the substantia nigra correlated with disease stage, while in PIGD patients increased diffusivity within the globus pallidus correlated with disease stage and motor severity. We conclude that PIGD patients have more severely affected microstructural changes within the substantia nigra compared to TD, and that microstructural changes within the globus pallidus may be particularly relevant for the manifestation of the PIGD subtype. C1 [Nagae, Lidia M.; Honce, Justin M.; Tanabe, Jody; Berman, Brian D.] Univ Colorado, Dept Biol, Anschutz Med Campus, Aurora, CO USA. [Shelton, Erika; Sillau, Stefan H.; Berman, Brian D.] Univ Colorado, Dept Neurol, Anschutz Med Campus, Aurora, CO USA. [Berman, Brian D.] Denver VA Med Ctr, Neurol Sect, Denver, CO USA. RP Berman, BD (reprint author), Univ Colorado, Dept Biol, Anschutz Med Campus, Aurora, CO USA.; Berman, BD (reprint author), Univ Colorado, Dept Neurol, Anschutz Med Campus, Aurora, CO USA.; Berman, BD (reprint author), Denver VA Med Ctr, Neurol Sect, Denver, CO USA. EM brian.berman@ucdenver.edu FU NIH/NCATS Colorado CTSI Grant [KL2 TR001080]; University of Colorado Department of Neurology; University of Colorado Center for NeuroScience FX This work was supported by NIH/NCATS Colorado CTSI Grant Number KL2 TR001080, the University of Colorado Department of Neurology, and the University of Colorado Center for NeuroScience. NR 30 TC 3 Z9 3 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD FEB 23 PY 2016 VL 10 AR 17 DI 10.3389/fnana.2016.00017 PG 9 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA DE5AI UT WOS:000370642000001 PM 26941615 ER PT J AU Benechet, AP Menon, M Xu, DQ Samji, T Maher, L Murooka, TT Mempel, TR Sheridan, BS Lemoine, FM Khanna, KM AF Benechet, Alexandre P. Menon, Manisha Xu, Daqi Samji, Tasleem Maher, Leigh Murooka, Thomas T. Mempel, Thorsten R. Sheridan, Brian S. Lemoine, Francois M. Khanna, Kamal M. TI T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T-cell migration; sphingosine phosphate receptor-1; T-cell activation; infection ID SPHINGOSINE 1-PHOSPHATE RECEPTOR; IN-VIVO; SPHINGOSINE-1-PHOSPHATE; LYMPHOCYTES; MOTILITY; S1P(1); EXPRESSION; RETENTION; ANTIGEN; ORGANS AB Viral clearance requires effector T-cell egress from the draining lymph node (dLN). The mechanisms that regulate the complex process of effector T-cell egress from the dLN after infection are poorly understood. Here, we visualized endogenous pathogen-specific effector T-cell migration within, and from, the dLN. We used an inducible mouse model with a temporally disrupted sphingosine-1-phosphate receptor-1 (S1PR1) gene specifically in endogenous effector T cells. Early after infection, WT and S1PR1(-/-) effector T cells localized exclusively within the paracortex. This localization in the paracortex by CD8 T cells was followed by intranodal migration by both WT and S1PR1(-/-) T cells to positions adjacent to both cortical and medullary lymphatic sinuses where the T cells exhibited intense probing behavior. However, in contrast to WT, S1PR1(-/-) effector T cells failed to enter the sinuses. We demonstrate that, even when LN retention signals such as CC chemokine receptor 7 (CCR7) are down-regulated, T cell intrinsic S1PR1 is the master regulator of effector T-cell emigration from the dLN. C1 [Benechet, Alexandre P.; Menon, Manisha; Xu, Daqi; Samji, Tasleem; Maher, Leigh; Sheridan, Brian S.; Khanna, Kamal M.] Univ Connecticut Hlth, Dept Immunol, Farmington, CT 06030 USA. [Benechet, Alexandre P.; Lemoine, Francois M.] Univ Paris 06, Sorbonne Univ, UMR S CR7, Ctr Immunol & Malad Infect Paris, F-75005 Paris, France. [Benechet, Alexandre P.; Lemoine, Francois M.] INSERM, Ctr Immunol & Malad Infect Paris, UMR S 1135, F-75005 Paris, France. [Murooka, Thomas T.; Mempel, Thorsten R.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Murooka, Thomas T.; Mempel, Thorsten R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Khanna, Kamal M.] Univ Connecticut Hlth, Dept Pediat, Farmington, CT 06030 USA. [Benechet, Alexandre P.] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, I-20132 Milan, Italy. [Xu, Daqi] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Sheridan, Brian S.] SUNY Stony Brook, Ctr Infect Dis, Stony Brook, NY 11794 USA. RP Khanna, KM (reprint author), Univ Connecticut Hlth, Dept Immunol, Farmington, CT 06030 USA.; Khanna, KM (reprint author), Univ Connecticut Hlth, Dept Pediat, Farmington, CT 06030 USA. EM kkhanna@uchc.edu OI Benechet, Alexandre/0000-0001-8746-2459 FU NIH [AI076457, AI097052, AI007387, AI097375] FX We thank Quynh-Mai Pham for assistance in performing experiments and Dr. Evan Jellison in the UConn Health Flow Cytometry Facility. We thank Dr. Tim Hla for critically reading the paper and Dr. Shobha Thangada for her assistance with the study. This work was supported by NIH Grants AI076457 (to B.S.S.), AI097052 (to T.R.M.), AI007387 (to T.T.M.), and AI097375 (to K.M.K.). NR 36 TC 2 Z9 2 U1 0 U2 5 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 FEB 23 PY 2016 VL 113 IS 8 BP 2182 EP 2187 DI 10.1073/pnas.1516485113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE4SK UT WOS:000370620300066 PM 26862175 ER PT J AU Schwer, B Wei, PC Chang, AN Kao, J Du, Z Meyers, RM Alt, FW AF Schwer, Bjoern Wei, Pei-Chi Chang, Amelia N. Kao, Jennifer Du, Zhou Meyers, Robin M. Alt, Frederick W. TI Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nonhomologous end-joining; neural stem cells; transcription; translocation; alternative end-joining ID CHROMOSOMAL TRANSLOCATIONS; SEQUENCING REVEALS; REGULATED TRANSCRIPTION; GENOMIC INSTABILITY; GENE-FUNCTION; B-CELLS; ATM; NEUROGENESIS; SYSTEM; REPAIR AB High-throughput, genome-wide translocation sequencing (HTGTS) studies of activated B cells have revealed that DNA double-strand breaks (DSBs) capable of translocating to defined bait DSBs are enriched around the transcription start sites (TSSs) of active genes. We used the HTGTS approach to investigate whether a similar phenomenon occurs in primary neural stem/progenitor cells (NSPCs). We report that breakpoint junctions indeed are enriched around TSSs that were determined to be active by global run-on sequencing analyses of NSPCs. Comparative analyses of transcription profiles in NSPCs and B cells revealed that the great majority of TSS-proximal junctions occurred in genes commonly expressed in both cell types, possibly because this common set has higher transcription levels on average than genes transcribed in only one or the other cell type. In the latter context, among all actively transcribed genes containing translocation junctions in NSPCs, those with junctions located within 2 kb of the TSS show a significantly higher transcription rate on average than genes with junctions in the gene body located at distances greater than 2 kb from the TSS. Finally, analysis of repair junction signatures of TSS-associated translocations in wild-type versus classical nonhomologous endjoining (C-NHEJ)-deficient NSPCs reveals that both C-NHEJ and alternative end-joining pathways can generate translocations by joining TSS-proximal DSBs to DSBs on other chromosomes. Our studies show that the generation of transcription-associated DSBs is conserved across divergent cell types. C1 [Schwer, Bjoern; Wei, Pei-Chi; Chang, Amelia N.; Kao, Jennifer; Du, Zhou; Meyers, Robin M.; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Schwer, Bjoern; Wei, Pei-Chi; Chang, Amelia N.; Kao, Jennifer; Du, Zhou; Meyers, Robin M.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Schwer, Bjoern; Wei, Pei-Chi; Chang, Amelia N.; Kao, Jennifer; Du, Zhou; Meyers, Robin M.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Schwer, B; Alt, FW (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Howard Hughes Med Inst, Boston, MA 02115 USA.; Schwer, B; Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.; Schwer, B; Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. EM Bjoern.Schwer@childrens.harvard.edu; alt@enders.tch.harvard.edu FU Porter Anderson Fund from Boston Children's Hospital; Howard Hughes Medical Institute; National Institute on Aging/NIH [K01AG043630]; National Cancer Center FX We thank members of the F.W.A. laboratory for stimulating discussions, Drs. Chunguang Guo, Monica Gostissa, and Jiazhi Hu for experimental advice; and Drs. Yi Zhang, Li Shen, and Fei-Long Meng for assistance with high-throughput sequencing. This work in the F.W.A. laboratory was supported by the Porter Anderson Fund from Boston Children's Hospital and the Howard Hughes Medical Institute. B.S. is a Martin D. Abeloff Scholar of The V Foundation for Cancer Research and is supported by National Institute on Aging/NIH Grant K01AG043630. P.-C.W. is supported by a National Cancer Center postdoctoral fellowship. NR 44 TC 8 Z9 8 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 FEB 23 PY 2016 VL 113 IS 8 BP 2258 EP 2263 DI 10.1073/pnas.1525564113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE4SK UT WOS:000370620300079 PM 26873106 ER PT J AU Sowd, GA Serrao, E Wang, H Wang, WF Fadel, HJ Poeschla, EM Engelman, AN AF Sowd, Gregory A. Serrao, Erik Wang, Hao Wang, Weifeng Fadel, Hind J. Poeschla, Eric M. Engelman, Alan N. TI A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV-1; integration; CPSF6; LEDGF; CFIm68 ID CLEAVAGE FACTOR-I; 3' UTR LENGTH; SITE SELECTION; DNA INTEGRATION; HUMAN GENOME; EARLY STEPS; LEDGF/P75; CELLS; INFECTION; REPLICATION AB Integration is vital to retroviral replication and influences the establishment of the latent HIV reservoir. HIV-1 integration favors active genes, which is in part determined by the interaction between integrase and lens epithelium-derived growth factor (LEDGF)/p75. Because gene targeting remains significantly enriched, relative to random in LEDGF/p75 deficient cells, other host factors likely contribute to gene-tropic integration. Nucleoporins 153 and 358, which bind HIV-1 capsid, play comparatively minor roles in integration targeting, but the influence of another capsid binding protein, cleavage and polyadenylation specificity factor 6 (CPSF6), has not been reported. In this study we knocked down or knocked out CPSF6 in parallel or in tandem with LEDGF/p75. CPSF6 knockout changed viral infectivity kinetics, decreased proviral formation, and preferentially decreased integration into transcriptionally active genes, spliced genes, and regions of chromatin enriched in genes and activating histone modifications. LEDGF/p75 depletion by contrast preferentially altered positional integration targeting within gene bodies. Dual factor knockout reduced integration into genes to below the levels observed with either single knockout and revealed that CPSF6 played a more dominant role than LEDGF/p75 in directing integration to euchromatin. CPSF6 complementation rescued HIV-1 integration site distribution in CPSF6 knockout cells, but complementation with a capsid binding mutant of CPSF6 did not. We conclude that integration targeting proceeds via two distinct mechanisms: capsid-CPSF6 binding directs HIV-1 to actively transcribed euchromatin, where the integrase-LEDGF/p75 interaction drives integration into gene bodies. C1 [Sowd, Gregory A.; Serrao, Erik; Wang, Hao; Wang, Weifeng; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Fadel, Hind J.] Mayo Clin, Dept Med, Div Infect Dis, Rochester, MN 55905 USA. [Poeschla, Eric M.] Univ Colorado, Sch Med, Div Infect Dis, Denver, CO 80045 USA. RP Engelman, AN (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. EM alan_engelman@dfci.harvard.edu FU National Institutes of Health [T32 AI007245, T32 AI007386, R01 AI052014, P30 AI060354] FX We thank David Levy for the gift of pNLENG1-ES-IRES and Jacek Skowronski for pSIN3+ and pCG-VPX plasmid DNAs. This work was supported by National Institutes of Health Grants T32 AI007245 (to G.A.S.), T32 AI007386 (to E.S.), R01 AI052014 (to A.N.E.), and P30 AI060354 (Harvard University Center for AIDS Research). NR 61 TC 15 Z9 15 U1 4 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 23 PY 2016 VL 113 IS 8 BP E1054 EP E1063 DI 10.1073/pnas.1524213113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE4SK UT WOS:000370620300016 PM 26858452 ER PT J AU Arora, P Wu, C Hamid, T Arora, G Agha, O Allen, K Tainsh, RET Hu, DJ Ryan, RA Domian, IJ Buys, ES Bloch, DB Prabhu, SD Bloch, KD Newton-Cheh, C Wang, TJ AF Arora, Pankaj Wu, Connie Hamid, Tariq Arora, Garima Agha, Obiajulu Allen, Kaitlin Tainsh, Robert E. T. Hu, Dongjian Ryan, Romy A. Domian, Ibrahim J. Buys, Emmanuel S. Bloch, Donald B. Prabhu, Sumanth D. Bloch, Kenneth D. Newton-Cheh, Christopher Wang, Thomas J. TI Acute Metabolic Influences on the Natriuretic Peptide System in Humans SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiomyocyte; glucose; micro ribonucleic acid; obesity ID FACTOR-KAPPA-B; SMOOTH-MUSCLE-CELLS; GLUCOSE; ACTIVATION; OBESITY; HEART; HYPERTENSION; MICRORNA-425; EXPRESSION; DECREASES AB BACKGROUND The cardiac natriuretic peptides (NPs), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), have central roles in sodium and blood pressure regulation. Extracardiac factors (e.g., obesity and diabetes) influence NP production, potentially altering cardiovascular responses to volume and pressure stress. OBJECTIVES This study examined the effects of acute carbohydrate intake on the NP system in humans, and investigated underlying mechanisms. METHODS Normotensive subjects (N = 33) were given a high-carbohydrate shake. Venous blood was sampled to measure N-terminal (NT)-proANP and NT-proBNP levels. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and HepG2 cells were treated with glucose, and expression levels of NPs and micro ribonucleic acid 425 (miR-425), a negative regulator of ANP, were examined. The role of nuclear factor kappa B (NF-kappa B) in the glucose-mediated effects was investigated using a NF-kappa B inhibitor and expression plasmids encoding NF-kappa B subunits. RESULTS We observed a 27% reduction in the levels of circulating NT-proANP (p < 0.001, maximal at 6 h) after carbohydrate challenge, with no effect on NT-proBNP levels in our human subjects. Glucose treatment of hESC-CMs for 6 h and 24 h increased levels of the primary transcript of miR-425 (pri-miR-425) and mature miR-425. A corresponding decrease in NPPA messenger RNA levels was also observed at both time points. Overexpression of NF-kappa B subunits in H9c2 cardiomyocytes increased miR-425 levels, whereas inhibition of NF-kappa B abrogated the glucose-mediated increase in pri-miR-425 levels in HepG2 cells. CONCLUSIONS Acute carbohydrate challenge is associated with a reduction in ANP production. The mechanism appears to involve a glucose-induced increase in the expression of miR-425, mediated by NF-kappa B signaling. (C) 2016 by the American College of Cardiology Foundation. C1 [Arora, Pankaj; Hamid, Tariq; Arora, Garima; Prabhu, Sumanth D.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Wu, Connie; Hu, Dongjian; Ryan, Romy A.; Domian, Ibrahim J.; Bloch, Kenneth D.; Newton-Cheh, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Dept Med,Res Inst, Boston, MA USA. [Wu, Connie; Agha, Obiajulu; Allen, Kaitlin; Tainsh, Robert E. T.; Buys, Emmanuel S.; Bloch, Donald B.; Bloch, Kenneth D.] Harvard Univ, Massachusetts Gen Hosp, Res Inst,Med Sch, Anesthesia Ctr Crit Care Res,Dept Anesthesia Crit, Boston, MA USA. [Wu, Connie; Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Hu, Dongjian] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Domian, Ibrahim J.] Harvard Stem Cell Inst, Cambridge, MA USA. [Bloch, Donald B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med,Res Inst, Boston, MA USA. [Newton-Cheh, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Res Inst, Boston, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, 2220 Pierce Ave,383 PRB, Nashville, TN 37232 USA. [Wang, Thomas J.] Vanderbilt Univ, Vanderbilt Translat & Clin Cardiovasc Res Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Wang, TJ (reprint author), Vanderbilt Univ, Div Cardiovasc Med, 2220 Pierce Ave,383 PRB, Nashville, TN 37232 USA. EM thomas.j.wang@vanderbilt.edu FU Harvard Catalyst [1 UL1 RR025758, R01-HL-086875, R01-HL-102780, R01-DK-082971]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital; National Heart, Lung, And Blood Institute [T32HL007208]; Leducq Foundation FX This study was supported by the following grants: Harvard Catalyst 1 UL1 RR025758; R01-HL-086875; R01-HL-102780; R01-DK-082971; funds of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital; T32HL007208 from the National Heart, Lung, And Blood Institute; and the Leducq Foundation. Drs. Arora, Bloch, Newton-Cheh, and Wang are named as co-inventors on a patent application relating to the use of miRNAs for the treatment of hypertension and other disorders. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Arora and Wu contributed equally to this work. NR 26 TC 4 Z9 4 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 23 PY 2016 VL 67 IS 7 BP 804 EP 812 DI 10.1016/j.jacc.2015.11.049 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD6GK UT WOS:000370022500011 PM 26892417 ER PT J AU Akers, JC Ramakrishnan, V Nolan, JP Duggan, E Fu, CC Hochberg, FH Chen, CC Carter, BS AF Akers, Johnny C. Ramakrishnan, Valya Nolan, John P. Duggan, Erika Fu, Chia-Chun Hochberg, Fred H. Chen, Clark C. Carter, Bob S. TI Comparative Analysis of Technologies for Quantifying Extracellular Vesicles (EVs) in Clinical Cerebrospinal Fluids (CSF) SO PLOS ONE LA English DT Article ID NANOPARTICLE TRACKING ANALYSIS; MEMBRANE-VESICLES; EXOSOMES; MICROVESICLES; QUANTIFICATION; BIOGENESIS AB Extracellular vesicles (EVs) have emerged as a promising biomarker platform for glioblastoma patients. However, the optimal method for quantitative assessment of EVs in clinical bio-fluid remains a point of contention. Multiple high-resolution platforms for quantitative EV analysis have emerged, including methods grounded in diffraction measurement of Brownian motion (NTA), tunable resistive pulse sensing (TRPS), vesicle flow cytometry (VFC), and transmission electron microscopy (TEM). Here we compared quantitative EV assessment using cerebrospinal fluids derived from glioblastoma patients using these methods. For EVs <150 nm in diameter, NTA detected more EVs than TRPS in three of the four samples tested. VFC particle counts are consistently 2-3 fold lower than NTA and TRPS, suggesting contribution of protein aggregates or other non-lipid particles to particle count by these platforms. While TEM yield meaningful data in terms of the morphology, its particle count are consistently two orders of magnitude lower relative to counts generated by NTA and TRPS. For larger particles (>150 nm in diameter), NTA consistently detected lower number of EVs relative to TRPS. These results unveil the strength and pitfalls of each quantitative method alone for assessing EVs derived from clinical cerebrospinal fluids and suggest that thoughtful synthesis of multi-platform quantitation will be required to guide meaningful clinical investigations. C1 [Akers, Johnny C.; Ramakrishnan, Valya; Chen, Clark C.; Carter, Bob S.] Univ Calif San Diego, Ctr Theoret & Appl Neurooncol, San Diego, CA 92103 USA. [Nolan, John P.; Duggan, Erika] Scintillon Inst Biomed & Bioenergy Res, San Diego, CA USA. [Fu, Chia-Chun] Izon Sci, Christchurch, New Zealand. [Hochberg, Fred H.] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. [Hochberg, Fred H.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA USA. RP Chen, CC (reprint author), Univ Calif San Diego, Ctr Theoret & Appl Neurooncol, San Diego, CA 92103 USA. EM clarkchen@ucsd.edu RI RAMAKRISHNAN, VALYA/L-6415-2016 FU NIH [UH2 TR000931-0, PO1 2P30CA023100-28]; Doris Duke Charitable Foundation; Sontag Foundation; Burroughs Wellcome Fund; Kimmel Scholar Award; Accelerated Brain Cancer Cure; William Guy Forbeck Research Foundation; Program of international science & technology cooperation of China [2014DFA31470] FX The work is supported by NIH UH2 TR000931-0, NIH PO1 2P30CA023100-28 (BSC and CCC). CCC is supported by the Doris Duke Charitable Foundation Clinical Scientist Development Award, Sontag Foundation Distinguished Scientist Award, Burroughs Wellcome Fund Career Awards for Medical Scientists, the Kimmel Scholar Award, a Grant from Accelerated Brain Cancer Cure, the William Guy Forbeck Research Foundation, and Program of international science & technology cooperation of China (2014DFA31470). Chia-Chun Fu is an employee of Izon Science. The funder provided support in the form of salaries for authors BSC, CCC, JCA, and VR. The specific roles of these authors are articulated in the 'author contributions' section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 4 Z9 4 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 22 PY 2016 VL 11 IS 2 AR e0149866 DI 10.1371/journal.pone.0149866 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3VL UT WOS:000371276100168 PM 26901428 ER PT J AU Chapman, KR Bing-Canar, H Alosco, ML Steinberg, EG Martin, B Chaisson, C Kowall, N Tripodis, Y Stern, RA AF Chapman, Kimberly R. Bing-Canar, Hanaan Alosco, Michael L. Steinberg, Eric G. Martin, Brett Chaisson, Christine Kowall, Neil Tripodis, Yorghos Stern, Robert A. TI Mini Mental State Examination and Logical Memory scores for entry into Alzheimer's disease trials SO ALZHEIMERS RESEARCH & THERAPY LA English DT Article DE Alzheimer's disease; Clinical trials; MMSE; Logical Memory; Eligibility; Mild cognitive impairment; Neurodegenerative disease ID MILD COGNITIVE IMPAIRMENT; UNIFORM DATA SET; CENTER NACC DATABASE; DIAGNOSTIC-ACCURACY; NEUROIMAGING BIOMARKERS; CEREBROSPINAL-FLUID; DEMENTIA; CENTERS; TESTS; SCALE AB Background: Specific cutoff scores on the Mini Mental State Examination (MMSE) and the Logical Memory (LM) test are used to determine inclusion in Alzheimer's disease (AD) clinical trials and diagnostic studies. These screening measures have known psychometric limitations, but no study has examined the diagnostic accuracy of the cutoff scores used to determine entry into AD clinical trials and diagnostic studies. Methods: ClinicalTrials.gov entries were reviewed for phases II and III active and recruiting AD studies using the MMSE and LM for inclusion. The diagnostic accuracy of MMSE and LM-II cutoffs used in AD trials and diagnostic studies was examined using 23,438 subjects with normal cognition, mild cognitive impairment (MCI), and AD dementia derived from the National Alzheimer's Coordinating Center database. Results: MMSE and LM cutoffs used in current AD clinical trials and diagnostic studies had limited diagnostic accuracy, particularly for distinguishing between normal cognition and MCI, and MCI from AD dementia. The MMSE poorly discriminated dementia stage. Conclusions: The MMSE and LM may result in inappropriate subject enrollment in large-scale, multicenter studies designed to develop therapeutics and diagnostic methods for AD. C1 [Chapman, Kimberly R.; Bing-Canar, Hanaan; Alosco, Michael L.; Steinberg, Eric G.; Martin, Brett; Chaisson, Christine; Kowall, Neil; Tripodis, Yorghos; Stern, Robert A.] Boston Univ, Alzheimers Dis & CTE Ctr, 72 East Concord St,Suite B7800, Boston, MA 02118 USA. [Alosco, Michael L.; Kowall, Neil; Stern, Robert A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Martin, Brett; Chaisson, Christine] Boston Univ, Data Coordinating Ctr, Sch Publ Hlth, Boston, MA 02118 USA. [Chaisson, Christine; Tripodis, Yorghos] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Kowall, Neil] Boston Univ, Dept Pathol, Sch Med, Boston, MA 02118 USA. [Kowall, Neil] VA Boston Healthcare Syst, Neurol Serv, Boston, MA 02130 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. RP Stern, RA (reprint author), Boston Univ, Alzheimers Dis & CTE Ctr, 72 East Concord St,Suite B7800, Boston, MA 02118 USA.; Stern, RA (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. EM bobstern@bu.edu OI Stern, Robert/0000-0002-5008-077X FU National Institute on Aging (NIA) under NIH [U01 AG016976]; NIA [P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681]; NIH postdoctoral fellowship [T32-AG06697]; [P30 AG019610]; [P30 AG013846]; [P50 AG008702]; [P50 AG025688]; [P30 AG010133]; [P50 AG005146]; [P50 AG005134]; [P50 AG016574]; [P50 AG005138]; [P30 AG008051]; [P30 AG013854]; [P30 AG008017]; [P30 AG010161]; [P30 AG010129]; [P50 AG016573]; [P50 AG016570]; [P50 AG005131] FX The NACC database is funded by the National Institute on Aging (NIA) under NIH grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs under grants P30 AG019610 (Eric Reiman, MD, principal investigator), P30 AG013846 (Neil Kowall, MD, principal investigator), P50 AG008702 (Scott Small, MD, principal investigator), P50 AG025688 (Allan Levey, MD, PhD, principal investigator), P30 AG010133 (Andrew Saykin, PsyD, principal investigator), P50 AG005146 (Marilyn Albert, PhD, principal investigator), P50 AG005134 (Bradley Hyman, MD, PhD, principal investigator), P50 AG016574 (Ronald Petersen, MD, PhD, principal investigator), P50 AG005138 (Mary Sano, PhD, principal investigator), P30 AG008051 (Steven Ferris, PhD, principal investigator), P30 AG013854 (M. Marsel Mesulam, MD, principal investigator), P30 AG008017 (Jeffrey Kaye, MD, principal investigator), P30 AG010161 (David Bennett, MD, principal investigator), P30 AG010129 (Charles DeCarli, MD, principal investigator), P50 AG016573 (Frank LaFerla, PhD, principal investigator), P50 AG016570 (David Teplow, PhD, principal investigator), P50 AG005131 (Douglas Galasko, MD, principal investigator), P50 AG023501 (Bruce Miller, MD, principal investigator), P30 AG035982 (Russell Swerdlow, MD, principal investigator), P30 AG028383 (Linda Van Eldik, PhD, principal investigator), P30 AG010124 (John Trojanowski, MD, PhD, principal investigator), P50 AG005133 (Oscar Lopez, MD, principal investigator), P50 AG005142 (Helena Chui, MD, principal investigator), P30 AG012300 (Roger Rosenberg, MD, principal investigator), P50 AG005136 (Thomas Montine, MD, PhD, principal investigator), P50 AG033514 (Sanjay Asthana, MD, FRCP, principal investigator), and P50 AG005681 (John Morris, MD, principal investigator). MLA is supported by NIH postdoctoral fellowship grant T32-AG06697. NR 41 TC 4 Z9 4 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD FEB 22 PY 2016 VL 8 AR 9 DI 10.1186/s13195-016-0176-z PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DE3TK UT WOS:000370552900001 PM 26899835 ER PT J AU Binagwaho, A Fawzi, MCS Agbonyitor, M Nsanzimana, S Karema, C Remera, E Mutabazi, V Shyirambere, C Cyamatare, P Nutt, C Wagner, C Condo, J Misago, N Kayiteshonga, Y AF Binagwaho, Agnes Fawzi, Mary C. Smith Agbonyitor, Mawuena Nsanzimana, Sabin Karema, Corine Remera, Eric Mutabazi, Vincent Shyirambere, Cyprien Cyamatare, Patrick Nutt, Cameron Wagner, Claire Condo, Jeanine Misago, Nancy Kayiteshonga, Yvonne TI Validating the Children's Depression Inventory in the context of Rwanda SO BMC PEDIATRICS LA English DT Article DE Rwanda; Children; Adolescents; Depression; Screening; HIV; Chronic disease; Validation ID HIV DISEASE PROGRESSION; MENTAL-HEALTH; PSYCHIATRIC MORBIDITY; INFECTED CHILDREN; GLYCEMIC CONTROL; ADOLESCENTS; METAANALYSIS; PREVALENCE; SYMPTOMS; VALIDITY AB Background: Depression is often co-morbid with chronic conditions, and when combined with HIV it can increase progression and reduce survival. A brief and accurate screening tool for depression among children living with HIV is necessary to increase access to mental health care and improve HIV-related outcomes in the long-term. Methods: A validation study was conducted, comparing the Children's Depression Inventory (CDI) with a structured clinical assessment as the gold standard among children living with HIV ages 7-14 years in Rwanda. The response rate was 87 % and the analysis was performed among 100 study participants. Results: Twenty-five percent of children had a diagnosis of depression based on the clinical interview. Sensitivity of the CDI ranged from 44 to 76 % and specificity was 92 to 100 % for cut-off scores from 5 to 9. The area under the curve (AUC) for receiver operating characteristic analysis, an estimate of overall accuracy, was 0.87 (95 % confidence interval: 0.77-0.97). Conclusions: The significant prevalence of depression among children living with HIV in Rwanda reflects a critical need to advance mental health care in this population. Although overall accuracy of the CDI is reasonable in this context, further research needs to be done to develop a more sensitive measure of depression in this vulnerable population. Development of a highly sensitive screening measure will be a fundamental step towards improving access to mental health care among children living with HIV, potentially improving health outcomes and quality of life in the long-term as this vulnerable population transitions into adulthood. C1 [Binagwaho, Agnes] Minist Hlth Rwanda, POB 84, Kigali, Rwanda. [Binagwaho, Agnes; Fawzi, Mary C. Smith] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. [Binagwaho, Agnes] Univ Global Hlth Equ, 260 Blvd Umuganda,POB 6955, Kigali, Rwanda. [Binagwaho, Agnes] Geisel Sch Med Dartmouth, 1 Rope Ferry Rd, Hanover, NH 03755 USA. [Agbonyitor, Mawuena] Univ Maryland, Sch Med, 685 W Baltimore St, Baltimore, MD 21201 USA. [Nsanzimana, Sabin; Karema, Corine; Remera, Eric; Mutabazi, Vincent; Misago, Nancy; Kayiteshonga, Yvonne] Rwanda Biomed Ctr, POB 83, Kigali, Rwanda. [Shyirambere, Cyprien; Cyamatare, Patrick] Univ Teaching Hosp Butare, Butare, Rwanda. [Nutt, Cameron] Partners Hlth, 641 Huntington Ave, Boston, MA 02115 USA. [Wagner, Claire] Dana Farber Canc Inst, Ctr Global Canc Med, 450 Brookline Ave, Boston, MA 02115 USA. [Condo, Jeanine] Univ Rwanda, Sch Publ Hlth, POB 5229, Kigali, Rwanda. RP Binagwaho, A (reprint author), Minist Hlth Rwanda, POB 84, Kigali, Rwanda.; Binagwaho, A (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. EM agnes_binagwaho@hms.harvard.edu FU Government of Rwanda; Firelight Foundation FX We would like to acknowledge the contributions of the clinical psychologists from the Centre Psychosocial of Kigali Teaching Hospital, Butare Teaching Hospital, and Ndera Hospital, Kacyiru Police Hospital. In addition, we would like to thank personnel of the Health Centres and HIV division and Mental Health division in the Rwanda Biomedical Centre as well as Jeffrey Lienert who assisted with some statistical analyses, as well as editing and formatting the manuscript. The study was funded by the Government of Rwanda and the Firelight Foundation. NR 33 TC 0 Z9 0 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD FEB 22 PY 2016 VL 16 AR 29 DI 10.1186/s12887-016-0565-2 PG 7 WC Pediatrics SC Pediatrics GA DE4HV UT WOS:000370590700001 PM 26898199 ER PT J AU Ogawa, T Kodera, Y Hirata, D Blackwell, TK Mizunuma, M AF Ogawa, Takahiro Kodera, Yukihiro Hirata, Dai Blackwell, T. Keith Mizunuma, Masaki TI Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf SO SCIENTIFIC REPORTS LA English DT Article ID GARLIC ALLIUM-SATIVUM; TRANSCRIPTION FACTOR SKN-1; C-ELEGANS; ORGANOSULFUR COMPOUNDS; S-ALLYLCYSTEINE; DIETARY RESTRICTION; CANCER CELLS; COLON-CANCER; LONGEVITY; MICE AB Identification of biologically active natural compounds that promote health and longevity, and understanding how they act, will provide insights into aging and metabolism, and strategies for developing agents that prevent chronic disease. The garlic-derived thioallyl compounds S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) have been shown to have multiple biological activities. Here we show that SAC and SAMC increase lifespan and stress resistance in Caenorhabditis elegans and reduce accumulation of reactive oxygen species (ROS). These compounds do not appear to activate DAF-16 (FOXO orthologue) or mimic dietary restriction (DR) effects, but selectively induce SKN-1 (Nrf1/2/3 orthologue) targets involved in oxidative stress defense. Interestingly, their treatments do not facilitate SKN-1 nuclear accumulation, but slightly increased intracellular SKN-1 levels. Our data also indicate that thioallyl structure and the number of sulfur atoms are important for SKN-1 target induction. Our results indicate that SAC and SAMC may serve as potential agents that slow aging. C1 [Ogawa, Takahiro; Hirata, Dai; Mizunuma, Masaki] Hiroshima Univ, Dept Mol Biotechnol, Grad Sch Adv Sci Matter, Higashihiroshima 7398530, Japan. [Ogawa, Takahiro; Kodera, Yukihiro] Wakunaga Pharmaceut Co Ltd, Drug Discovery Lab, Hiroshima 7391195, Japan. [Blackwell, T. Keith] Harvard Stem Cell Inst, Joslin Diabet Ctr, Boston, MA 02215 USA. [Blackwell, T. Keith] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. RP Ogawa, T; Mizunuma, M (reprint author), Hiroshima Univ, Dept Mol Biotechnol, Grad Sch Adv Sci Matter, Higashihiroshima 7398530, Japan.; Ogawa, T (reprint author), Wakunaga Pharmaceut Co Ltd, Drug Discovery Lab, Hiroshima 7391195, Japan. EM ogawa_t@wakunaga.co.jp; mmizu49120@hiroshima-u.ac.jp FU NIH office of Research Infrastructure Programs [P40 OD010440]; Japan Society for the Promotion of Science; DRC award [P30DK036836]; NIH [GM062891, GM094398] FX Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH office of Research Infrastructure Programs (P40 OD010440). KU4 was generous gift from Naoki Hisamoto (Nagoya university, Japan). We thank Kira Glover-Cutter, Takami Oka, Keiichi Itakura for helpful discussion. M.M. was supported in part by the programs Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. Supported by funding from the NIH to T.K.B. (GM062891 and GM094398), and a DRC award to the Joslin Diabetes Center (P30DK036836). NR 54 TC 1 Z9 1 U1 0 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 FEB 22 PY 2016 VL 6 AR 21611 DI 10.1038/srep21611 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE3CS UT WOS:000370505000001 PM 26899496 ER PT J AU Ruddy, KJ Risendal, BC Garber, JE Partridge, AH AF Ruddy, Kathryn J. Risendal, Betsy C. Garber, Judy E. Partridge, Ann H. TI Cancer Survivorship Care: An Opportunity to Revisit Cancer Genetics SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID INFORMATION NONDISCRIMINATION ACT; BREAST-CANCER; DECISION-MAKING; LYNCH SYNDROME; RISK; MUTATIONS; BRCA1; SUSCEPTIBILITY; BARRIERS; IMPACT C1 [Ruddy, Kathryn J.] Mayo Clin, Rochester, MN USA. [Risendal, Betsy C.] Univ Colorado, Ctr Canc, Aurora, CO USA. [Garber, Judy E.; Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ruddy, KJ (reprint author), Mayo Clin, Rochester, MN USA. FU NCATS NIH HHS [KL2TR000136-09, UL1 TR000135, KL2 TR000136] NR 29 TC 0 Z9 0 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 FEB 20 PY 2016 VL 34 IS 6 BP 539 EP + DI 10.1200/JCO.2015.63.5375 PG 5 WC Oncology SC Oncology GA DJ6ON UT WOS:000374332900009 PM 26712228 ER PT J AU Carey, LA Berry, DA Cirrincione, CT Barry, WT Pitcher, BN Harris, LN Ollila, DW Krop, IE Henry, NL Weckstein, DJ Anders, CK Singh, B Hoadley, KA Iglesia, M Cheang, MCU Perou, CM Winer, EP Hudis, CA AF Carey, Lisa A. Berry, Donald A. Cirrincione, Constance T. Barry, William T. Pitcher, Brandelyn N. Harris, Lyndsay N. Ollila, David W. Krop, Ian E. Henry, Norah Lynn Weckstein, Douglas J. Anders, Carey K. Singh, Baljit Hoadley, Katherine A. Iglesia, Michael Cheang, Maggie Chon U. Perou, Charles M. Winer, Eric P. Hudis, Clifford A. TI Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC BREAST-CANCER; OPEN-LABEL; ADJUVANT TRASTUZUMAB; EXPRESSION; BENEFIT; SURVIVAL; GENES; CHEMOTHERAPY; MULTICENTER; PERTUZUMAB AB Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays. Results Among 305 randomly assigned patients (THL, n - 118; TH, n - 120; TL, n - 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%). Conclusion pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease. (C) 2015 by American Society of Clinical Oncology C1 [Carey, Lisa A.; Ollila, David W.; Anders, Carey K.; Hoadley, Katherine A.; Iglesia, Michael; Perou, Charles M.] Univ N Carolina, Chapel Hill, NC USA. [Cirrincione, Constance T.; Pitcher, Brandelyn N.] Duke Univ, Alliance Stat & Data Ctr, Durham, NC USA. [Berry, Donald A.] MD Anderson, Alliance Stat & Data Ctr, Houston, TX USA. [Barry, William T.] Dana Farber Canc Inst, Alliance Stat & Data Ctr, Boston, MA 02115 USA. [Krop, Ian E.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Harris, Lyndsay N.] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Henry, Norah Lynn] Univ Michigan, Ann Arbor, MI 48109 USA. [Weckstein, Douglas J.] New Hampshire Hematol Oncol, Hooksett, NH USA. [Singh, Baljit] NYU, New York, NY 10003 USA. [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Cheang, Maggie Chon U.] Inst Canc Res, Clin Trials & Stat Unit, Belmont, CA USA. RP Carey, LA (reprint author), Univ N Carolina, Div Hematol Oncol, 170 Manning Dr,CB7305, Chapel Hill, NC 27514 USA. EM lisa_carey@med.unc.edu OI Perou, Charles/0000-0001-9827-2247 FU National Cancer Institute (NCI), National Institutes of Health [U10CA180821, U10CA180882]; NCI [1U10CA180838, 1U10CA180867, 1U10CA180801, 1U10CA180791, CA31946]; Breast Cancer Research Foundation (Alliance); Susan G. Komen; GlaxoSmithKline; University of North Carolina Specialized Program of Research Excellence in Breast Cancer (NCI Grant) [P50-CA58223]; Alliance Statistics and Data Center by NCI [CA33601] FX Supported by the National Cancer Institute (NCI), National Institutes of Health, under Awards No. U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology, as well as NCI Grants No. 1U10CA180838, 1U10CA180867, 1U10CA180801, and 1U10CA180791, and in part by grants from the Breast Cancer Research Foundation (Alliance, L.A.C., C.M.P.), Susan G. Komen (L. A. C.), GlaxoSmithKline, and the University of North Carolina Specialized Program of Research Excellence in Breast Cancer (NCI Grant No. P50-CA58223). Alliance/Cancer and Leukemia Group B is supported by NCI Grant No. CA31946 and Alliance Statistics and Data Center by NCI Grant No. CA33601. NR 37 TC 33 Z9 33 U1 3 U2 5 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 FEB 20 PY 2016 VL 34 IS 6 BP 542 EP + DI 10.1200/JCO.2015.62.1268 PG 15 WC Oncology SC Oncology GA DJ6ON UT WOS:000374332900010 PM 26527775 ER PT J AU Basch, E Deal, AM Kris, MG Scher, HI Hudis, CA Sabbatini, P Rogak, L Bennett, AV Dueck, AC Atkinson, TM Chou, JF Dulko, D Sit, L Barz, A Novotny, P Fruscione, M Sloan, JA Schrag, D AF Basch, Ethan Deal, Allison M. Kris, Mark G. Scher, Howard I. Hudis, Clifford A. Sabbatini, Paul Rogak, Lauren Bennett, Antonia V. Dueck, Amylou C. Atkinson, Thomas M. Chou, Joanne F. Dulko, Dorothy Sit, Laura Barz, Allison Novotny, Paul Fruscione, Michael Sloan, Jeff A. Schrag, Deborah TI Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; CLINICAL-PRACTICE; CHEMOTHERAPY; CARE; ONCOLOGY; IMPACT; COMMUNICATION; IMPROVEMENT; TOXICITIES; PROVIDERS AB Purpose There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes, but evidence of impact on clinical outcomes is limited. Methods We randomly assigned patients receiving routine outpatient chemotherapy for advanced solid tumors at Memorial Sloan Kettering Cancer Center to report 12 common symptoms via tablet computers or to receive usual care consisting of symptom monitoring at the discretion of clinicians. Those with home computers received weekly e-mail prompts to report between visits. Treating physicians received symptom printouts at visits, and nurses received e-mail alerts when participants reported severe or worsening symptoms. The primary outcome was change in health-related quality of life (HRQL) at 6 months compared with baseline, measured by the EuroQol EQ-5D Index. Secondary endpoints included emergency room (ER) visits, hospitalizations, and survival. Results Among 766 patients allocated, HRQL improved among more participants in the intervention group than usual care (34% v 18%) and worsened among fewer (38% v 53%; P < .001). Overall, mean HRQL declined by less in the intervention group than usual care (1.4-v 7.1-point drop; P,.001). Patients receiving intervention were less frequently admitted to the ER (34% v 41%; P = .02) or hospitalized (45% v 49%; P = .08) and remained on chemotherapy longer (mean, 8.2 v 6.3 months; P = .002). Although 75% of the intervention group was alive at 1 year, 69% with usual care survived the year (P = .05), with differences also seen in quality-adjusted survival (mean of 8.7 v. 8.0 months; P = .004). Benefits were greater for participants lacking prior computer experience. Most patients receiving intervention (63%) reported severe symptoms during the study. Nurses frequently initiated clinical actions in response to e-mail alerts. Conclusion Clinical benefits were associated with symptom self-reporting during cancer care. (C) 2015 by American Society of Clinical Oncology C1 [Basch, Ethan; Kris, Mark G.; Scher, Howard I.; Hudis, Clifford A.; Sabbatini, Paul; Rogak, Lauren; Atkinson, Thomas M.; Chou, Joanne F.; Dulko, Dorothy; Sit, Laura; Fruscione, Michael; Schrag, Deborah] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Basch, Ethan; Deal, Allison M.; Bennett, Antonia V.] Univ N Carolina, Chapel Hill, NC USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ USA. [Barz, Allison] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Novotny, Paul; Sloan, Jeff A.] Mayo Clin, Rochester, MN USA. [Schrag, Deborah] Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Basch, E (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Canc Outcomes Res Program, 170 Manning Dr, Chapel Hill, NC 27599 USA. EM ebasch@med.unc.edu FU National Cancer Institute; Society of Memorial Sloan Kettering FX Supported by the National Cancer Institute and a grant from the Society of Memorial Sloan Kettering. NR 37 TC 35 Z9 36 U1 4 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 FEB 20 PY 2016 VL 34 IS 6 BP 557 EP + DI 10.1200/JCO.2015.63.0830 PG 11 WC Oncology SC Oncology GA DJ6ON UT WOS:000374332900012 PM 26644527 ER PT J AU O'Sullivan, CC Holmes, E Campbell, C Bradbury, I Zujewski, JA Gelber, RD AF O'Sullivan, Ciara C. Holmes, Eileen Campbell, Christine Bradbury, Ian Zujewski, Jo Anne Gelber, Richard D. TI Treatment of Lymph Node-Negative, Early-Stage HER2-Positive Breast Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ADJUVANT TRASTUZUMAB; SERIES C1 [O'Sullivan, Ciara C.; Zujewski, Jo Anne] NCI, NIH, Bethesda, MD 20892 USA. [Holmes, Eileen; Campbell, Christine; Bradbury, Ian] Frontier Sci, Kingussie, Inverness, Scotland. [Gelber, Richard D.] Harvard Univ, Sch Med, Boston, MA USA. [Gelber, Richard D.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. RP O'Sullivan, CC (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 10 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 FEB 20 PY 2016 VL 34 IS 6 BP 640 EP + DI 10.1200/JCO.2015.65.1034 PG 2 WC Oncology SC Oncology GA DJ6ON UT WOS:000374332900025 PM 26644531 ER PT J AU Tolstorukov, MY Virnik, K Zhurkin, VB Adhya, S AF Tolstorukov, Michael Y. Virnik, Konstantin Zhurkin, Victor B. Adhya, Sankar TI Organization of DNA in a bacterial nucleoid SO BMC MICROBIOLOGY LA English DT Article DE Bacterial; Nucleoid; MNase; Digestion; Sequencing; Genomic; DNA; Packaging; Structural; Organization ID ESCHERICHIA-COLI CHROMOSOME; SEQUENCE-DIRECTED CURVATURE; PROKARYOTIC DNA; GENE-EXPRESSION; MICROCOCCAL NUCLEASE; ELECTRON-MICROSCOPY; FOLDED CHROMOSOMES; BINDING PROTEINS; CHIP-SEQ; H-NS AB Background: It is unclear how DNA is packaged in a bacterial cell in the absence of nucleosomes. To investigate the initial level of DNA condensation in bacterial nucleoid we used in vivo DNA digestion coupled with high-throughput sequencing of the digestion-resistant fragments. To this end, we transformed E. coli cells with a plasmid expressing micrococcal nuclease. The nuclease expression was under the control of AraC repressor, which enabled us to perform an inducible digestion of bacterial nucleoid inside a living cell. Results: Analysis of the genomic localization of the digestion-resistant fragments revealed their non-random distribution. The patterns observed in the distribution of the sequenced fragments indicate the presence of short DNA segments protected from the enzyme digestion, possibly because of interaction with DNA-binding proteins. The average length of such digestion-resistant segments is about 50 bp and the characteristic repeat in their distribution is about 90 bp. The gene starts are depleted of the digestion-resistant fragments, suggesting that these genomic regions are more exposed than genomic sequences on average. Sequence analysis of the digestion-resistant segments showed that while the GC-content of such sequences is close to the genome-wide value, they are depleted of A-tracts as compared to the bulk genomic DNA or to the randomized sequence of the same nucleotide composition. Conclusions: Our results suggest that DNA is packaged in the bacterial nucleoid in a non-random way that facilitates interaction of the DNA binding factors with regulatory regions of the genome. C1 [Tolstorukov, Michael Y.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tolstorukov, Michael Y.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Virnik, Konstantin] FDA, Ctr Biol, Off Vaccines, Lab Immunoregulat,Div Viral Prod, Silver Spring, MD 20993 USA. [Zhurkin, Victor B.] NCI, Lab Cell Biol, NIH, Bethesda, MD 20892 USA. [Adhya, Sankar] NCI, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. EM adhyas@mail.nih.gov NR 77 TC 1 Z9 1 U1 4 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD FEB 20 PY 2016 VL 16 AR 22 DI 10.1186/s12866-016-0637-3 PG 11 WC Microbiology SC Microbiology GA DE2RK UT WOS:000370474300001 PM 26897370 ER PT J AU Maertens, JA Raad, II Marr, KA Patterson, TF Kontoyiannis, DP Cornely, OA Bow, EJ Rahav, G Neofytos, D Aoun, M Baddley, JW Giladi, M Heinz, WJ Herbrecht, R Hope, W Karthaus, M Lee, DG Lortholary, O Morrison, VA Oren, I Selleslag, D Shoham, S Thompson, GR Lee, M Maher, RM Schmitt-Hoffmann, AH Zeiher, B Ullmann, AJ AF Maertens, Johan A. Raad, Issam I. Marr, Kieren A. Patterson, Thomas F. Kontoyiannis, Dimitrios P. Cornely, Oliver A. Bow, Eric J. Rahav, Galia Neofytos, Dionysios Aoun, Mickael Baddley, John W. Giladi, Michael Heinz, Werner J. Herbrecht, Raoul Hope, William Karthaus, Meinolf Lee, Dong-Gun Lortholary, Olivier Morrison, Vicki A. Oren, Ilana Selleslag, Dominik Shoham, Shmuel Thompson, George R., III Lee, Misun Maher, Rochelle M. Schmitt-Hoffmann, Anne-Hortense Zeiher, Bernhardt Ullmann, Andrew J. TI Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial SO LANCET LA English DT Article ID PHARMACODYNAMIC TARGET DETERMINATION; LIPOSOMAL AMPHOTERICIN-B; CELL TRANSPLANT PATIENTS; MYCOSES STUDY-GROUP; EUROPEAN-ORGANIZATION; PULMONARY ASPERGILLOSIS; CLINICAL-PRACTICE; THERAPY; INFECTIONS; CANCER AB Background Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. Methods This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1: 1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. Findings 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1.0% (95% CI -7.8 to 5.7). Because the upper bound of the 95% CI (5.7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0.122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0.016), eye disorders (39 [15%] vs 69 [27%]; p=0.002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0.037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0.001). Interpretation Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. C1 [Maertens, Johan A.] Katholieke Univ Leuven, Univ Ziekenhuizen Leuven, Dept Hematol, Louvain, Belgium. [Raad, Issam I.] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Houston, TX 77030 USA. [Marr, Kieren A.; Shoham, Shmuel] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Marr, Kieren A.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Neofytos, Dionysios] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD USA. [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis, Houston, TX 77030 USA. [Cornely, Oliver A.] Univ Cologne, ZKS Koln Ctr Integrated Oncol CIO Koln Bonn, Cologne Excellence Cluster Cellular Stress Respon, Dept Internal Med,Clin Trials Ctr Cologne,German, D-50931 Cologne, Germany. [Bow, Eric J.] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada. [Bow, Eric J.] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada. [Bow, Eric J.] CancerCare Manitoba, Infect Control Serv, Winnipeg, MB, Canada. [Rahav, Galia] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Rahav, Galia] Tel Aviv Univ, Sackler Sch Med, Ramat Gan, Israel. [Aoun, Mickael] Inst Jules Bordet, Div Infect Dis, B-1000 Brussels, Belgium. [Baddley, John W.] Univ Alabama Birmingham, Birmingham, AL USA. [Baddley, John W.] Vet Affairs Med Ctr, Birmingham, AL USA. [Giladi, Michael] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Infect Dis Unit, IL-69978 Tel Aviv, Israel. [Giladi, Michael] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Heinz, Werner J.] Univ Wurzburg, Med Ctr, D-97070 Wurzburg, Germany. [Herbrecht, Raoul] Hop Univ Strasbourg, Dept Hematol & Oncol, Strasbourg, France. [Herbrecht, Raoul] Univ Strasbourg, Strasbourg, France. [Hope, William] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England. [Karthaus, Meinolf] Klinikum Neuperlach, Klin Hamatol & Onkol, Munich, Germany. [Lee, Dong-Gun] Catholic Univ Korea, Seoul St Marys Hosp, Dept Internal Med, Div Infect Dis, Seoul, South Korea. [Lortholary, Olivier] Univ Paris 05, Ctr Infectiol Necker Pasteur, Hop Necker Enfants Malades, IHU Imagine, Paris, France. [Lortholary, Olivier] Inst Pasteur, Ctr Natl Reference Mycoses Invas & Antifong, Paris, France. [Morrison, Vicki A.] Univ Minnesota, Minneapolis, MN USA. [Morrison, Vicki A.] Vet Affairs Med Ctr, Minneapolis, MN USA. [Oren, Ilana] Rambam Hlth Care Campus, Infect Dis Unit, Haifa, Israel. [Oren, Ilana] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. [Selleslag, Dominik] Algemeen Ziekenhuis St Jan, Brugge, Belgium. [Thompson, George R., III] Univ Calif Davis, Med Ctr, Davis, CA 95616 USA. [Lee, Misun; Maher, Rochelle M.; Zeiher, Bernhardt] Astellas Pharma Global Dev, Northbrook, IL USA. [Schmitt-Hoffmann, Anne-Hortense] Basilea Pharmaceut Int, Basel, Switzerland. [Ullmann, Andrew J.] Univ Wurzburg, Dept Internal Med 2, Infect Dis, Oderdurrbacher Str 6, D-97080 Wurzburg, Germany. RP Ullmann, AJ (reprint author), Univ Wurzburg, Dept Internal Med 2, Infect Dis, Oderdurrbacher Str 6, D-97080 Wurzburg, Germany. EM andrew.ullmann@uni-wuerzburg.de OI Patterson, Thomas /0000-0002-9513-7127; Heinz, Werner/0000-0002-7833-9202; Herbrecht, Raoul/0000-0002-9381-4876; Hope, William/0000-0001-6187-878X FU Astellas Pharma Global Development FX Isavuconazole was co-developed by Astellas Pharma US and Basilea Pharmaceutica International. We acknowledge the contributions of the medical director of the SECURE trial, Neddie Zadeikis (Astellas Pharma Global Development during the conduct of the study) in the design and conduct of the study. Editorial assistance was provided by Radhika Bhatia, of Envision Scientific Solutions, funded by Astellas Pharma Global Development. NR 32 TC 48 Z9 48 U1 14 U2 20 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 FEB 20 PY 2016 VL 387 IS 10020 BP 760 EP 769 DI 10.1016/S0140-6736(15)01159-9 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DE1WU UT WOS:000370418000035 PM 26684607 ER PT J AU Nou, E Lu, MT Looby, SE Fitch, KV Kim, EA Lee, H Hoffmann, U Grinspoon, SK Lo, J AF Nou, Eric Lu, Michael T. Looby, Sara E. Fitch, Kathleen V. Kim, Elli A. Lee, Hang Hoffmann, Udo Grinspoon, Steven K. Lo, Janet TI Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV SO AIDS LA English DT Article DE atherosclerosis; cardiovascular; HIV; oxidized LDL; statin ID ACUTE MYOCARDIAL-INFARCTION; SUBCLINICAL ATHEROSCLEROSIS; INFECTED PATIENTS; HEART-DISEASE; MONOCYTE ACTIVATION; ELEVATED LEVELS; PLASMA-LEVELS; RISK; INFLAMMATION; LDL AB Objective:Circulating oxidized low-density lipoprotein (oxLDL) levels are elevated in HIV-infected patients and have been associated with atherosclerosis. Statins have been shown to reduce plaque on coronary computed tomography angiography (cCTA) in HIV-infected individuals. Thus, we investigated the effect of statins on serum oxLDL levels and the relationship between changes in oxLDL and coronary atherosclerosis on cCTA in patients with HIV.Design:We previously conducted a 12-month randomized, placebo-controlled trial with atorvastatin in 40 HIV-infected patients on stable antiretroviral therapy with subclinical coronary atherosclerosis and low-density lipoprotein (LDL)-cholesterol less than 130 mg/dl.Methods:In the current analysis, patients underwent cCTA and measurements of serum oxLDL, sCD14, sCD163, lipoprotein phospholipase-A(2), and fasting lipids at baseline and end of the study.Results:Nineteen patients were randomized to atorvastatin and 21 patients to placebo. Serum oxLDL decreased -22.7% (95% CI -28.7 to -16.7) in the atorvastatin group and increased 7.5% (95% CI -3.3 to 18.4) in the placebo group (P < 0.0001). Change in oxLDL significantly correlated with changes in noncalcified plaque volume, total plaque volume, positively remodeled plaque, and low attenuation plaque. The association between changes in oxLDL and noncalcified plaque volume was independent of the baseline 10-year Framingham risk, LDL, CD4(+) cell count, and viral load.Conclusion:Statins lower oxLDL levels in HIV-infected patients, and reductions in oxLDL are related to improvements in coronary atherosclerosis, independent of traditional cardiovascular risk factors. Reductions in oxLDL may be one mechanism through which statins exert beneficial effects on reducing atherosclerosis in HIV-infected individuals. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Nou, Eric; Looby, Sara E.; Fitch, Kathleen V.; Kim, Elli A.; Grinspoon, Steven K.; Lo, Janet] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Lu, Michael T.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiovasc Imaging Sect, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, LON 207,55 Fruit St, Boston, MA 02114 USA. RP Lo, J (reprint author), Massachusetts Gen Hosp, Ctr Biostat, LON 207,55 Fruit St, Boston, MA 02114 USA. EM jlo@mgh.harvard.edu FU National Institutes of Health [5T32DK007028-40, K23HL092792, 5T32HL076136, 5K24HL113128, R01HL095123, P30 DK040561]; Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery; Harvard Clinical and Translational Science Center from the National Center for Research Resources [1 UL1 RR025758-04] FX This work was supported by the National Institutes of Health (5T32DK007028-40 to E.N., K23HL092792 to J.L., 5T32HL076136 to M.T.L., 5K24HL113128 to U.H., and R01HL095123 and P30 DK040561 to S.K.G.); Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery; and Harvard Clinical and Translational Science Center from the National Center for Research Resources (1 UL1 RR025758-04). Funding sources had no role in the design of the study, data analysis, or writing of the manuscript. NR 30 TC 9 Z9 9 U1 0 U2 1 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 FEB 20 PY 2016 VL 30 IS 4 BP 583 EP 590 DI 10.1097/QAD.0000000000000946 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DC7ST UT WOS:000369421400006 PM 26558731 ER PT J AU Baxi, SM Scherzer, R Greenblatt, RM Minkoff, H Sharma, A Cohen, M Young, MA Abraham, AG Shlipak, MG AF Baxi, Sanjiv M. Scherzer, Rebecca Greenblatt, Ruth M. Minkoff, Howard Sharma, Anjali Cohen, Mardge Young, Mary A. Abraham, Alison G. Shlipak, Michael G. CA Womens Interagency HIV Study TI Higher tenofovir exposure is associated with longitudinal declines in kidney function in women living with HIV SO AIDS LA English DT Article DE adverse drug effect; HIV; kidney function; pharmacokinetics; tenofovir; Women's Interagency HIV Study ID DISOPROXIL FUMARATE; INFECTED PATIENTS; RENAL TOXICITY; INCOMPLETE REVERSIBILITY; ANTIRETROVIRAL ACTIVITY; PLASMA-CONCENTRATIONS; CLINICAL-TRIALS; PHASE I/II; PHARMACOKINETICS; ALAFENAMIDE AB Objective:Tenofovir disoproxil fumarate is a commonly used antiretroviral drug, but risk factors for tenofovir (TFV)-associated kidney disease are not fully understood. We used intensive pharmacokinetic studies in a cohort of HIV-infected women on TFV-based therapy to study the relationship between TFV exposure and subsequent kidney function.Design:This is a nested study within the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected women. Participants on TFV-based therapy underwent 24-h intensive pharmacokinetic sampling after witnessed dose. Kidney function was measured over the succeeding 7 years by serum creatinine [estimated glomerular filtration rate calculated by serum creatinine (eGFRcr)].Methods:Multivariable linear mixed models evaluated the relationship of baseline TFV area under the-time concentration curves (AUCs) with subsequent changes in kidney function. Covariates included age, diabetes, hypertension, race, BMI, ritonavir use, duration of TFV exposure, current CD4(+) cell count, and HIV viral load.Results:Of the 105 participants, persons within the highest baseline TFV AUC tertile had significantly lower eGFRcr compared with those in the lowest tertile (meanstandard error: 80 +/- 4.3 vs. 104 +/- 2.5ml/min per 1.73m(2), P<0.0001). By year 7, this difference widened (72 +/- 4.9 vs. 105 +/- 2.9, P<0.0001). After multivariable adjustment, TFV AUC in the highest tertile remained associated with lower eGFRcr relative to values in the lowest tertile at both baseline (-15ml/min per 1.73m(2), P=0.0047) and year 7 (-23ml/min per 1.73m(2), P=0.0002).Conclusion:Through intensive TFV pharmacokinetic sampling, we found a strong association between greater TFV exposure and subsequent decline in kidney function. Variations in TFV drug exposure may partially account for subsequent nephrotoxicity in persons infected with HIV. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Baxi, Sanjiv M.; Scherzer, Rebecca; Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Baxi, Sanjiv M.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Scherzer, Rebecca; Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA 94143 USA. [Greenblatt, Ruth M.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Minkoff, Howard] Suny Downstate Med Ctr, Div Infect Dis, Brooklyn, NY 11203 USA. [Sharma, Anjali] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Cohen, Mardge] John H Stroger Jr Hosp Cook Cty, CORE Ctr, Div Infect Dis, Chicago, IL USA. [Young, Mary A.] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Abraham, Alison G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Baxi, SM (reprint author), Univ Calif San Francisco, Div Infect Dis, 513 Parnassus Ave,Room S380, San Francisco, CA 94143 USA. EM sanjiv.baxi@ucsf.edu FU Bronx WIHS [U01-AI-035004]; Brooklyn WIHS [U01-AI-031834]; Chicago WIHS [U01-AI-034993]; Metropolitan Washington WIHS [U01-AI-034994]; Connie Wofsy Women's HIV Study, Northern California [U01-AI-034989, R01 AI 65233]; WIHS Data Management and Analysis Center [U01-AI-042590]; Southern California WIHS [U01-HD-032632]; National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI); National Institute on Drug Abuse (NIDA); National Institute on Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Deafness and other Communication Disorders (NIDCD); NIH Office of Research on Women's Health; UCSF CTSA [UL1-TR000004]; UCSF Traineeship in AIDS Prevention Studies [US National Institutes of Health (NIH)] [T32 MH-19105]; National Institutes of Health, University of California, San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR) [P30-AI027763]; US NIH National Institute on Aging [2R01AG03485306] FX WIHS (Principal Investigators): Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen), U01-AI-034993; Metropolitan Washington WIHS (Mary Young), U01-AI-034994; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien) U01-AI-034989; and R01 AI 65233 (NIAID/NIH, P.I. Greenblatt); WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Alexandra Levine and Marek Nowicki), U01-HD-032632 (WIHS I-WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA). S.M.B. is supported by the UCSF Traineeship in AIDS Prevention Studies [US National Institutes of Health (NIH) T32 MH-19105]. This research was also supported by a grant from the National Institutes of Health, University of California, San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR), P30-AI027763 (Principal Investigators Paul Volberding and Warner Greene). M.G.S. and R.S. by the US NIH National Institute on Aging grant 2R01AG03485306. NR 43 TC 5 Z9 5 U1 0 U2 1 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 FEB 20 PY 2016 VL 30 IS 4 BP 609 EP 617 DI 10.1097/QAD.0000000000000958 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DC7ST UT WOS:000369421400009 PM 26558723 ER PT J AU Siedner, MJ Kim, JH Nakku, RS Hemphill, L Triant, VA Haberer, JE Martin, JN Boum, Y Kwon, DS Tsai, AC Hunt, PW Okello, S Bangsberg, DR AF Siedner, Mark J. Kim, June-Ho Nakku, Ruth Sentongo Hemphill, Linda Triant, Virginia A. Haberer, Jessica E. Martin, Jeffrey N. Boum, Yap, II Kwon, Douglas S. Tsai, Alexander C. Hunt, Peter W. Okello, Samson Bangsberg, David R. TI HIV infection and arterial stiffness among older-adults taking antiretroviral therapy in rural Uganda SO AIDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANKLE-BRACHIAL INDEX; CARDIOVASCULAR EVENTS; CAROTID-ARTERY; ALL-CAUSE; DISEASE; MORTALITY; METAANALYSIS; ASSOCIATION; RISK AB HIV infection is associated with arterial stiffness, but no studies have assessed this relationship in sub-Saharan Africa. We enrolled 205 participants over 40 years old in Uganda: 105 on antiretroviral therapy for a median of 7 years, and a random sample of 100 age and sex-matched HIV-uninfected controls from the clinic catchment area. The prevalence of arterial stiffness (ankle brachial index >1.2) was 33%, 18%, 19% and 2% in HIV+ men, HIV- men, HIV+ women, and HIV- women. In multivariable models adjusted for cardiovascular risk factors, HIV+ individuals had over double the prevalence of arterial stiffness (adjusted prevalence ratio 2.86, 95% confidence interval 1.41-5.79, P=0.003). C1 [Siedner, Mark J.; Triant, Virginia A.; Kwon, Douglas S.; Bangsberg, David R.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Siedner, Mark J.; Haberer, Jessica E.; Tsai, Alexander C.; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Siedner, Mark J.; Hemphill, Linda; Triant, Virginia A.; Haberer, Jessica E.; Kwon, Douglas S.; Tsai, Alexander C.; Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Kim, June-Ho] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Nakku, Ruth Sentongo; Tsai, Alexander C.; Okello, Samson; Bangsberg, David R.] Mbarara Univ Sci & Technol, Fac Internal Med, Mbarara, Uganda. [Hemphill, Linda] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Martin, Jeffrey N.; Hunt, Peter W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Boum, Yap, II] Epictr Res Base, Mbarara, Uganda. [Kwon, Douglas S.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Boum, Yap, II] Mbarara Univ Sci & Technol, Dept Microbiol, Mbarara, Uganda. RP Siedner, MJ (reprint author), Massachusetts Gen Hosp, 722 Nashua St,Suite 722, Boston, MA 02114 USA. EM msiedner@mgh.harvard.edu OI Okello, Samson/0000-0001-7377-6094; Tsai, Alexander/0000-0001-6397-7917 FU National Institutes of Health [R21HL124712, K23MH099916, R56AI100765, R21AI078774, R01MH054907, P01AI027763, P01AI076174, UM1 CA181255]; Harvard Center for AIDS Research; Doris Duke Charitable Foundation; Sullivan Family Foundation; [K23MH096620] FX This study was funded by the National Institutes of Health (R21HL124712, K23MH099916, R56AI100765, R21AI078774, R01MH054907, P01AI027763, P01AI076174 and UM1 CA181255), the Harvard Center for AIDS Research, the Doris Duke Charitable Foundation, and the Sullivan Family Foundation. The authors also acknowledge salary support through K23MH096620. The funders 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 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 FEB 20 PY 2016 VL 30 IS 4 BP 667 EP 670 DI 10.1097/QAD.0000000000000992 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DC7SW UT WOS:000369421700002 PM 26636926 ER PT J AU Scheckel, C Drapeau, E Frias, MA Park, CY Fak, J Zucker-Scharff, I Kou, Y Haroutunian, V Ma'ayan, A Buxbaum, JD Darnell, RB AF Scheckel, Claudia Drapeau, Elodie Frias, Maria A. Park, Christopher Y. Fak, John Zucker-Scharff, Ilana Kou, Yan Haroutunian, Vahram Ma'ayan, Avi Buxbaum, Joseph D. Darnell, Robert B. TI Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain SO ELIFE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; DIFFERENTIAL EXPRESSION ANALYSIS; GAP-43 GENE-EXPRESSION; RO 60-KDA AUTOANTIGEN; MESSENGER-RNA; ALZHEIMERS-DISEASE; NEURITE OUTGROWTH; PC12 CELLS; HITS-CLIP; EXON INCLUSION AB Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing. C1 [Scheckel, Claudia; Frias, Maria A.; Park, Christopher Y.; Fak, John; Zucker-Scharff, Ilana; Darnell, Robert B.] Rockefeller Univ, Mol Neurooncol Lab, 1230 York Ave, New York, NY 10021 USA. [Scheckel, Claudia; Frias, Maria A.; Park, Christopher Y.; Fak, John; Zucker-Scharff, Ilana; Darnell, Robert B.] Rockefeller Univ, Howard Hughes Med Inst, 1230 York Ave, New York, NY 10021 USA. [Drapeau, Elodie; Kou, Yan; Buxbaum, Joseph D.] Seaver Autism Ctr Res & Treatment, New York, NY USA. [Drapeau, Elodie; Haroutunian, Vahram; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Park, Christopher Y.; Darnell, Robert B.] New York Genome Ctr, New York, NY USA. [Kou, Yan; Ma'ayan, Avi] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, LINCS Data Integrat & Coordinat Ctr BD2K, Mt Sinai Knowledge Management Ctr Illuminating Dr, New York, NY 10029 USA. [Haroutunian, Vahram] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Haroutunian, Vahram] James J Peters VA Med Ctr, New York, NY USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth Inst, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Darnell, RB (reprint author), Rockefeller Univ, Mol Neurooncol Lab, 1230 York Ave, New York, NY 10021 USA.; Darnell, RB (reprint author), Rockefeller Univ, Howard Hughes Med Inst, 1230 York Ave, New York, NY 10021 USA.; Buxbaum, JD (reprint author), Seaver Autism Ctr Res & Treatment, New York, NY USA.; Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Darnell, RB (reprint author), New York Genome Ctr, New York, NY USA.; Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA.; Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth Inst, New York, NY 10029 USA.; Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. EM buxbaum@mssm.edu; darnelr@rockefeller.edu OI Buxbaum, Joseph/0000-0001-8898-8313 FU EMBO; SNF; Seaver Foundation; National Institutes of Health [ADRC AG005138, AG02219, HHSN27120130031C, R01GM098316, U54CA189201, U54HL127624, NS34389]; G Harold and Leila Y. Mathers Foundation; Simons Foundation; Howard Hughes Medical Institute FX EMBO Long-Term Fellowship Claudia Scheckel; SNF Early and Advanced Postdoc Mobility Fellowship Claudia Scheckel; Seaver Foundation Graduate Fellowship Yan Kou; National Institutes of Health ADRC AG005138 Vahram Haroutunian; National Institutes of Health AG02219 Vahram Haroutunian; National Institutes of Health HHSN27120130031C Vahram Haroutunian; National Institutes of Health R01GM098316 Avi Ma'ayan; National Institutes of Health U54CA189201 Avi Ma'ayan; National Institutes of Health U54HL127624 Avi Ma'ayan; G Harold and Leila Y. Mathers Foundation Joseph D Buxbaum; National Institutes of Health ADRC AG005138 Joseph D Buxbaum; National Institutes of Health NS081706 Robert B Darnell; Simons Foundation Robert B Darnell; National Institutes of Health NS34389 Robert B Darnell; Howard Hughes Medical Institute Robert B Darnell NR 112 TC 7 Z9 7 U1 1 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 19 PY 2016 VL 5 AR e10421 DI 10.7554/eLife.10421 PG 35 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG2EX UT WOS:000371880400001 ER PT J AU Musunuru, K Kathiresan, S AF Musunuru, Kiran Kathiresan, Sekar TI Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis SO CIRCULATION RESEARCH LA English DT Article DE coronary disease; genetics; triglycerides; atherosclerosis; lipoproteins ID CORONARY-HEART-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; SEQUENCING IDENTIFIES RARE; TYPE-2 DIABETES-MELLITUS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR EVENTS; COLLABORATIVE ANALYSIS; REMNANT CHOLESTEROL; PHOSPHOLIPASE A(2); VASCULAR-DISEASE AB Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials. C1 [Musunuru, Kiran; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Musunuru, Kiran] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Musunuru, Kiran; Kathiresan, Sekar] Broad Inst MIT & Harvard, Cambridge, MA USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Kathiresan, S (reprint author), MGH Ctr Human Genet Res, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan@partners.org FU NHLBI NIH HHS [R01 HL107816, T32 HL116275] NR 55 TC 9 Z9 9 U1 2 U2 4 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 FEB 19 PY 2016 VL 118 IS 4 BP 579 EP 585 DI 10.1161/CIRCRESAHA.115.306398 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DF4QO UT WOS:000371335100005 PM 26892959 ER PT J AU Tarkin, JM Dweck, MR Evans, NR Takx, RAP Brown, AJ Tawakol, A Fayad, ZA Rudd, JHF AF Tarkin, Jason M. Dweck, Marc R. Evans, Nicholas R. Takx, Richard A. P. Brown, Adam J. Tawakol, Ahmed Fayad, Zahi A. Rudd, James H. F. TI Imaging Atherosclerosis SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; molecular imaging; coronary artery disease; multimodal imaging; risk factors ID CORONARY-ARTERY-DISEASE; FRACTIONAL FLOW RESERVE; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; OPTICAL COHERENCE TOMOGRAPHY; MAGNETIC-RESONANCE ANGIOGRAPHY; THIN-CAP FIBROATHEROMA; RANDOMIZED CONTROLLED-TRIAL; NEAR-INFRARED SPECTROSCOPY; ISCHEMIC-HEART-DISEASE AB Advances in atherosclerosis imaging technology and research have provided a range of diagnostic tools to characterize high-risk plaque in vivo; however, these important vascular imaging methods additionally promise great scientific and translational applications beyond this quest. When combined with conventional anatomic- and hemodynamic-based assessments of disease severity, cross-sectional multimodal imaging incorporating molecular probes and other novel noninvasive techniques can add detailed interrogation of plaque composition, activity, and overall disease burden. In the catheterization laboratory, intravascular imaging provides unparalleled access to the world beneath the plaque surface, allowing tissue characterization and measurement of cap thickness with micrometer spatial resolution. Atherosclerosis imaging captures key data that reveal snapshots into underlying biology, which can test our understanding of fundamental research questions and shape our approach toward patient management. Imaging can also be used to quantify response to therapeutic interventions and ultimately help predict cardiovascular risk. Although there are undeniable barriers to clinical translation, many of these hold-ups might soon be surpassed by rapidly evolving innovations to improve image acquisition, coregistration, motion correction, and reduce radiation exposure. This article provides a comprehensive review of current and experimental atherosclerosis imaging methods and their uses in research and potential for translation to the clinic. C1 [Tarkin, Jason M.; Brown, Adam J.; Rudd, James H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge CB2 2QQ, England. [Evans, Nicholas R.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 2QQ, England. [Dweck, Marc R.] Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Takx, Richard A. P.; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Takx, Richard A. P.; Tawakol, Ahmed] Harvard Univ, Sch Med, Boston, MA USA. [Dweck, Marc R.; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, Imaging Sci Labs, New York, NY 10029 USA. [Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Dept Cardiol, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. RP Rudd, JHF (reprint author), Univ Cambridge, Div Cardiovasc Med, Addenbrookes Ctr Clin Invest, Box 110,Hills Rd, Cambridge CB2 2QQ, England. EM Jhfr2@cam.ac.uk OI dweck, marc/0000-0001-9847-5917 FU Wellcome Trust [104492/Z/14/Z]; British Heart Foundation [FS/14/78/31020]; Dunhill Medical Trust [RTF44/0114]; British Heart Foundation; HEFCE; NIHR Cambridge Biomedical Research Centre; Wellcome Trust FX J.M.T. is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). M.D. is supported by the British Heart Foundation (FS/14/78/31020). N.R.E. is supported by a research training fellowship from the Dunhill Medical Trust (RTF44/0114). A.J.B. is supported by the British Heart Foundation. J.H.F.R. is part-supported by the HEFCE, the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust. NR 208 TC 12 Z9 12 U1 9 U2 20 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 FEB 19 PY 2016 VL 118 IS 4 BP 750 EP 769 DI 10.1161/CIRCRESAHA.115.306247 PG 20 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DF4QO UT WOS:000371335100017 PM 26892971 ER PT J AU Li, CW Menconi, F Osman, R Mezei, M Jacobson, EM Concepcion, E David, CS Kastrinsky, DB Ohlmeyer, M Tomer, Y AF Li, Cheuk Wun Menconi, Francesca Osman, Roman Mezei, Mihaly Jacobson, Eric M. Concepcion, Erlinda David, Chella S. Kastrinsky, David B. Ohlmeyer, Michael Tomer, Yaron TI Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cell surface protein; endocrinology; major histocompatibility complex (MHC); peptides; small molecule; structural model; thyroid; thyroid hormone; thyroglobulin; thyroiditis ID MYELIN BASIC-PROTEIN; HLA-DR; TRANSGENIC MICE; GRAVES-DISEASE; HASHIMOTOS-THYROIDITIS; THYROGLOBULIN PEPTIDES; MULTIPLE-SCLEROSIS; UNITED-STATES; L-THYROXINE; CEPHARANTHINE AB We previously showed that an HLA-DR variant containing arginine at position 74 of the DR1 chain (DR1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). We also identified 5 thyroglobulin (Tg) peptides that bound to DR1-Arg74. We hypothesized that blocking the binding of these peptides to DR1-Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DR1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DR1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DR1-Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD. C1 [Li, Cheuk Wun; Menconi, Francesca; Jacobson, Eric M.; Concepcion, Erlinda; Tomer, Yaron] Icahn Sch Med Mt Sinai, Div Endocrinol, Box 1055,One Gustave L Levy Pl, New York, NY 10029 USA. [Osman, Roman; Mezei, Mihaly; Kastrinsky, David B.; Ohlmeyer, Michael] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, Box 1055,One Gustave L Levy Pl, New York, NY 10029 USA. [David, Chella S.] Mayo Clin, Coll Med, Dept Immunol, Rochester, MN 55905 USA. [Tomer, Yaron] Bronx Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Tomer, Y (reprint author), Icahn Sch Med Mt Sinai, Div Endocrinol, Box 1055,One Gustave L Levy Pl, New York, NY 10029 USA. EM Yaron.Tomer@mssm.edu FU National Institutes of Health from NIDDK [DK061659, DK073681]; NIAID [T32 AI007605]; Department of Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health Grants DK061659 and DK073681 from the NIDDK (to Y. T.) and Grant T32 AI007605 from the NIAID (to C. W. L.). This material is based upon work supported in part by the Department of Veterans Affairs. The authors declare that they have no conflicts of interest with the contents of this article. NR 66 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 19 PY 2016 VL 291 IS 8 BP 4079 EP 4090 DI 10.1074/jbc.M115.694687 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF4RQ UT WOS:000371338400033 PM 26703475 ER PT J AU Laukka, T Mariani, CJ Ihantola, T Cao, JZ Hokkanen, J Kaelin, WG Godley, LA Koivunen, P AF Laukka, Tuomas Mariani, Christopher J. Ihantola, Tuukka Cao, John Z. Hokkanen, Juho Kaelin, William G., Jr. Godley, Lucy A. Koivunen, Peppi TI Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE 5-hydroxymethylcytosine (5-hmC); epigenetics; hypoxia; hypoxia-inducible factor (HIF); leukemia; AML; TET; fumarate; succinate ID HYPERMETHYLATOR PHENOTYPE; PROLYL 4-HYDROXYLASES; SDH MUTATIONS; 5-HYDROXYMETHYLCYTOSINE; PARAGANGLIOMA; CANCER; DNA; PROTEINS; HIF; FH AB The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs 1-3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic and inhibitory properties of Tets and show that the K-m value of Tets 1 and 2 for O-2 is 30 m, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe2+ and 2-oxoglutarate-binding residues increased the K-m values for these factors 30-80-fold and reduced the V-max values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant tumors, were identified as potent Tet inhibitors in vitro, with IC50 values approximate to 400-500 m. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIF stabilization. The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization. C1 [Laukka, Tuomas; Ihantola, Tuukka; Koivunen, Peppi] Univ Oulu, Fac Biochem & Mol Med, Oulu Ctr Cell Matrix Res, Bioctr Oulu, FIN-90014 Oulu, Finland. [Mariani, Christopher J.; Cao, John Z.; Godley, Lucy A.] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Mariani, Christopher J.] Univ Chicago, Comm Mol Pathogenesis & Mol Med, Chicago, IL 60637 USA. [Cao, John Z.; Godley, Lucy A.] Univ Chicago, Comm Canc Biol, Chicago, IL 60637 USA. [Hokkanen, Juho] Admescope Ltd, Typpitie 1, FIN-90620 Oulu, Finland. [Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kaelin, William G., Jr.] Brigham & Womens Hosp, Boston, MA 02215 USA. [Kaelin, William G., Jr.; Koivunen, Peppi] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Koivunen, P (reprint author), Univ Oulu, Fac Biochem & Mol Med, Oulu Ctr Cell Matrix Res, Bioctr Oulu, FIN-90014 Oulu, Finland. EM peppi.koivunen@oulu.fi FU Academy of Finland [120156, 140765, 218129, 266719]; S. Juselius Foundation; Emil Aaltonen Foundation; Jane and Aatos Erkko Foundation; Finnish Cancer Organizations FX This work was supported by Academy of Finland Grants 120156, 140765, 218129, and 266719 (to P. K.), and grants from the S. Juselius Foundation (to P. K.), the Emil Aaltonen Foundation (to P. K.), the Jane and Aatos Erkko Foundation (to P. K.), and the Finnish Cancer Organizations (to P. K.). The authors declare that they have no conflicts of interest with the contents of this article. NR 39 TC 16 Z9 16 U1 9 U2 19 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 FEB 19 PY 2016 VL 291 IS 8 BP 4256 EP 4265 DI 10.1074/jbc.M115.688762 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF4RQ UT WOS:000371338400048 PM 26703470 ER PT J AU Jeong, HW Choi, RH McClellan, JL Piroli, GG Frizzell, N Tseng, YH Goodyear, LJ Koh, HJ AF Jeong, Ha-Won Choi, Ran Hee McClellan, Jamie L. Piroli, Gerardo G. Frizzell, Norma Tseng, Yu-Hua Goodyear, Laurie J. Koh, Ho-Jin TI Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Brown adipose tissue; UCP1; Insulin signaling ID ADIPOSE-TISSUE; GLUCOSE-HOMEOSTASIS; SKELETAL-MUSCLE; RECEPTOR SUBSTRATE-1; TRB3; OBESITY; ACTIVATION; GENE; THERMOGENESIS; SENSITIVITY AB Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. (C) 2016 Elsevier Inc. All rights reserved. C1 [Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L.; Koh, Ho-Jin] Univ S Carolina, Dept Exercise Sci, Div Appl Physiol, Columbia, SC 29208 USA. [Piroli, Gerardo G.; Frizzell, Norma] Univ S Carolina, Sch Med, Dept Pharmacol Physiol & Neurosci, Columbia, SC 29208 USA. [Tseng, Yu-Hua; Goodyear, Laurie J.] Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. [Tseng, Yu-Hua; Goodyear, Laurie J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Koh, HJ (reprint author), Univ S Carolina, Dept Exercise Sci, 921 Assembly St, Columbia, SC 29208 USA. EM kohh@mailbox.sc.edu OI Koh, Ho-Jin/0000-0001-5922-0938 FU NIH [5P20GM103641-03, 1P20GM109091-01]; departmental start-up grant FX The authors thank Dr. M. Montminy (Salk Institute) for providing TRB3 antibody, Regeneron for TRB3KO mice, and Dr. M. Shim (University of South Carolina) for technical help. This work was supported by NIH grants to H.J.K. (5P20GM103641-03 and 1P20GM109091-01) and departmental start-up grant to H.J.K. NR 31 TC 0 Z9 0 U1 3 U2 10 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 FEB 19 PY 2016 VL 470 IS 4 BP 783 EP 791 DI 10.1016/j.bbrc.2016.01.064 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DE4EP UT WOS:000370582300001 PM 26801556 ER PT J AU Li, J Brock, J Jack, B Mittman, B Naylor, M Sorra, J Mays, G Williams, MV AF Li, Jing Brock, Jane Jack, Brian Mittman, Brian Naylor, Mary Sorra, Joanna Mays, Glen Williams, Mark V. CA Project ACHIEVE Team TI Project ACHIEVE - using implementation research to guide the evaluation of transitional care effectiveness SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Transitional care; Implementation research; Comparative effectiveness; Patient centered ID HOSPITAL READMISSIONS; PUBLIC-HEALTH; FRAMEWORK; DISCHARGE; INTERVENTION; QUALITY; TRIAL; REHOSPITALIZATION; PROGRAM; SCIENCE AB Background: Poorly managed hospital discharges and care transitions between health care facilities can cause poor outcomes for both patients and their caregivers. Unfortunately, the usual approach to health care delivery does not support continuity and coordination across the settings of hospital, doctors' offices, home or nursing homes. Though complex efforts with multiple components can improve patient outcomes and reduce 30-day readmissions, research has not identified which components are necessary. Also we do not know how delivery of core components may need to be adjusted based on patient, caregiver, setting or characteristics of the community, or how system redesign can be accelerated. Methods/design: Project ACHIEVE focuses on diverse Medicare populations such as individuals with multiple chronic diseases, patients with low health literacy/numeracy and limited English proficiency, racial and ethnic minority groups, low-income groups, residents of rural areas, and individuals with disabilities. During the first phase, we will use focus groups to identify the transitional care outcomes and components that matter most to patients and caregivers to inform development and validation of assessment instruments. During the second phase, we will evaluate the comparative effectiveness of multi-component care transitions programs occurring across the U.S. Using a mixed-methods approach for this evaluation, we will study historical (retrospective) and current and future (prospective) groups of patients, caregivers and providers using site visits, surveys, and clinical and claims data. In this natural experiment observational study, we use a fractional factorial study design to specify comparators and estimate the individual and combined effects of key transitional care components. Discussion: Our study will determine which evidence-based transitional care components and/or clusters most effectively produce patient and caregiver desired outcomes overall and among diverse patient and caregiver populations in different healthcare settings. Using the results, we will develop concrete, actionable recommendations regarding how best to implement these strategies. Finally, this work will provide tools for hospitals, community-based organizations, patients, caregivers, clinicians and other stakeholders to help them make informed decisions about which strategies are most effective and how best to implement them in their communities. C1 [Li, Jing] Univ Kentucky, Ctr Hlth Serv Res, Lexington, KY USA. [Li, Jing] Univ Kentucky, Internal Med, Lexington, KY USA. [Brock, Jane] Care Transit Theme Support Ctr, Englewood, CO USA. [Jack, Brian] Boston Univ, Sch Med, Family Med, Boston, MA 02118 USA. [Mittman, Brian] Kaiser Permanente, Res & Evaluat, Pasadena, CA USA. [Mittman, Brian] VA Ctr Implementat Practice & Res, US Dept Vet Affairs, Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mittman, Brian] Univ Calif Los Angeles, Sch Med, Clin Translat Sci Inst, Los Angeles, CA USA. [Naylor, Mary] Univ Penn, Sch Nursing, NewCourtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Sorra, Joanna] Westat Corp, Washington, DC USA. [Mays, Glen] Univ Kentucky, Natl Coordinating Ctr Publ Hlth Serv & Syst Res, Lexington, KY USA. [Williams, Mark V.] Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, Kentucky Clin J525, Lexington, KY 40536 USA. RP Williams, MV (reprint author), Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, Kentucky Clin J525, Lexington, KY 40536 USA. EM mark.will@uky.edu FU Patient Centered Outcomes Research Institute (PCORI), U.S [TC-1403-14049] FX Support for this research was provided by Contract No. TC-1403-14049, Patient Centered Outcomes Research Institute (PCORI), U.S. NR 33 TC 2 Z9 2 U1 6 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD FEB 19 PY 2016 VL 16 AR 70 DI 10.1186/s12913-016-1312-y PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DE1SK UT WOS:000370406500001 PM 26896024 ER PT J AU Bennett, AV Dueck, AC Mitchell, SA Mendoza, TR Reeve, BB Atkinson, TM Castro, KM Denicoff, A Rogak, LJ Harness, JK Bearden, JD Bryant, D Siegel, RD Schrag, D Basch, E AF Bennett, Antonia V. Dueck, Amylou C. Mitchell, Sandra A. Mendoza, Tito R. Reeve, Bryce B. Atkinson, Thomas M. Castro, Kathleen M. Denicoff, Andrea Rogak, Lauren J. Harness, Jay K. Bearden, James D. Bryant, Donna Siegel, Robert D. Schrag, Deborah Basch, Ethan CA Natl Canc Inst PRO-CTCAE Study Grp TI Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article DE PRO-CTCAE; Patient-Reported Outcomes; Symptoms; Adverse Events; Mode of Administration; Interactive Voice Response System ID PRACTICES TASK-FORCE; CLINICAL-TRIALS; RELIABILITY; METAANALYSIS; ONCOLOGY; QLQ-C30; DESIGNS; SAMPLE AB Background: PRO-CTCAE is a library of items that measure cancer treatment-related symptomatic adverse events (NCI Contracts: HHSN261201000043C and HHSN 261201000063C). The objective of this study is to examine the equivalence and acceptability of the three data collection modes (Web-enabled touchscreen tablet computer, Interactive voice response system [IVRS], and paper) available within the US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system. Methods: Participants (n = 112; median age 56.5; 24 % high school or less) receiving treatment for cancer at seven US sites completed 28 PRO-CTCAE items (scoring range 0-4) by three modes (order randomized) at a single study visit. Subjects completed one page (approx. 15 items) of the EORTC QLQ-C30 between each mode as a distractor. Item scores by mode were compared using intraclass correlation coefficients (ICC); differences in scores within the 3-mode crossover design were evaluated with mixed-effects models. Difficulties with each mode experienced by participants were also assessed. Results: 103 (92 %) completed questionnaires by all three modes. The median ICC comparing tablet vs IVRS was 0.78 (range 0.55-0.90); tablet vs paper: 0.81 (0.62-0.96); IVRS vs paper: 0.78 (0.60-0.91); 89 % of ICCs were >= 0.70. Item-level mean differences by mode were small (medians [ranges] for tablet vs. IVRS = -0.04 [-0.16-0.22]; tablet vs paper = -0.02 [-0.11-0.14]; IVRS vs paper = 0.02 [-0.07-0.19]), and 57/81 (70 %) items had bootstrapped 95 % CI around the effect sizes within +/-0.20. The median time to complete the questionnaire by tablet was 3.4 min; IVRS: 5.8; paper: 4.0. The proportion of participants by mode who reported "no problems" responding to the questionnaire was 86 % tablet, 72 % IVRS, and 98 % paper. Conclusions: Mode equivalence of items was moderate to high, and comparable to test-retest reliability (median ICC = 0.80). Each mode was acceptable to a majority of respondents. Although the study was powered to detect moderate or larger discrepancies between modes, the observed ICCs and very small mean differences between modes provide evidence to support study designs that are responsive to patient or investigator preference for mode of administration, and justify comparison of results and pooled analyses across studies that employ different PRO-CTCAE modes of administration. C1 [Bennett, Antonia V.; Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, Campus Box 7411, Chapel Hill, NC 27599 USA. [Dueck, Amylou C.] Mayo Clin, Coll Med, Div Hlth Sci Res, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. [Mitchell, Sandra A.; Castro, Kathleen M.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, 9609 Med Ctr Dr,East Tower,Suite 3-448, Rockville, MD 20850 USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, 1400 Pressler St,Unit 1450, Houston, TX 77030 USA. [Atkinson, Thomas M.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. [Denicoff, Andrea] NCI, Canc Therapy Evaluat Program, 9609 Med Ctr Dr,MSC 9737, Bethesda, MD 20892 USA. [Rogak, Lauren J.; Schrag, Deborah] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,2nd Floor, New York, NY 10017 USA. [Harness, Jay K.] St Joseph Hosp Orange, Ctr Canc Prevent & Treatment, 1100 West Stewart Dr, Orange, CA 92868 USA. [Bearden, James D.] Spartanburg Reg Healthcare Syst, Gibbs Canc Ctr, 101 East Wood St, Spartanburg, SC 29303 USA. [Bearden, James D.] Spartanburg Reg Healthcare Syst, Res Inst, 101 East Wood St, Spartanburg, SC 29303 USA. [Bryant, Donna] Canc Program Our Lady Lake & Mary Bird Perkins, 1950 Essen Lane, Baton Rouge, LA 70809 USA. [Siegel, Robert D.] Hartford Hosp, Helen & Harry Gray Canc Ctr, 85 Retreat Ave, Hartford, CT 06106 USA. [Schrag, Deborah] Dana Farber Canc Inst, 450 Brookline Ave,D 1008, Boston, MA 02215 USA. [Basch, Ethan] Univ N Carolina, Dept Med, Campus Box 7305, Chapel Hill, NC 27599 USA. RP Mitchell, SA (reprint author), NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, 9609 Med Ctr Dr,East Tower,Suite 3-448, Rockville, MD 20850 USA. EM mitchlls@mail.nih.gov FU U.S. National Cancer Institute [HHSN261200800043C, HHSN261201000063C, HHSN261200800001E] FX Work described in this paper was supported by contracts from the U.S. National Cancer Institute, HHSN261200800043C, HHSN261201000063C, and HHSN261200800001E NR 27 TC 3 Z9 3 U1 4 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD FEB 19 PY 2016 VL 14 AR 24 DI 10.1186/s12955-016-0426-6 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DE1SH UT WOS:000370406200001 PM 26892667 ER PT J AU Butler, TC Barton, JP Kardar, M Chakraborty, AK AF Butler, Thomas C. Barton, John P. Kardar, Mehran Chakraborty, Arup K. TI Identification of drug resistance mutations in HIV from constraints on natural evolution SO PHYSICAL REVIEW E LA English DT Article ID DYNAMICS IN-VIVO; REVERSE-TRANSCRIPTASE; PROTEASE; POPULATION; PREDICTION; SEQUENCES; CONTACTS; THERAPY AB Human immunodeficiency virus (HIV) evolves with extraordinary rapidity. However, its evolution is constrained by interactions between mutations in its fitness landscape. Here we show that an Ising model describing these interactions, inferred from sequence data obtained prior to the use of antiretroviral drugs, can be used to identify clinically significant sites of resistance mutations. Successful predictions of the resistance sites indicate progress in the development of successful models of real viral evolution at the single residue level and suggest that our approach may be applied to help design new therapies that are less prone to failure even where resistance data are not yet available. C1 [Butler, Thomas C.; Barton, John P.; Kardar, Mehran; Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Butler, Thomas C.; Barton, John P.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02142 USA. [Barton, John P.; Chakraborty, Arup K.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Kardar, M; Chakraborty, AK (reprint author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02142 USA.; Chakraborty, AK (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem, Inst Med Engn & Sci, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Biol Engn, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM kardar@mit.edu; arupc@mit.edu OI Barton, John/0000-0003-1467-421X FU Ragon Institute of MGH, MIT, and Harvard; National Science Foundation [PHY11-25915, DMR-12-06323] FX We thank Daniel Kuritzkes, Martin Hirsch, Andrew Ferguson, Dariusz Murakowski, and Hanrong Chen for helpful discussions. This research was funded by the Ragon Institute of MGH, MIT, and Harvard and National Science Foundation under Grants No. PHY11-25915 and No. DMR-12-06323. NR 35 TC 1 Z9 1 U1 1 U2 4 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD FEB 19 PY 2016 VL 93 IS 2 AR 022412 DI 10.1103/PhysRevE.93.022412 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA DE4SJ UT WOS:000370620200005 PM 26986367 ER PT J AU Shen, KY Luk, S Elman, J Murray, R Mukundan, S Parekkadan, B AF Shen, Keyue Luk, Samantha Elman, Jessica Murray, Ryan Mukundan, Shilpaa Parekkadan, Biju TI Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis SO SCIENTIFIC REPORTS LA English DT Article ID FIBROBLAST ACTIVATION PROTEIN; TUMOR-ASSOCIATED MACROPHAGES; PHASE-II TRIAL; ANTICANCER THERAPIES; COLORECTAL-CANCER; BREAST-CANCER; PROGRESSION; SAFETY; MICROENVIRONMENT; MYOFIBROBLASTS AB Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy. C1 [Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju] Shriners Hosp Children, Boston, MA 02114 USA. [Parekkadan, Biju] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Shen, Keyue] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Elman, Jessica] Tufts Univ, Cell Mol & Dev Biol Program, Boston, MA 02111 USA. RP Shen, KY; Parekkadan, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med & Surg Serv, Boston, MA 02114 USA.; Parekkadan, B (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Shen, KY (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM keyue.shen@usc.edu; biju_parekkadan@hms.harvard.edu FU Shriners Hospitals for Children; National Institutes of Health [R01EB012521, K01DK087770]; Massachusetts General Hospital Fund for Medical Discovery FX We thank Dr. Robert A. Weinberg for the MDA-MB-231/GFP cells; Dr. Carlos A. Ramos for the SFG. iCasp9.2A.Delta CD19 plasmid; Dr. Akira Orimo for the experimental cancer associated fibroblasts; Yoshiko Iwamoto for assistance with histology. This work was supported in part by the Shriners Hospitals for Children (B.P), National Institutes of Health Grants R01EB012521 (B.P.) and K01DK087770 (B.P.), and also by Massachusetts General Hospital Fund for Medical Discovery (K.S.). NR 38 TC 1 Z9 1 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 FEB 19 PY 2016 VL 6 AR 21239 DI 10.1038/srep21239 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE3MF UT WOS:000370532700002 PM 26893143 ER PT J AU Hoban, MD Orkin, SH Bauer, DE AF Hoban, Megan D. Orkin, Stuart H. Bauer, Daniel E. TI Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease SO BLOOD LA English DT Review ID HUMAN BETA-GLOBIN; HEMATOPOIETIC STEM-CELLS; LOCUS-CONTROL REGION; INACTIVATING LENTIVIRAL VECTORS; BONE-MARROW-TRANSPLANTATION; HIGH-LEVEL EXPRESSION; HUMAN CORD BLOOD; ZINC-FINGER NUCLEASES; CRISPR-CAS NUCLEASES; FETAL-HEMOGLOBIN AB Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial g-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development. C1 [Hoban, Megan D.; Orkin, Stuart H.; Bauer, Daniel E.] Harvard Univ, Med Sch,Boston Childrens Hosp, Harvard Stem Cell Inst,Div Hematol Oncol, Dept Pediat Oncol,Dana Farber Canc Inst,Dept Pedi, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Dana Farber Canc Inst, Harvard Stem Cell Inst, Harvard Med, Dept Pediat, 44 Binney St, Boston, MA 02115 USA. EM orkin@bloodgroup.tch.harvard.edu FU National Institutes of Health, National Heart, Lung, and Blood Institute [T32HL007574, R01HL032259, P01HL032262]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK049216, K08DK093705]; Doris Duke Charitable Foundation; Charles H. Hood Foundation; Cooley's Anemia Foundation FX This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute grants T32HL007574 (M.D.H.), R01HL032259, and P01HL032262, and National Institute of Diabetes and Digestive and Kidney Diseases grants P30DK049216 (Center of Excellence in Molecular Hematology) (S.H.O.) and K08DK093705 (Career Development Award) (D.E.B.). This work was also supported by the Doris Duke Charitable Foundation, the Charles H. Hood Foundation, and the Cooley's Anemia Foundation (D.E.B.). NR 153 TC 18 Z9 18 U1 17 U2 34 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 FEB 18 PY 2016 VL 127 IS 7 BP 839 EP 848 DI 10.1182/blood-2015-09-618587 PG 10 WC Hematology SC Hematology GA DI3JW UT WOS:000373395900011 PM 26758916 ER PT J AU Chapuy, B Roemer, MGM Stewart, C Tan, YX Abo, RP Zhang, LY Dunford, AJ Meredith, DM Thorner, AR Jordanova, ES Liu, G Feuerhake, F Ducar, MD Illerhaus, G Gusenleitner, D Linden, EA Sun, HH Homer, H Aono, M Pinkus, GS Ligon, AH Ligon, KL Ferry, JA Freeman, GJ van Hummelen, P Golub, TR Getz, G Rodig, SJ de Jong, D Monti, S Shipp, MA AF Chapuy, Bjoern Roemer, Margaretha G. M. Stewart, Chip Tan, Yuxiang Abo, Ryan P. Zhang, Liye Dunford, Andrew J. Meredith, David M. Thorner, Aaron R. Jordanova, Ekaterina S. Liu, Gang Feuerhake, Friedrich Ducar, Matthew D. Illerhaus, Gerald Gusenleitner, Daniel Linden, Erica A. Sun, Heather H. Homer, Heather Aono, Miyuki Pinkus, Geraldine S. Ligon, Azra H. Ligon, Keith L. Ferry, Judith A. Freeman, Gordon J. van Hummelen, Paul Golub, Todd R. Getz, Gad Rodig, Scott J. de Jong, Daphne Monti, Stefano Shipp, Margaret A. TI Targetable genetic features of primary testicular and primary central nervous system lymphomas SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; INTEGRATIVE ANALYSIS REVEALS; IMMUNE-PRIVILEGED SITES; HODGKIN-LYMPHOMA; HIGH PREVALENCE; CANCER; MUTATIONS; EXPRESSION; RECURRENT; PROLIFERATION AB Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL. C1 [Chapuy, Bjoern; Roemer, Margaretha G. M.; Homer, Heather; Aono, Miyuki; Freeman, Gordon J.; Shipp, Margaret A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Roemer, Margaretha G. M.; de Jong, Daphne] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Stewart, Chip; Dunford, Andrew J.; Golub, Todd R.; Getz, Gad] Broad Inst, Cambridge, MA USA. [Tan, Yuxiang; Zhang, Liye; Liu, Gang; Gusenleitner, Daniel; Monti, Stefano] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02118 USA. [Abo, Ryan P.; Thorner, Aaron R.; Ducar, Matthew D.; van Hummelen, Paul] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Meredith, David M.; Sun, Heather H.; Pinkus, Geraldine S.; Ligon, Azra H.; Ligon, Keith L.; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Jordanova, Ekaterina S.] Vrije Univ Amsterdam, Med Ctr, Ctr Gynaecol Oncol, Amsterdam, Netherlands. [Feuerhake, Friedrich] Hannover Med Sch, Dept Pathol, Hannover, Germany. [Illerhaus, Gerald] Univ Hosp Freiburg, Dept Hematol & Oncol, Freiburg, Germany. [Linden, Erica A.] Massachusetts Gen Hosp, North Shore Canc Ctr, Danvers, MA USA. [Ferry, Judith A.; Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Shipp, MA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM margaret_shipp@dfci.harvard.edu FU National Institutes of Health, National Cancer Institute [R01 CA161026]; LLS Translational Research Award; Claudia Adams Barr Program in Basic Cancer Research; National Institutes of Health, National Institute of Allergy and Infectious Diseases [PO1 AI056299]; Slim Initiative for Genomic Medicine; Carlos Slim Foundation in Mexico FX This work was supported by National Institutes of Health, National Cancer Institute grant R01 CA161026 and an LLS Translational Research Award (M.A.S.), a Claudia Adams Barr Program in Basic Cancer Research (B.C.), National Institutes of Health, National Institute of Allergy and Infectious Diseases grant PO1 AI056299 (G.J.F.), and the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico (Broad). NR 71 TC 14 Z9 14 U1 3 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 18 PY 2016 VL 127 IS 7 BP 869 EP 881 DI 10.1182/blood-2015-10-673236 PG 13 WC Hematology SC Hematology GA DI3JW UT WOS:000373395900014 PM 26702065 ER PT J AU Wong, TN Miller, CA Klco, JM Petti, A Demeter, R Helton, NM Li, TD Fulton, RS Heath, SE Mardis, ER Westervelt, P DiPersio, JF Walter, MJ Welch, JS Graubert, TA Wilson, RK Ley, TJ Link, DC AF Wong, Terrence N. Miller, Christopher A. Klco, Jeffery M. Petti, Allegra Demeter, Ryan Helton, Nichole M. Li, Tiandao Fulton, Robert S. Heath, Sharon E. Mardis, Elaine R. Westervelt, Peter DiPersio, John F. Walter, Matthew J. Welch, John S. Graubert, Timothy A. Wilson, Richard K. Ley, Timothy J. Link, Daniel C. TI Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; MYELODYSPLASTIC SYNDROME; MUTATIONS; EVOLUTION; ABNORMALITIES; REMISSION; PATIENT; CANCER AB There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these "rising" clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy. C1 [Wong, Terrence N.; Helton, Nichole M.; Heath, Sharon E.; Westervelt, Peter; DiPersio, John F.; Walter, Matthew J.; Welch, John S.; Ley, Timothy J.; Link, Daniel C.] Washington Univ, Sch Med, Div Oncol, St Louis, MO 63110 USA. [Miller, Christopher A.; Petti, Allegra; Demeter, Ryan; Li, Tiandao; Fulton, Robert S.; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63110 USA. [Miller, Christopher A.; Petti, Allegra] Washington Univ, Sch Med, Div Genom & Bioinformat, St Louis, MO 63110 USA. [Klco, Jeffery M.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Mardis, Elaine R.; Westervelt, Peter; DiPersio, John F.; Walter, Matthew J.; Welch, John S.; Wilson, Richard K.; Ley, Timothy J.; Link, Daniel C.] Washington Univ, Siteman Canc Ctr, St Louis, MO 63110 USA. [Graubert, Timothy A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Link, DC (reprint author), Washington Univ, Sch Med, 660 S Euclid Ave,Campus Box 8007, St Louis, MO 63110 USA. EM dlink@dom.wustl.edu RI Li, Tiandao/F-4039-2012 OI Li, Tiandao/0000-0003-1650-0555 FU National Institutes of Health, National Cancer Institute [PO1 CA101937]; National Human Genome Research Institute [U54 HG003079]; National Heart, Lung, and Blood Institute [T32 HL007088, K12 HL087107]; National Cancer Institute [P30CA91842] FX The authors thank Amy Schmidt and Dr Brandon McKethan (BioRad) for technical assistance. This work was supported by National Institutes of Health, National Cancer Institute grant PO1 CA101937 (D.C.L. and T.J.L.), National Human Genome Research Institute grant U54 HG003079 (R.K.W.), and National Heart, Lung, and Blood Institute grants T32 HL007088 (T.N.W.) and K12 HL087107 (T.N.W.). Technical support was provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core and the High Speed Cell Sorting Core at Washington University School of Medicine, which are supported by National Cancer Institute grant P30CA91842. NR 24 TC 14 Z9 14 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 18 PY 2016 VL 127 IS 7 BP 893 EP 897 DI 10.1182/blood-2015-10-677021 PG 5 WC Hematology SC Hematology GA DI3JW UT WOS:000373395900016 PM 26631115 ER PT J AU Kanate, AS Mussetti, A Kharfan-Dabaja, MA Ahn, KW DiGilio, A Beitinjaneh, A Chhabra, S Fenske, TS Freytes, C Gale, RP Ganguly, S Hertzberg, M Klyuchnikov, E Lazarus, HM Olsson, R Perales, MA Rezvani, A Riches, M Saad, A Slavin, S Smith, SM Sureda, A Yared, J Ciurea, S Armand, P Salit, R Bolanos-Meade, J Hamadani, M AF Kanate, Abraham S. Mussetti, Alberto Kharfan-Dabaja, Mohamed A. Ahn, Kwang W. DiGilio, Alyssa Beitinjaneh, Amer Chhabra, Saurabh Fenske, Timothy S. Freytes, Cesar Gale, Robert Peter Ganguly, Siddhartha Hertzberg, Mark Klyuchnikov, Evgeny Lazarus, Hillard M. Olsson, Richard Perales, Miguel-Angel Rezvani, Andrew Riches, Marcie Saad, Ayman Slavin, Shimon Smith, Sonali M. Sureda, Anna Yared, Jean Ciurea, Stefan Armand, Philippe Salit, Rachel Bolanos-Meade, Javier Hamadani, Mehdi TI Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; HEMATOLOGIC MALIGNANCIES; CHRONIC GRAFT; BLOOD GRAFTS; PHASE-II; IN-VITRO; OUTCOMES AB We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD. C1 [Kanate, Abraham S.] W Virginia Univ, Osborn Hematopoiet Malignancy & Transplantat Prog, Morgantown, WV 26506 USA. [Mussetti, Alberto] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, SC Ematol & Trapianto Midollo Osseo, Via Venezian 1, I-20133 Milan, Italy. [Kharfan-Dabaja, Mohamed A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Ahn, Kwang W.; DiGilio, Alyssa; Hamadani, Mehdi] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Dept Med, Milwaukee, WI 53226 USA. [Ahn, Kwang W.] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Beitinjaneh, Amer] Emily Couric Clin Canc Ctr, Div Hematol Oncol, Dept Med, Charlottesville, VA USA. [Chhabra, Saurabh] Med Univ S Carolina, Div Hematol Oncol, Charleston, SC 29425 USA. [Fenske, Timothy S.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Hematol Oncol, Milwaukee, WI 53226 USA. [Freytes, Cesar] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Freytes, Cesar] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Hematol Res Ctr, Div Expt Med, London, England. [Ganguly, Siddhartha] Univ Kansas, Med Ctr, Blood & Marrow Transplantat, Div Hematol & Oncol, Kansas City, KS 66103 USA. [Hertzberg, Mark] Prince Wales Hosp, Dept Haematol, Randwick, NSW 2031, Australia. [Klyuchnikov, Evgeny] Univ Canc Ctr, Dept Stem Cell Transplantat, Hamburg, Germany. [Lazarus, Hillard M.] Univ Hosp, Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Olsson, Richard] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Adult Marrow Transplantat Serv, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Rezvani, Andrew] Stanford Univ, Med Ctr, Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Riches, Marcie] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. [Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Slavin, Shimon] Int Ctr Cell Therapy & Canc Immunotherapy, Tel Aviv, Israel. [Smith, Sonali M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Sureda, Anna] Hosp Duran I Reynals, Inst Catala Oncol, Serv Hematol, Barcelona, Spain. [Yared, Jean] Univ Maryland, Greenebaum Canc Ctr, Blood & Marrow Transplantat Program, Div Hematol Oncol,Dept Med, Baltimore, MD 21201 USA. [Ciurea, Stefan] Univ Texas Houston, MD Anderson Canc Ctr, Dept Hematol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Armand, Philippe] Dana Farber Canc Inst, Dept Med Oncol Hematol Malignancies, Boston, MA 02115 USA. [Salit, Rachel] Fred Hutchinson Canc Res Ctr, Dept Hematol Oncol, 1124 Columbia St, Seattle, WA 98104 USA. [Bolanos-Meade, Javier] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Div Hematol Malignancies, Baltimore, MD USA. RP Hamadani, M (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM mhamadani@mcw.edu RI Mussetti, Alberto/C-9500-2017 OI Mussetti, Alberto/0000-0002-4088-036X FU Public Health Service Grant/Cooperative Agreement from the National Institutes of Health National Cancer Institute (NCI) [U24-CA076518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration (HRSA/US Department of Health and Human Services [DHHS]) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc; Amgen, Inc; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc; Gamida Cell Teva Joint Venture Ltd; Genentech, Inc; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; Medical College of Wisconsin; Merck Co, Inc; Millennium: The Takeda Oncology Co; Milliman USA, Inc; Miltenyi Biotec, Inc; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Osiris Therapeutics, Inc; Otsuka America Pharmaceutical, Inc; Perkin Elmer, Inc; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc; St. Baldrick's Foundation; StemCyte, a Global Cord Blood Therapeutics Co; Stemsoft Software, Inc; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc; THERAKOS, Inc; University of Minnesota; University of Utah; Wellpoint, Inc FX The CIBMTR was supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Institutes of Health National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/US Department of Health and Human Services [DHHS]); grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc; *Amgen, Inc; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc; *Gamida Cell Teva Joint Venture Ltd; Genentech, Inc; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc; Millennium: The Takeda Oncology Co; *Milliman USA, Inc; *Miltenyi Biotec, Inc; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Osiris Therapeutics, Inc; Otsuka America Pharmaceutical, Inc; Perkin Elmer, Inc; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc; St. Baldrick's Foundation; StemCyte, a Global Cord Blood Therapeutics Co; Stemsoft Software, Inc; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc; *THERAKOS, Inc; University of Minnesota; University of Utah; and *Wellpoint, Inc (*corporate members). NR 36 TC 22 Z9 24 U1 2 U2 3 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 FEB 18 PY 2016 VL 127 IS 7 BP 938 EP 947 DI 10.1182/blood-2015-09-671834 PG 10 WC Hematology SC Hematology GA DI3JW UT WOS:000373395900021 PM 26670632 ER PT J AU Walker, S Wang, C Walradt, T Hong, BS Tanner, JR Levinsohn, JL Goh, G Subtil, A Lessin, SR Heymann, WR Vonderheid, EC King, BA Lifton, RP Choi, J AF Walker, Sarah Wang, Chen Walradt, Trent Hong, Bok Sil Tanner, Justin R. Levinsohn, Jonathan L. Goh, Gerald Subtil, Antonio Lessin, Stuart R. Heymann, Warren R. Vonderheid, Eric C. King, Brett A. Lifton, Richard P. Choi, Jaehyuk TI Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome SO BLOOD LA English DT Letter ID DISORDERS; CELLS; LEUKEMIA C1 [Walker, Sarah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wang, Chen; Walradt, Trent; Hong, Bok Sil; Levinsohn, Jonathan L.; Subtil, Antonio; King, Brett A.; Choi, Jaehyuk] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT USA. [Tanner, Justin R.; Choi, Jaehyuk] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Goh, Gerald] UCL, Inst Canc, London, England. [Lessin, Stuart R.] Univ Penn, Fox Chase Canc Ctr, Div Dermatol, Philadelphia, PA 19104 USA. [Heymann, Warren R.] Rowan Univ, Cooper Med Sch, Div Dermatol, Camden, NJ USA. [Heymann, Warren R.] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Vonderheid, Eric C.] Johns Hopkins Med Inst, Sidney Kimmel Canc Ctr, Baltimore, MD 21205 USA. [Lifton, Richard P.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Lifton, Richard P.] Yale Univ, Sch Med, Yale Ctr Mendelian Genom, New Haven, CT 06510 USA. [Choi, Jaehyuk] Dept Vet Affairs Connecticut Healthcare, Dept Dermatol, West Haven, CT USA. [Choi, Jaehyuk] Northwestern Univ, Feinberg Sch Med, Dept Biochem & Mol Genet, Chicago, IL 60611 USA. RP Choi, J (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Robert H Lurie Med Res Ctr 5 115, 303 E Super St, Chicago, IL 60611 USA. EM jaehyuk.choi@northwestern.edu OI Choi, Jaehyuk/0000-0003-2379-2226 FU Howard Hughes Medical Institute; NCI NIH HHS [1K08CA191019, K08 CA191019, P30 CA060553] NR 17 TC 4 Z9 5 U1 0 U2 3 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 FEB 18 PY 2016 VL 127 IS 7 BP 948 EP 951 DI 10.1182/blood-2015-06-654277 PG 4 WC Hematology SC Hematology GA DI3JW UT WOS:000373395900022 PM 26702067 ER PT J AU Fu, QS Fu, TM Cruz, AC Sengupta, P Thomas, SK Wang, SQ Siegel, RM Wu, H Chou, JJ AF Fu, Qingshan Fu, Tian-Min Cruz, Anthony C. Sengupta, Prabuddha Thomas, Stacy K. Wang, Shuqing Siegel, Richard M. Wu, Hao Chou, James J. TI Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor SO MOLECULAR CELL LA English DT Article ID NECROSIS-FACTOR RECEPTOR; PLASMA-MEMBRANE; PROTON CHANNEL; FAS MUTATIONS; EGF RECEPTOR; DOMAIN; COMPLEX; REVEALS; ARCHITECTURE; ASSOCIATION AB Fas (CD95, Apo-1, or TNFRSF6) is a prototypical apoptosis-inducing death receptor in the tumor necrosis factor receptor (TNFR) superfamily. While the extracellular domains of TNFRs form trimeric complexes with their ligands and the intracellular domains engage in higher-order oligomerization, the role of the transmembrane (TM) domains is unknown. We determined the NMR structures of mouse and human Fas TM domains in bicelles that mimic lipid bilayers. Surprisingly, these domains use proline motifs to create optimal packing in homotrimer assembly distinct from classical trimeric coiled-coils in solution. Cancer-associated and structure-based mutations in Fas TM disrupt trimerization in vitro and reduce apoptosis induction in vivo, indicating the essential role of intramembrane trimerization in receptor activity. Our data suggest that the structures represent the signaling-active conformation of Fas TM, which appears to be different from the pre-ligand conformation. Analysis of other TNFR sequences suggests proline-containing sequences as common motifs for receptor TM trimerization. C1 [Fu, Qingshan; Fu, Tian-Min; Wu, Hao; Chou, James J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Fu, Tian-Min; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Cruz, Anthony C.; Thomas, Stacy K.; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, NIH, Bethesda, MD 20892 USA. [Sengupta, Prabuddha] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Organelle Biol, NIH, Bethesda, MD 20892 USA. [Wang, Shuqing] Tianjin Med Univ, Sch Pharm, Tianjin 300070, Peoples R China. RP Wu, H; Chou, JJ (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 02115 USA. EM wu@crystal.harvard.edu; chou@crystal.harvard.edu FU NIH [P41 EB-002026, HL103526, AI050872]; NIH NIAMS [Z01-AR041133] FX The NMR data were collected at MIT-Harvard CMR (supported by NIH grant P41 EB-002026). We thank the NIAMS Flow Cytometry Core for technical assistance. This work was supported by NIH grants HL103526 to J.J.C. and AI050872 to H.W. and by NIH NIAMS intramural research program and project grant Z01-AR041133 to R.M.S. We would like to thank Timothy Springer for the insightful discussion. NR 42 TC 10 Z9 11 U1 6 U2 12 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 FEB 18 PY 2016 VL 61 IS 4 BP 602 EP 613 DI 10.1016/j.molcel.2016.01.009 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IF UT WOS:000372326300012 PM 26853147 ER PT J AU Borne, Y Smith, JG Nilsson, PM Melander, O Hedblad, B Engstrom, G AF Borne, Yan Smith, J. Gustav Nilsson, Peter M. Melander, Olle Hedblad, Bo Engstroem, Gunnar TI Total and Differential Leukocyte Counts in Relation to Incidence of Diabetes Mellitus: A Prospective Population-Based Cohort Study SO PLOS ONE LA English DT Article ID INTIMA-MEDIA THICKNESS; NECROSIS-FACTOR-ALPHA; BLOOD-CELL COUNT; INSULIN SENSITIVITY; GENETIC-VARIANTS; MALMO DIET; ADAPTER PROTEIN; INTERLEUKIN-6; DISEASE; CANCER AB Objective High concentrations of leukocytes in blood have been associated with diabetes mellitus. This prospective study aimed to explore whether total and differential leukocyte counts are associated with incidence of diabetes. A missense variant R262W in the SH2B3 (SH2B adaptor protein 3) gene, coding for a protein that negatively regulates hematopoietic cell proliferation, was also studied in relation to incidence of diabetes. Methods and Results Leukocyte count and its subtypes (neutrophils, lymphocytes and mixed cells) were analyzed in 26,667 men and women, 45-73 years old, from the population-based Malmo Diet and Cancer study. Information about the R262W polymorphism (rs3184504) in SH2B3 was genotyped in 24,489 subjects. Incidence of diabetes was studied during a mean follow-up of 14 years. Cox proportional hazards regression was used to examine incidence of diabetes by total and differential leukocyte counts. Mendelian randomization analysis using R262W as an instrumental variable was performed with two-stage least squares regression. A total of 2,946 subjects developed diabetes during the follow-up period. After taking several possible confounders into account, concentrations of total leukocyte count, neutrophils and lymphocytes were all significantly associated with incidence of diabetes. The adjusted hazard ratios (95% confidence interval; quartile 4 vs quartile 1) were 1.37 (1.22-1.53) for total leukocytes, 1.33 (1.19-1.49) for neutrophils and 1.29 (1.15-1.44) for lymphocytes. The R262W polymorphism was strongly associated with leukocytes (0.11x10(9) cells/l per T allele, p = 1.14 x10(-12)), lymphocytes (p = 4.3 x10(-16)), neutrophils (p = 8.0 x10(-6)) and mixed cells (p = 3.0 x10(-6)). However, there was no significant association between R262W and fasting glucose, HbA1c or incidence of diabetes. Conclusions Concentrations of total leukocytes, neutrophils and lymphocytes are associated with incidence of diabetes. However, the lack of association with the R262W polymorphism suggests that the associations may not be causal, although limitations in statistical power and balancing pleiotropic effects cannot be excluded. C1 [Borne, Yan; Nilsson, Peter M.; Melander, Olle; Hedblad, Bo; Engstroem, Gunnar] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden. [Smith, J. Gustav] Skane Univ Hosp, Lund, Sweden. [Smith, J. Gustav] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Smith, J. Gustav] Harvard Univ, Sch Med, Boston, MA USA. [Smith, J. Gustav] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Smith, J. Gustav] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Nilsson, Peter M.; Melander, Olle] Skane Univ Hosp, Dept Internal Med, Malmo, Sweden. RP Borne, Y (reprint author), Lund Univ, Dept Clin Sci, Malmo, Sweden. EM Yan.Borne@med.lu.se FU Swedish Research Council [2011-3891, 2014-2265]; Swedish Heart and Lung Foundation [20100244, 20130249]; Lundstrom Foundation; Skane University Hospital FX The study was supported by grants from the Swedish Research Council (Dnr 2011-3891; 2014-2265), the Swedish Heart and Lung Foundation (Grant Nos. 20100244; 20130249), the Lundstrom Foundation and by funds from the Skane University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The Swedish National Diabetes Register (NDR), the Malmo HbA1c register (MHR), the Diabetes 2000 registers and the National Board of Health and Welfare are acknowledged for valuable assistance in retrieval of diabetes end-points. The study was supported by grants from the Swedish Heart and Lung foundation and the Swedish Research council. NR 41 TC 0 Z9 0 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 18 PY 2016 VL 11 IS 2 AR e0148963 DI 10.1371/journal.pone.0148963 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3CO UT WOS:000371221500018 PM 26891449 ER PT J AU Sanford, EL Choy, KW Donahoe, PK Tracy, AA Hila, R Loscertales, M Longoni, M AF Sanford, Ethan L. Choy, Kwong W. Donahoe, Patricia K. Tracy, Adam A. Hila, Regis Loscertales, Maria Longoni, Mauro TI MiR-449a Affects Epithelial Proliferation during the Pseudoglandular and Canalicular Phases of Avian and Mammal Lung Development SO PLOS ONE LA English DT Article ID CONGENITAL DIAPHRAGMATIC-HERNIA; REPLICATION-COMPETENT RETROVIRUSES; N-MYC ONCOGENE; PROGENITOR CELLS; GENE-EXPRESSION; DIFFERENTIATION; MORPHOGENESIS; MICRORNAS; AIRWAY; PATHOGENESIS AB Congenital diaphragmatic hernia is associated with pulmonary hypoplasia and respiratory distress, which result in high mortality and morbidity. Although several transgenic mouse models of lung hypoplasia exist, the role of miRNAs in this phenotype is incompletely characterized. In this study, we assessed microRNA expression levels during the pseudoglandular to canalicular phase transition of normal human fetal lung development. At this critical time, when the distal respiratory portion of the airways begins to form, microarray analysis showed that the most significantly differentially expressed miRNA was miR-449a. Prediction algorithms determined that N-myc is a target of miR-449a and identified the likely miR-449a: N-myc binding sites, confirmed by luciferase assays and targeted mutagenesis. Functional ex vivo knock-down in organ cultures of murine embryonic lungs, as well as in ovo overexpression in avian embryonic lungs, suggested a role for miR-449a in distal epithelial proliferation. Finally, miR-449a expression was found to be abnormal in rare pulmonary specimens of human fetuses with Congenital Diaphragmatic Hernia in the pseudoglandular or canalicular phase. This study confirms the conserved role of miR-449a for proper pulmonary organogenesis, supporting the delicate balance between expansion of progenitor cells and their terminal differentiation, and proposes the potential involvement of this miRNA in human pulmonary hypoplasia. C1 [Sanford, Ethan L.; Hila, Regis; Loscertales, Maria; Longoni, Mauro] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Sanford, Ethan L.] Harvard Univ, Sch Med, Hlth Sci & Technol Med Program, Boston, MA USA. [Sanford, Ethan L.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Choy, Kwong W.] Chinese Univ Hong Kong, Dept Obstet & Gynaecol, Hong Kong, Hong Kong, Peoples R China. [Donahoe, Patricia K.; Tracy, Adam A.; Loscertales, Maria; Longoni, Mauro] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Donahoe, Patricia K.; Tracy, Adam A.] Broad Inst & Harvard, Cambridge, MA USA. RP Loscertales, M; Longoni, M (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA.; Loscertales, M; Longoni, M (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. EM mloscertales@mgh.harvard.edu; mlongoni@mgh.harvard.edu FU National Institute of Child Health and Human Development [P01 HD068250-03] FX Funding was provided by National Institute of Child Health and Human Development P01 HD068250-03 to P.K.D. (www.nichd.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 18 PY 2016 VL 11 IS 2 AR e0149425 DI 10.1371/journal.pone.0149425 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3CO UT WOS:000371221500046 PM 26891231 ER PT J AU Hong, S Carlson, J Lee, H Weissleder, R AF Hong, Seonki Carlson, Jonathan Lee, Hakho Weissleder, Ralph TI Bioorthogonal Radiopaque Hydrogel for Endoscopic Delivery and Universal Tissue Marking SO ADVANCED HEALTHCARE MATERIALS LA English DT Article DE bioorthogonal radiopaque hydrogels; endoscopic delivery; hybrid materials; hydrogels; medical applications ID TETRAZINE-NORBORNENE CHEMISTRY; INDIA INK; SURGERY; CANCER; MARKERS C1 [Hong, Seonki; Carlson, Jonathan; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. RP Weissleder, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA.; Weissleder, R (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU NIH [R01EB010011, HHSN268201000044C] FX The authors thank Gregory Wojtkiewicz for his assistance in CT imaging of mice as part of the CSB Imaging Core. This work was supported in part by NIH Grants R01EB010011 and HHSN268201000044C. NR 31 TC 1 Z9 1 U1 4 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD FEB 18 PY 2016 VL 5 IS 4 BP 421 EP 426 DI 10.1002/adhm.201500780 PG 6 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA DF1KA UT WOS:000371097100005 PM 26688173 ER PT J AU Asch, DA Pauly, MV Muller, RW AF Asch, David A. Pauly, Mark V. Muller, Ralph W. TI Asymmetric Thinking about Return on Investment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Asch, David A.; Muller, Ralph W.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asch, David A.; Pauly, Mark V.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. RP Asch, DA (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.; Asch, DA (reprint author), Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA.; Asch, DA (reprint author), Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 18 PY 2016 VL 374 IS 7 BP 606 EP 608 DI 10.1056/NEJMp1512297 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DD9ER UT WOS:000370229000005 PM 26886519 ER PT J AU Koven, S AF Koven, Suzanne TI The Doctor's New Dilemma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Koven, Suzanne] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Koven, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 18 PY 2016 VL 374 IS 7 BP 608 EP 609 DI 10.1056/NEJMp1513708 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DD9ER UT WOS:000370229000006 PM 26886520 ER PT J AU Terry, AR Kahle, KT Larvie, M Vyas, JM Stemmer-Rachamimov, A AF Terry, Anna R. Kahle, Kristopher T. Larvie, Mykol Vyas, Jatin M. Stemmer-Rachamimov, Anat TI Case 5-2016: A 43-Year-Old Man with Altered Mental Status and a History of Alcohol Use SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BACTERIAL-MENINGITIS; GLIOMATOSIS CEREBRI; THERAPY; ADULTS C1 [Terry, Anna R.] Duke Univ, Sch Med, Dept Neurosurg, Raleigh, NC USA. [Terry, Anna R.] Duke Raleigh Hosp, Raleigh, NC USA. [Kahle, Kristopher T.] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. [Kahle, Kristopher T.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Kahle, Kristopher T.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Larvie, Mykol] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Vyas, Jatin M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Larvie, Mykol] Harvard Univ, Dept Radiol, Sch Med, Boston, MA 02115 USA. [Vyas, Jatin M.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Stemmer-Rachamimov, Anat] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Terry, AR (reprint author), Duke Univ, Sch Med, Dept Neurosurg, Raleigh, NC USA.; Terry, AR (reprint author), Duke Raleigh Hosp, Raleigh, NC USA. NR 10 TC 1 Z9 1 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 FEB 18 PY 2016 VL 374 IS 7 BP 671 EP 680 DI 10.1056/NEJMcpc1509361 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DD9ER UT WOS:000370229000014 PM 26886525 ER PT J AU Baggett, TP Rigotti, NA Campbell, EG AF Baggett, Travis P. Rigotti, Nancy A. Campbell, Eric G. TI Cost of Smoking among Homeless Adults SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Baggett, Travis P.; Rigotti, Nancy A.; Campbell, Eric G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Baggett, TP (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM tbaggett@mgh.harvard.edu FU NIDA NIH HHS [K23 DA034008, K23DA034008] NR 5 TC 1 Z9 1 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 18 PY 2016 VL 374 IS 7 BP 697 EP 698 DI 10.1056/NEJMc1508556 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DD9ER UT WOS:000370229000034 PM 26886544 ER PT J AU Hartlieb, KJ Liu, WG Fahrenbach, AC Blackburn, AK Frasconi, M Hafezi, N Dey, SK Sarjeant, AA Stern, CL Goddard, WA Stoddart, JF AF Hartlieb, Karel J. Liu, Wei-Guang Fahrenbach, Albert C. Blackburn, Anthea K. Frasconi, Marco Hafezi, Nema Dey, Sanjeev K. Sarjeant, Amy A. Stern, Charlotte L. Goddard, William A., III Stoddart, J. Fraser TI Quantum Mechanical and Experimental Validation that Cyclobis(paraquat-p-phenylene) Forms a 1:1 Inclusion Complex with Tetrathiafulvalene SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE DFT calculations; donor-acceptor systems; rotaxanes; tetrathiafulvalene ID DENSITY-FUNCTIONAL THEORY; TEMPLATE-DIRECTED SYNTHESIS; TRANSITION-METAL-COMPLEXES; DONOR-ACCEPTOR; DIFFERENTIAL-OVERLAP; INTERMEDIATE NEGLECT; EXCITED-STATES; SYNTHETIC RECEPTOR; MOLECULAR SWITCH; REDOX AB The promiscuous encapsulation of -electron-rich guests by the -electron-deficient host, cyclobis(paraquat-p-phenylene) (CBPQT(4+)), involves the formation of 1:1 inclusion complexes. One of the most intensely investigated charge-transfer (CT) bands, assumed to result from inclusion of a guest molecule inside the cavity of CBPQT(4+), is an emerald-green band associated with the complexation of tetrathiafulvalene (TTF) and its derivatives. This interpretation was called into question recently in this journal based on theoretical gas-phase calculations that reinterpreted this CT band in terms of an intermolecular side-on interaction of TTF with one of the bipyridinium (BIPY2+) units of CBPQT(4+), rather than the encapsulation of TTF inside the cavity of CBPQT(4+). We carried out DFT calculations, including solvation, that reveal conclusively that the CT band emerging upon mixing TTF with CBPQT(4+) arises from the formation of a 1:1 inclusion complex. In support of this conclusion, we have performed additional experiments on a [2]rotaxane in which a TTF unit, located in the middle of its short dumbbell, is prevented sterically from interacting with either one of the two BIPY2+ units of a CBPQT(4+) ring residing on a separate [2]rotaxane in a side-on fashion. This [2]rotaxane has similar UV/Vis and (HNMR)-H-1 spectroscopic properties with those of 1:1 inclusion complexes of TTF and its derivatives with CBPQT(4+). The [2]rotaxane exists as an equimolar mixture of cis- and trans-isomers associated with the disubstituted TTF unit in its dumbbell component. Solid-state structures were obtained for both isomers, validating the conclusion that the TTF unit, which gives rise to the CT band, resides inside CBPQT(4+). C1 [Hartlieb, Karel J.; Fahrenbach, Albert C.; Blackburn, Anthea K.; Frasconi, Marco; Hafezi, Nema; Dey, Sanjeev K.; Sarjeant, Amy A.; Stern, Charlotte L.; Stoddart, J. Fraser] Northwestern Univ, Dept Chem, 2145 Sheridan Rd, Evanston, IL 60208 USA. [Liu, Wei-Guang; Goddard, William A., III] CALTECH, Mat & Proc Simulat Ctr MC 139 74, Pasadena, CA 91125 USA. [Fahrenbach, Albert C.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Stoddart, JF (reprint author), Northwestern Univ, Dept Chem, 2145 Sheridan Rd, Evanston, IL 60208 USA.; Goddard, WA (reprint author), CALTECH, Mat & Proc Simulat Ctr MC 139 74, Pasadena, CA 91125 USA. EM wag@wag.caltech.edu; stoddart@northwestern.edu RI Frasconi, Marco/C-4767-2014 OI Frasconi, Marco/0000-0003-2010-175X FU Joint Center of Excellence in Integrated Nano-Systems (JCIN) at the King Abdulaziz City of Science and Technology (KACST) [34-945]; Northwestern University (NU); KACST; NU; US National Science Foundation [EFRI-1332411, DMR-1436985]; National Science Foundation (NSF) Graduate Research Fellowship; Fulbright New Zealand; New Zealand Federation of Graduate Women FX This research is part (project 34-945) of the Joint Center of Excellence in Integrated Nano-Systems (JCIN) at the King Abdulaziz City of Science and Technology (KACST) and Northwestern University (NU). The authors would like to thank both KACST and NU for their continued support of this research. W.G.L. and W.A.G. acknowledge support from the US National Science Foundation (EFRI-1332411 and DMR-1436985). A.C.F. acknowledges support from a National Science Foundation (NSF) Graduate Research Fellowship. A.K.B. acknowledges Fulbright New Zealand for a Fulbright Graduate Award and the New Zealand Federation of Graduate Women for a Postgraduate Fellowship award. NR 87 TC 2 Z9 2 U1 13 U2 34 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD FEB 18 PY 2016 VL 22 IS 8 BP 2736 EP 2745 DI 10.1002/chem.201502157 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA DD8QW UT WOS:000370193000023 PM 26784535 ER PT J AU Gao, JX Barzel, B Barabasi, AL AF Gao, Jianxi Barzel, Baruch Barabasi, Albert-Laszlo TI Universal resilience patterns in complex networks SO NATURE LA English DT Article ID FOOD WEBS; DYNAMICS; INTERNET; SYSTEMS AB Resilience, a system's ability to adjust its activity to retain its basic functionality when errors, failures and environmental changes occur, is a defining property of many complex systems(1). Despite widespread consequences for human health(2), the economy(3) and the environment(4), events leading to loss of resilience-from cascading failures in technological systems(5) to mass extinctions in ecological networks(6)-are rarely predictable and are often irreversible. These limitations are rooted in a theoretical gap: the current analytical framework of resilience is designed to treat low-dimensional models with a few interacting components(7), and is unsuitable for multi-dimensional systems consisting of a large number of components that interact through a complex network. Here we bridge this theoretical gap by developing a set of analytical tools with which to identify the natural control and state parameters of a multi-dimensional complex system, helping us derive effective one-dimensional dynamics that accurately predict the system's resilience. The proposed analytical framework allows us systematically to separate the roles of the system's dynamics and topology, collapsing the behaviour of different networks onto a single universal resilience function. The analytical results unveil the network characteristics that can enhance or diminish resilience, offering ways to prevent the collapse of ecological, biological or economic systems, and guiding the design of technological systems resilient to both internal failures and environmental changes. C1 [Gao, Jianxi; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Barzel, Baruch] Bar Ilan Univ, Dept Math, IL-52900 Ramat Gan, Israel. [Barabasi, Albert-Laszlo] Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary. RP Barabasi, AL (reprint author), Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA.; Barabasi, AL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary. EM alb@neu.edu RI gao, jianxi/I-1300-2013; Gao, Jianxi/C-8494-2015 OI gao, jianxi/0000-0002-3952-208X; Gao, Jianxi/0000-0002-3952-208X NR 29 TC 30 Z9 30 U1 56 U2 140 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 18 PY 2016 VL 530 IS 7590 BP 307 EP 312 DI 10.1038/nature16948 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE0PP UT WOS:000370327100031 PM 26887493 ER PT J AU Ballandras-Colas, A Browne, M Cook, NJ Dewdney, TG Domeler, B Cherepanov, P Lyumkis, D Engelman, AN AF Ballandras-Colas, Allison Browne, Monica Cook, Nicola J. Dewdney, Tamaria G. Domeler, Barrios Cherepanov, Peter Lyumkis, Dmitry Engelman, Alan N. TI Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function SO NATURE LA English DT Article ID SARCOMA-VIRUS INTEGRASE; VIRAL-DNA ENDS; PHOTO-CROSS-LINKING; DIVISION-OF-LABOR; HIV-1 INTEGRASE; IN-VITRO; MACROMOLECULAR STRUCTURES; RETROVIRAL INTEGRATION; CRYSTAL-STRUCTURE; STRAND TRANSFER AB Retroviral integrase catalyses the integration of viral DNA into host target DNA, which is an essential step in the life cycle of all retroviruses(1). Previous structural characterization of integrase-viral DNA complexes, or intasomes, from the spumavirus prototype foamy virus revealed a functional integrase tetramer(2-)5, and it is generally believed that intasomes derived from other retroviral genera use tetrameric integrase(6-9). However, the intasomes of orthoretroviruses, which include all known pathogenic species, have not been characterized structurally. Here, using single-particle cryo-electron microscopy and X-ray crystallography, we determine an unexpected octameric integrase architecture for the intasome of the betaretrovirus mouse mammary tumour virus. The structure is composed of two core integrase dimers, which interact with the viral DNA ends and structurally mimic the integrase tetramer of prototype foamy virus, and two flanking integrase dimers that engage the core structure via their integrase carboxy-terminal domains. Contrary to the belief that tetrameric integrase components are sufficient to catalyse integration, the flanking integrase dimers were necessary for mouse mammary tumour virus integrase activity. The integrase octamer solves a conundrum for betaretroviruses as well as alpharetroviruses by providing critical carboxy-terminal domains to the intasome core that cannot be provided in cis because of evolutionarily restrictive catalytic core domain-carboxy-terminal domain linker regions. The octameric architecture of the intasome of mouse mammary tumour virus provides new insight into the structural basis of retroviral DNA integration. C1 [Ballandras-Colas, Allison; Dewdney, Tamaria G.; Engelman, Alan N.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Immunol & Virol, 450 Brookline Ave, Boston, MA 02215 USA. [Ballandras-Colas, Allison; Dewdney, Tamaria G.; Engelman, Alan N.] Harvard Univ, Dept Med, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA. [Browne, Monica; Lyumkis, Dmitry] Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Browne, Monica; Lyumkis, Dmitry] Salk Inst Biol Studies, Helmsley Ctr Genom Med, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Cook, Nicola J.; Cherepanov, Peter] Imperial Canc Res Fund, Clare Hall Labs, Francis Crick Inst, Potters Bar EN6 3LD, Herts, England. [Domeler, Barrios] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Med, St Marys Campus,Norfolk Pl, London W2 1PG, England. RP Engelman, AN (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Immunol & Virol, 450 Brookline Ave, Boston, MA 02215 USA.; Engelman, AN (reprint author), Harvard Univ, Dept Med, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA.; Lyumkis, D (reprint author), Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.; Lyumkis, D (reprint author), Salk Inst Biol Studies, Helmsley Ctr Genom Med, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM dlyumkis@salk.edu; alan.engelman@dfci.harvard.edu RI Cherepanov, Peter/F-6859-2010 OI Cherepanov, Peter/0000-0002-0634-538X FU US National Institutes of Health (NIH) [R01 AI070042]; NIH [P50 GM103368, P50 GM082251, P30 AI060354, P41 GM103331]; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; US National Science Foundation [NSF-ACI-1339649, TG-MCB070039]; San Antonio Cancer Institute [CA054174] FX We acknowledge support from US National Institutes of Health (NIH) grants R01 AI070042 (to A.N.E.), NIH P50 GM103368 and the Leona M. and Harry B. Helmsley Charitable Trust grant number 2012-PG-MED002 (to D.L., both funding sources provided equal support), NIH P50 GM082251 (to P.C.), NIH P30 AI060354 (Harvard University Center for AIDS Research), and US National Science Foundation grants NSF-ACI-1339649 and TG-MCB070039 (to B.D.). B.D. acknowledges support from San Antonio Cancer Institute grant CA054174 for the Center for Analytical Ultracentrifugation of Macromolecular Assemblies at the University of Texas Health Science Center at San Antonio. Molecular graphics and analyses were performed with the USCF Chimera package (supported by NIH P41 GM103331). CryoEM data collection was in part facilitated by the National Resource for Automated Molecular Microscopy (9 P41 GM103310). We thank B. Anderson and J.-C. Ducom at The Scripps Research Institute for help with EM data collection and network infrastructure, J. Fitzpatrick and F. Dwyer for computational support at The Salk Institute, V. Pye for help with X-ray structure refinement and the staff of BM14 (European Synchrotron Radiation Facility, Grenoble, France) and I03 (Diamond Light Source, Oxfordshire, UK) beamlines for assistance with data collection. NR 60 TC 10 Z9 10 U1 4 U2 16 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 FEB 18 PY 2016 VL 530 IS 7590 BP 358 EP + DI 10.1038/nature16955 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE0PP UT WOS:000370327100042 PM 26887496 ER PT J AU Garcia, PL Miller, AL Kreitzburg, KM Council, LN Gamblin, TL Christein, JD Heslin, MJ Arnoletti, JP Richardson, JH Chen, D Hanna, CA Cramer, SL Yang, ES Qi, J Bradner, JE Yoon, KJ AF Garcia, P. L. Miller, A. L. Kreitzburg, K. M. Council, L. N. Gamblin, T. L. Christein, J. D. Heslin, M. J. Arnoletti, J. P. Richardson, J. H. Chen, D. Hanna, C. A. Cramer, S. L. Yang, E. S. Qi, J. Bradner, J. E. Yoon, K. J. TI The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models SO ONCOGENE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; SALMONELLA-TYPHIMURIUM A1-R; C-MYC; GENE-EXPRESSION; CANCER-CELLS; SELECTIVE-INHIBITION; CLINICAL BENEFIT; BREAST-CANCER; MOUSE MODELS; DNA-DAMAGE AB The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P < 0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P < 0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1. C1 [Garcia, P. L.; Miller, A. L.; Kreitzburg, K. M.; Gamblin, T. L.; Yoon, K. J.] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA. [Hanna, C. A.] Univ Alabama Birmingham, Div Anat Pathol, Dept Pathol, Birmingham, AL USA. [Christein, J. D.; Heslin, M. J.; Arnoletti, J. P.; Richardson, J. H.] Univ Alabama Birmingham, Div Gen Surg Gastrointestinal Surg Surg Oncol, Dept Surg, Birmingham, AL USA. [Chen, D.] Univ Alabama Birmingham, Div Prevent Med, Dept Med, Birmingham, AL USA. [Cramer, S. L.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Yang, E. S.] Univ Alabama Birmingham, Dept Radiat Oncol, Birmingham, AL USA. [Qi, J.; Bradner, J. E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Yoon, KJ (reprint author), Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA. EM kyoon@uab.edu FU UAB/UMN SPORE in pancreatic cancer [P50 CA101955] FX We thank Drs Donald J Buchsbaum, William E Grizzle, Mary-Ann Bjornsti and Christopher Klug for their insightful guidance and helpful discussions. This research was supported in part by UAB/UMN SPORE in pancreatic cancer (P50 CA101955). NR 69 TC 17 Z9 18 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD FEB 18 PY 2016 VL 35 IS 7 BP 833 EP 845 DI 10.1038/onc.2015.126 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DE0RO UT WOS:000370332200004 PM 25961927 ER PT J AU Yonesaka, K Hirotani, K Kawakami, H Takeda, M Kaneda, H Sakai, K Okamoto, I Nishio, K Janne, PA Nakagawa, K AF Yonesaka, K. Hirotani, K. Kawakami, H. Takeda, M. Kaneda, H. Sakai, K. Okamoto, I. Nishio, K. Jaenne, P. A. Nakagawa, K. TI Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib SO ONCOGENE LA English DT Article ID ADVANCED SOLID TUMORS; KINASE DOMAIN; INACTIVE HER3; EGFR; GEFITINIB; AMPLIFICATION; RESISTANCE; THERAPY; ERBB3; ACTIVATION AB Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients. C1 [Yonesaka, K.; Kawakami, H.; Takeda, M.; Kaneda, H.; Nakagawa, K.] Kinki Univ, Sch Med, Dept Med Oncol, 377-2 Ohnohigashi Osaka Sayamashi, Osaka 5898511, Japan. [Kawakami, H.] Daiichi Sankyo Pharmaceut Dev, Tokyo, Japan. [Sakai, K.; Nishio, K.] Kinki Univ, Sch Med, Dept Genome Biol, Osaka 589, Japan. [Okamoto, I.] Kyushu Univ, Ctr Clin & Translat Res, Fukuoka 812, Japan. [Jaenne, P. A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Jaenne, P. A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jaenne, P. A.] Harvard Univ, Sch Med, Brigham Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Yonesaka, K (reprint author), Kinki Univ, Sch Med, Dept Med Oncol, 377-2 Ohnohigashi Osaka Sayamashi, Osaka 5898511, Japan.; Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,HIM223, Boston, MA 02215 USA. EM yonesaka@sakai.med.kindai.ac.jp; pjanne@partners.org FU Daiichi-Sankyo Pharmaceutical Development FX We thank Haruka Yamaguchi, Yume Shinkai, Michiko Kitano and Mami Kitano for technical support. This work was financially funded in part by Daiichi-Sankyo Pharmaceutical Development. NR 37 TC 11 Z9 11 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD FEB 18 PY 2016 VL 35 IS 7 BP 878 EP 886 DI 10.1038/onc.2015.142 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DE0RO UT WOS:000370332200008 PM 25961915 ER PT J AU Chiu, CN Rihel, J Lee, DA Singh, C Mosser, EA Chen, SJ Sapin, V Pham, U Engle, J Niles, BJ Montz, CJ Chakravarthy, S Zimmerman, S Salehi-Ashtiani, K Vidal, M Schier, AF Prober, DA AF Chiu, Cindy N. Rihel, Jason Lee, Daniel A. Singh, Chanpreet Mosser, Eric A. Chen, Shijia Sapin, Viveca Uyen Pham Engle, Jae Niles, Brett J. Montz, Christin J. Chakravarthy, Sridhara Zimmerman, Steven Salehi-Ashtiani, Kourosh Vidal, Marc Schier, Alexander F. Prober, David A. TI A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States SO NEURON LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; STRESSOR-INDUCED ALTERATIONS; CONTRACTILE ACTIVITY; ENERGY HOMEOSTASIS; LOCOMOTOR-ACTIVITY; LARVAL ZEBRAFISH; RAT; EXPRESSION; NEURONS; WAKEFULNESS AB Neuromodulation of arousal states ensures that an animal appropriately responds to its environment and engages in behaviors necessary for survival. However, the molecular and circuit properties underlying neuromodulation of arousal states such as sleep and wakefulness remain unclear. To tackle this challenge in a systematic and unbiased manner, we performed a genetic overexpression screen to identify genes that affect larval zebrafish arousal. We found that the neuropeptide neuromedin U (Nmu) promotes hyperactivity and inhibits sleep in zebrafish larvae, whereas nmu mutant animals are hypoactive. We show that Nmu-induced arousal requires Nmu receptor 2 and signaling via corticotropin releasing hormone (Crh) receptor 1. In contrast to previously proposed models, we find that Nmu does not promote arousal via the hypothalamic-pituitary-adrenal axis, but rather probably acts via brainstem crh-expressing neurons. These results reveal an unexpected functional and anatomical interface between the Nmu system and brainstem arousal systems that represents a novel wake-promoting pathway. C1 [Chiu, Cindy N.; Lee, Daniel A.; Singh, Chanpreet; Mosser, Eric A.; Chen, Shijia; Sapin, Viveca; Uyen Pham; Engle, Jae; Niles, Brett J.; Montz, Christin J.; Chakravarthy, Sridhara; Prober, David A.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Rihel, Jason] UCL, Dept Cell & Dev Biol, Mortimer St, London WC1E 6BT, England. [Rihel, Jason; Zimmerman, Steven; Schier, Alexander F.] Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 02138 USA. [Salehi-Ashtiani, Kourosh; Vidal, Marc] Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Salehi-Ashtiani, Kourosh; Vidal, Marc] Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Salehi-Ashtiani, Kourosh; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Schier, Alexander F.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Schier, Alexander F.] Harvard Univ, Div Sleep Med, Cambridge, MA 02138 USA. [Chiu, Cindy N.] Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA. [Mosser, Eric A.] Northwestern Univ, Program Biol Sci, Evanston, IL 60208 USA. [Salehi-Ashtiani, Kourosh] NYU, Div Sci & Math, Abu Dhabi, U Arab Emirates. [Salehi-Ashtiani, Kourosh] NYU, Ctr Genom & Syst Biol, Abu Dhabi, U Arab Emirates. RP Prober, DA (reprint author), CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.; Schier, AF (reprint author), Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 02138 USA.; Schier, AF (reprint author), Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.; Schier, AF (reprint author), Harvard Univ, Div Sleep Med, Cambridge, MA 02138 USA. EM schier@fas.harvard.edu; dprober@caltech.edu RI Zebrafish, UCL/A-3125-2009; OI Salehi-Ashtiani, Kourosh/0000-0002-6521-5243; Rihel, Jason/0000-0003-4067-2066 FU NIH [NS084769, NS077842, HL109625, NS060996, NS070911, DA031367]; European Research Council; High-Tech Fund of the Dana-Farber Cancer Institute; Ellison Foundation; Mallinckrodt Foundation; Rita Allen Foundation; Brain and Behavior Research Foundation FX We thank Melanie Pribisko, Alex Mack Cruz, Axel Dominguez, Sohini Khan, and Kenna Molinder for technical assistance. This work was supported by grants from the NIH (D.A.L.: NS084769; S. Chen: NS077842; A.F.S.: HL109625; D.A.P.: NS060996, NS070911, DA031367); the European Research Council Starting Grant and UCL Excellence Fellowship (J.R.); the High-Tech Fund of the Dana-Farber Cancer Institute and the Ellison Foundation (M.V.); and the Mallinckrodt, Rita Allen and the Brain and Behavior Research Foundations (D.A.P.). We declare no conflicts of interest. NR 52 TC 5 Z9 5 U1 7 U2 10 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 FEB 17 PY 2016 VL 89 IS 4 BP 842 EP 856 DI 10.1016/j.neuron.2016.01.007 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DI5UE UT WOS:000373565200017 PM 26889812 ER PT J AU Chambers, AR Resnik, J Yuan, YS Whitton, JP Edge, AS Liberman, MC Polley, DB AF Chambers, Anna R. Resnik, Jennifer Yuan, Yasheng Whitton, Jonathon P. Edge, Albert S. Liberman, M. Charles Polley, Daniel B. TI Central Gain Restores Auditory Processing following Near-Complete Cochlear Denervation SO NEURON LA English DT Article ID HEARING-LOSS; BALANCED INHIBITION; NERVE DEGENERATION; RECEPTIVE-FIELDS; ACOUSTIC TRAUMA; CORTEX; NEURONS; PLASTICITY; SPEECH; NEUROPATHY AB Sensory organ damage induces a host of cellular and physiological changes in the periphery and the brain. Here, we show that some aspects of auditory processing recover after profound cochlear denervation due to a progressive, compensatory plasticity at higher stages of the central auditory pathway. Lesioning >95% of cochlear nerve afferent synapses, while sparing hair cells, in adult mice virtually eliminated the auditory brainstem response and acoustic startle reflex, yet tone detection behavior was nearly normal. As sound-evoked responses from the auditory nerve grew progressively weaker following denervation, sound-evoked activity in the cortex- and, to a lesser extent, the midbrain-rebounded or surpassed control levels. Increased central gain supported the recovery of rudimentary sound features encoded by firing rate, but not features encoded by precise spike timing such as modulated noise or speech. These findings underscore the importance of central plasticity in the perceptual sequelae of cochlear hearing impairment. C1 [Chambers, Anna R.; Resnik, Jennifer; Whitton, Jonathon P.; Edge, Albert S.; Liberman, M. Charles; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Resnik, Jennifer; Edge, Albert S.; Liberman, M. Charles; Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02114 USA. [Yuan, Yasheng] Fudan Univ, Dept Otolaryngol, Shanghai 200031, Peoples R China. [Chambers, Anna R.] Johannes Gutenberg Univ Mainz, Hanns Dieter Husch Weg 19, D-55128 Mainz, Germany. RP Polley, DB (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA.; Polley, DB (reprint author), Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02114 USA. EM polley@meei.harvard.edu OI Resnik, Jennifer/0000-0002-0573-0008; Polley, Daniel/0000-0002-5120-2409 FU Autifony Therapeutics [R01 DC009836, R01 DC007174, R01 DC 00188, P30 05209]; Lauer Tinnitus Research Center FX We thank Mark Liu and Krupa Shukla for assisting with behavioral measurements, Leslie Liberman for preparing cochlear whole mount sections, and Ken Hancock for programming assistance. This work was supported by R01 DC009836 (D.B.P.), R01 DC007174 (A.S.E.), R01 DC 00188 (M.C.L.), P30 05209 (M.C.L.), a research grant from Autifony Therapeutics (D.B.P.), and the Lauer Tinnitus Research Center (M.C.L. and D.B.P.). NR 56 TC 16 Z9 16 U1 2 U2 8 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 FEB 17 PY 2016 VL 89 IS 4 BP 867 EP 879 DI 10.1016/j.neuron.2015.12.041 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DI5UE UT WOS:000373565200019 PM 26833137 ER PT J AU Belsky, JB Morris, DC Bouchebl, R Filbin, MR Bobbitt, KR Jaehne, AK Rivers, EP AF Belsky, Justin B. Morris, Daniel C. Bouchebl, Ralph Filbin, Michael R. Bobbitt, Kevin R. Jaehne, Anja K. Rivers, Emanuel P. TI Plasma levels of F-actin and F:G-actin ratio as potential new biomarkers in patients with septic shock SO BIOMARKERS LA English DT Article DE thymosin beta 4; F-actin; Actin; actin binding protein; G-actin; septic shock; coronary artery bypass graft ID SEVERE SEPSIS; INFLAMMATORY RESPONSE; GELSOLIN; RESUSCITATION; MORTALITY; THERAPY; MUSCLE AB Objective: To compare plasma levels of F-actin, G-actin and thymosin beta 4 (TB4) in humans with septic shock, noninfectious systemic inflammatory response syndrome (SIRS) and healthy controls. Results: F-actin was significantly elevated in septic shock as compared with noninfectious SIRS and healthy controls. G-actin levels were greatest in the noninfectious SIRS group but significantly elevated in septic shock as compared with healthy controls. TB4 was not detectable in the septic shock or noninfectious SIRS group above the assay's lowest detection range (78 ng/ml). Conclusions: F-actin is significantly elevated in patients with septic shock as compared with noninfectious SIRS. F-actin and the F:G-actin ratio are potential biomarkers for the diagnosis of septic shock. C1 [Belsky, Justin B.; Filbin, Michael R.] Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St,Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. [Morris, Daniel C.; Jaehne, Anja K.; Rivers, Emanuel P.] Henry Ford Hosp, Dept Emergency Med, Detroit, MI 48202 USA. [Bouchebl, Ralph] Amer Univ Beirut, Dept Emergency Med, Beirut, Lebanon. [Bobbitt, Kevin R.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Jaehne, Anja K.] Northstar Hlth Syst, Dept Qual, Iron River, MI USA. RP Belsky, JB (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St,Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM jbelsky@partners.org OI Jaehne, Anja Kathrin/0000-0002-0744-2886 FU Henry Ford Hospital Graduate Medical Education Research Grant FX J.B.B., D.C.M. and E.P.R. have filed a patent utilizing the levels of F-actin, G-actin and TB4 to diagnose and guide treatment of patients with septic shock. The remaining authors report no declarations of interest. We would like to thank the Henry Ford Hospital Graduate Medical Education Research Grant for financial support to complete this project as well as Dr Jasreen Kaur, Dr Victor Coba and Dr. Arturo Suarez for assistance in identification of patients and data collection. NR 20 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1354-750X EI 1366-5804 J9 BIOMARKERS JI Biomarkers PD FEB 17 PY 2016 VL 21 IS 2 BP 180 EP 185 DI 10.3109/1354750X.2015.1126646 PG 6 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA DI1BL UT WOS:000373230900013 PM 26754286 ER PT J AU Frelinger, AL Torres, AS Caiafa, A Morton, CA Berny-Lang, MA Gerrits, AJ Carmichael, SL Neculaes, VB Michelson, AD AF Frelinger, A. L., III Torres, A. S. Caiafa, A. Morton, C. A. Berny-Lang, M. A. Gerrits, A. J. Carmichael, S. L. Neculaes, V. B. Michelson, A. D. TI Platelet-rich plasma stimulated by pulse electric fields: Platelet activation, procoagulant markers, growth factor release and cell proliferation SO PLATELETS LA English DT Article DE Growth factors; platelets; platelet-rich plasma; pulse electric field; wound healing ID ALPHA-GRANULES; EPITHELIAL-CELLS; BOVINE THROMBIN; FLOW-CYTOMETRY; PROTEINS; ANGIOGENESIS; GEL; MICROPARTICLES; PATHWAY; SURGERY AB Therapeutic use of activated platelet-rich plasma (PRP) has been explored for wound healing, hemostasis and antimicrobial wound applications. Pulse electric field (PEF) stimulation may provide more consistent platelet activation and avoid complications associated with the addition of bovine thrombin, the current state of the art ex vivo activator of therapeutic PRP. The aim of this study was to compare the ability of PEF, bovine thrombin and thrombin receptor activating peptide (TRAP) to activate human PRP, release growth factors and induce cell proliferation in vitro. Human PRP was prepared in the Harvest SmartPreP2 System and treated with vehicle, PEF, bovine thrombin, TRAP or Triton X-100. Platelet activation and procoagulant markers and microparticle generation were measured by flow cytometry. Released growth factors were measured by ELISA. The releasates were tested for their ability to stimulate proliferation of human epithelial cells in culture. PEF produced more platelet-derived microparticles, P-selectin-positive particles and procoagulant annexin V-positive particles than bovine thrombin or TRAP. These differences were associated with higher levels of released epidermal growth factor after PEF than after bovine thrombin or TRAP but similar levels of platelet-derived, vascular-endothelial, and basic fibroblast growth factors, and platelet factor 4. Supernatant from PEF-treated platelets significantly increased cell proliferation compared to plasma. In conclusion, PEF treatment of fresh PRP results in generation of microparticles, exposure of prothrombotic platelet surfaces, differential release of growth factors compared to bovine thrombin and TRAP and significant cell proliferation. These results, together with PEF's inherent advantages, suggest that PEF may be a superior alternative to bovine thrombin activation of PRP for therapeutic applications. C1 [Frelinger, A. L., III; Berny-Lang, M. A.; Gerrits, A. J.; Carmichael, S. L.; Michelson, A. D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Platelet Res Studies,Div Hematol Oncol,Boston, 44 Binney St, Boston, MA 02115 USA. [Torres, A. S.; Caiafa, A.; Morton, C. A.; Neculaes, V. B.] GE Global Res Ctr, Niskayuna, NY USA. RP Frelinger, AL (reprint author), Boston Childrens Hosp, Ctr Platelet Res Studies, Div Hematol Oncol, Karp 07212,300 Longwood Ave, Boston, MA 02115 USA. EM andrew.frelinger@childrens.harvard.edu FU GE Global Research; Bristol-Myers Squibb; Cellphire; Eisai; GLSynthesis; Lilly/Daiichi Sankyo; Pfizer; Sysmex FX This study was supported by a research grant from GE Global Research to Boston Children's Hospital (PI: A.D.M.). A.L.F. and A.D.M. are the PI or co-PI on grants to Boston Children's Hospital from Bristol-Myers Squibb, Cellphire, Eisai, GLSynthesis, Lilly/Daiichi Sankyo, Pfizer and Sysmex. A.S.T., A.C., C.A.M. and V.B.N. are employees of GE Global Research Center. The other authors report no conflicts of interest. NR 42 TC 1 Z9 2 U1 3 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0953-7104 EI 1369-1635 J9 PLATELETS JI Platelets PD FEB 17 PY 2016 VL 27 IS 2 BP 128 EP 135 DI 10.3109/09537104.2015.1048214 PG 8 WC Cell Biology; Hematology SC Cell Biology; Hematology GA DF9ZF UT WOS:000371720500006 PM 26030682 ER PT J AU Xu, WF Li, HZ Ji, ZG Yan, WG Zhang, YS Zhang, XB Li, Q AF Xu, Weifeng Li, Hanzhong Ji, Zhigang Yan, Weigang Zhang, Yushi Zhang, Xuebin Li, Qian TI Retroperitoneal Laparoscopic Management of Paraganglioma: A Single Institute Experience SO PLOS ONE LA English DT Article ID ADRENAL PHEOCHROMOCYTOMA; RESECTION; OUTCOMES; ERA AB Objectives To explore the feasibility and safety of retroperitoneal laparoscopic resection of paraganglioma (RLPG) in a large study population. Methods In a six-year period, 49 patients with primary retroperitoneal paragangliomas (PG) underwent retroperitoneal laparoscopic surgery in a single center. Medical records were reviewed, and collected the following data, which were clinical characteristics, perioperative data (operative time, estimated blood loss, intraoperative hemodynamic changes, intraoperative and postoperative complications, and open conversions), and follow-up data (recurrence or distant metastases). Results All PGs were removed with negative tumor margin confirmed by postoperative histopathology. The operative time of RLPG was 101.59 +/- 31.12 minutes, and the estimated blood loss was 169.78 +/- 176.70ml. Intraoperative hypertensive and hypotensive episodes occurred in 25 cases and 27 cases, respectively. Two open conversions occurred. Two intraoperative complications occurred but were successfully managed endoscopically. Postoperative complications were minor and unremarkable. No local recurrence or distant metastasis were observed during the follow-up period. Conclusions Our experience indicates the feasibility and safety of resection of PGs in a relatively large study population. C1 [Xu, Weifeng; Li, Hanzhong; Ji, Zhigang; Yan, Weigang; Zhang, Yushi; Zhang, Xuebin] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Urol, Beijing 100730, Peoples R China. [Li, Qian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Li, HZ (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Urol, Beijing 100730, Peoples R China. EM windslipper@163.com NR 23 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2016 VL 11 IS 2 AR e0149433 DI 10.1371/journal.pone.0149433 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3BJ UT WOS:000371218400082 PM 26885838 ER PT J AU Keating, J Judy, R Newton, A Singhal, S AF Keating, Jane Judy, Ryan Newton, Andrew Singhal, Sunil TI Near-infrared operating lamp for intraoperative molecular imaging of a mediastinal tumor SO BMC MEDICAL IMAGING LA English DT Article DE Intraoperative imaging; Cancer; Near-infrared; Indocyanine green; Mediastinal tumors AB Background: Near-Infrared (NIR) intraoperative molecular imaging is a new diagnostic modality utilized during cancer surgery for the identification of tumors, metastases and lymph nodes. Surgeons typically use headlamps during an operation to increase visible light; however, these light sources are not adapted to function simultaneously with NIR molecular imaging technology. Here, we design a NIR cancelling headlamp and utilize it during surgery to assess whether intraoperative molecular imaging of mediastinal tumors is possible. Methods: A NIR cancelling headlamp was designed and tested using NIR spectroscopy preoperatively. Next, a 46 year-old-female was referred to the thoracic surgery clinic for a 5.8 cm mediastinal mass noted on chest x-ray. Prior to surgery, she was given intravenous indocyanine green (ICG). Then, the prototype headlamp was used in conjunction with our intraoperative molecular imaging device. The tumor was imaged both in vivo and following resection prior to pathological examination. Results: NIR spectroscopy confirmed NIR light excitation of the unfiltered headlamp and the absence of NIR emitted light after addition of the filter. Next, in vivo imaging confirmed fluorescence of the tumor, but also demonstrated a significant amount of NIR background fluorescence emanating from the unfiltered headlamp. During imaging with the filtered headlamp, we again demonstrated a markedly fluorescent tumor but with a reduced false positive NIR signal. Final pathology was well-differentiated thymoma with negative surgical margins. Conclusions: NIR intraoperative molecular imaging using a systemic injection of intravenous ICG was successful in localizing a thymoma. Additionally, a simple design and implementation of a NIR cancelling headlamp reduces false positive NIR fluorescence. C1 [Keating, Jane] Univ Penn, Dept Surg, 6 White Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. Philadelphia VA Med Ctr, 6 White Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. RP Keating, J (reprint author), Univ Penn, Dept Surg, 6 White Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM janejkeating@gmail.com FU [NIH R01 CA163256] FX Funding for the clinical trial in which this case report was involved was provided by grant NIH R01 CA163256. NR 11 TC 0 Z9 0 U1 4 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2342 J9 BMC MED IMAGING JI BMC Med. Imag. PD FEB 17 PY 2016 VL 16 AR 15 DI 10.1186/s12880-016-0120-5 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DE0LK UT WOS:000370316200001 PM 26883511 ER PT J AU Yassour, M Lim, MY Yun, HS Tickle, TL Sung, J Song, YM Lee, K Franzosa, EA Morgan, XC Gevers, D Lander, ES Xavier, RJ Birren, BW Ko, G Huttenhower, C AF Yassour, Moran Lim, Mi Young Yun, Hyun Sun Tickle, Timothy L. Sung, Joohon Song, Yun-Mi Lee, Kayoung Franzosa, Eric A. Morgan, Xochitl C. Gevers, Dirk Lander, Eric S. Xavier, Ramnik J. Birren, Bruce W. Ko, GwangPyo Huttenhower, Curtis TI Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes SO GENOME MEDICINE LA English DT Article ID INSULIN-RESISTANCE; HEALTHY TWIN; WEIGHT-GAIN; BODY-WEIGHT; INFLAMMATION; METAGENOME; WOMEN; DIET; ASSOCIATION; ENTEROTYPES AB Background: Obesity and type 2 diabetes (T2D) are linked both with host genetics and with environmental factors, including dysbioses of the gut microbiota. However, it is unclear whether these microbial changes precede disease onset. Twin cohorts present a unique genetically-controlled opportunity to study the relationships between lifestyle factors and the microbiome. In particular, we hypothesized that family-independent changes in microbial composition and metabolic function during the sub-clinical state of T2D could be either causal or early biomarkers of progression. Methods: We collected fecal samples and clinical metadata from 20 monozygotic Korean twins at up to two time points, resulting in 36 stool shotgun metagenomes. While the participants were neither obese nor diabetic, they spanned the entire range of healthy to near-clinical values and thus enabled the study of microbial associations during sub-clinical disease while accounting for genetic background. Results: We found changes both in composition and in function of the sub-clinical gut microbiome, including a decrease in Akkermansia muciniphila suggesting a role prior to the onset of disease, and functional changes reflecting a response to oxidative stress comparable to that previously observed in chronic T2D and inflammatory bowel diseases. Finally, our unique study design allowed us to examine the strain similarity between twins, and we found that twins demonstrate strain-level differences in composition despite species-level similarities. Conclusions: These changes in the microbiome might be used for the early diagnosis of an inflamed gut and T2D prior to clinical onset of the disease and will help to advance toward microbial interventions. C1 [Yassour, Moran; Franzosa, Eric A.; Morgan, Xochitl C.; Gevers, Dirk; Lander, Eric S.; Xavier, Ramnik J.; Birren, Bruce W.; Huttenhower, Curtis] Broad Inst, 415 Main St, Cambridge, MA 02142 USA. [Yassour, Moran; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Yassour, Moran; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lim, Mi Young; Yun, Hyun Sun; Sung, Joohon; Ko, GwangPyo] Seoul Natl Univ, Sch Publ Hlth, 1 Gwanak Ro, Seoul, South Korea. [Tickle, Timothy L.; Franzosa, Eric A.; Morgan, Xochitl C.; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. [Tickle, Timothy L.] Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA. [Song, Yun-Mi] Sungkyunkwan Sch Med, Samsung Med Ctr, 25-2 Sungkyunkwan Ro, Seoul, South Korea. [Lee, Kayoung] Busan Paik Hosp, Inje Coll Med, 197 Inje Ro, Gimhae Si, Gyeongsangnam D, South Korea. [Gevers, Dirk] Janssen Human Microbiome Inst, Janssen Res & Dev, Cambridge, MA USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 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, Cambridge, MA 02139 USA. RP Huttenhower, C (reprint author), Broad Inst, 415 Main St, Cambridge, MA 02142 USA.; Huttenhower, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM chuttenh@hsph.harvard.edu FU NIDDK NIH HHS [P30 DK043351] NR 53 TC 8 Z9 9 U1 8 U2 41 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD FEB 17 PY 2016 VL 8 AR 17 DI 10.1186/s13073-016-0271-6 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DD9FR UT WOS:000370231600001 PM 26884067 ER PT J AU Vu, HT Chakrabarti, S Hinczewski, M Thirumalai, D AF Vu, Huong T. Chakrabarti, Shaon Hinczewski, Michael Thirumalai, D. TI Broad Velocity Distributions in SFIV Helicases are a Consequence of Heterogeneity SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Vu, Huong T.; Thirumalai, D.] Univ Maryland, IPST, Biophys, College Pk, MD 20742 USA. [Chakrabarti, Shaon] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chakrabarti, Shaon] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Hinczewski, Michael] Case Western Reserve Univ, Dept Phys, Cleverland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 336-Pos BP 64A EP 64A PG 1 WC Biophysics SC Biophysics GA DK7GP UT WOS:000375093500331 ER PT J AU Dexter, JP Ward, PS Dasgupta, T Hosios, AM Gunawardena, J Vander Heiden, MG AF Dexter, Joseph P. Ward, Patrick S. Dasgupta, Tathagata Hosios, Aaron M. Gunawardena, Jeremy Vander Heiden, Matthew G. TI 2-Hydroxyglutarate Production by Mutant Isocitrate Dehydrogenase is Independent of Substrate Channeling but Sensitive to Compartment-Specific Metabolite Levels SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Dexter, Joseph P.; Dasgupta, Tathagata; Gunawardena, Jeremy] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Ward, Patrick S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hosios, Aaron M.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Hosios, Aaron M.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 730-Pos BP 145A EP 145A PG 1 WC Biophysics SC Biophysics GA DK7GS UT WOS:000375093800218 ER PT J AU Fontana, J Jurado, KA Cheng, NQ Engelman, AN Steven, AC AF Fontana, Juan Jurado, Kellie A. Cheng, Naiqian Engelman, Alan N. Steven, Alasdair C. TI Cryo-Electron Tomography and Nucleocapsid Protein Labeling by Tomo-Bubblegram Imaging Reveal a Role for HIV-1 Integrase in Viral Maturation SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Fontana, Juan; Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. [Jurado, Kellie A.; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 779-Pos BP 155A EP 155A PG 1 WC Biophysics SC Biophysics GA DK7GS UT WOS:000375093800267 ER PT J AU Masia, R McCarty, WJ Lahmann, C Luther, J Chung, RT Yarmush, ML Yellen, G AF Masia, Ricard McCarty, William J. Lahmann, Carolina Luther, Jay Chung, Raymond T. Yarmush, Martin L. Yellen, Gary TI Live Cell Imaging of Cytosolic NADH/NAD(+) Ratio in Hepatocytes using the Fluorescent Sensor Peredox SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Masia, Ricard] Massachusetts Gen Hosp, Pathol, Boston, MA 02114 USA. [Masia, Ricard; Lahmann, Carolina; Yellen, Gary] Harvard Univ, Sch Med, Neurobiol, Boston, MA USA. [McCarty, William J.; Yarmush, Martin L.] Massachusetts Gen Hosp, Surg, Boston, MA 02114 USA. [Luther, Jay; Chung, Raymond T.] Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 1651-Pos BP 335A EP 335A PG 1 WC Biophysics SC Biophysics GA DK7YE UT WOS:000375142200118 ER PT J AU Demir, O Richards, C Albin, JS Shaban, NM Anderson, BD Amaro, RE Harris, RS AF Demir, Ozlem Richards, Christopher Albin, John S. Shaban, Nadine M. Anderson, Brett D. Amaro, Rommie E. Harris, Reuben S. TI The Binding Interface between Human APOBEC3F and HIV-1 Vif Elucidated by Genetic and Computational Approaches SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Demir, Ozlem; Amaro, Rommie E.] Univ Calif San Diego, Chem & Biochem, La Jolla, CA 92093 USA. [Richards, Christopher; Albin, John S.; Shaban, Nadine M.; Anderson, Brett D.; Harris, Reuben S.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA. [Albin, John S.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 1902-Pos BP 385A EP 385A PG 1 WC Biophysics SC Biophysics GA DK7YE UT WOS:000375142200370 ER PT J AU Yuan, A Mourtada, R Elmore, DE Walensky, LD AF Yuan, Amy Mourtada, Rida Elmore, Donald E. Walensky, Loren D. TI Investigating the Relationship Between Helicity and Activity in Antimicrobial Peptides with Stabilized alpha-Helical Structures SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Yuan, Amy; Elmore, Donald E.] Wellesley Coll, Dept Chem, Wellesley, MA 02181 USA. [Mourtada, Rida] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Elmore, Donald E.] Wellesley Coll, Biochem Program, Wellesley, MA 02181 USA. [Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 2059-Pos BP 415A EP 416A PG 4 WC Biophysics SC Biophysics GA DK7YI UT WOS:000375142700029 ER PT J AU Radwanski, PB Ho, HT Liu, B Belevych, A Armoundas, A Dillmann, W Knollmann, B Mohler, P Hund, T Gyorke, S AF Radwanski, Przemysaw B. Ho, Hsiang-Ting Liu, Bin Belevych, Andriy Armoundas, Antonis Dillmann, Wolfgang Knollmann, Bjorn Mohler, Peter Hund, Thomas Gyorke, Sandor TI Catecholaminergic Stimulation of Neuronal Na+ Channels Accounts for Triggered Arrhythmia Mechanism in CPVT SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Radwanski, Przemysaw B.] Ohio State Univ, Pharm, Columbus, OH 43210 USA. [Ho, Hsiang-Ting; Liu, Bin; Belevych, Andriy; Mohler, Peter; Gyorke, Sandor] Ohio State Univ, Physiol, Columbus, OH 43210 USA. [Armoundas, Antonis] Massachusetts Gen Hosp, Charlestown, MA USA. [Dillmann, Wolfgang] Univ Calif San Diego, La Jolla, CA 92093 USA. [Knollmann, Bjorn] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Hund, Thomas] Ohio State Univ, Biomed Engn, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 2156-Pos BP 435A EP 435A PG 1 WC Biophysics SC Biophysics GA DK7YI UT WOS:000375142700125 ER PT J AU Jayakar, SS Zhou, XJ Savechenkov, PY Bruzik, KS Miller, KW Cohen, JB AF Jayakar, Selwyn S. Zhou, Xiaojuan Savechenkov, Pavel Y. Bruzik, Karol S. Miller, Keith W. Cohen, Jonathan B. TI Identifying GABA-A Receptor Modulators that Bind to Intersubunit Sites in the GABA-A Receptor Transmembrane Domain SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Jayakar, Selwyn S.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Zhou, Xiaojuan; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Savechenkov, Pavel Y.; Bruzik, Karol S.] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL USA. [Miller, Keith W.] Harvard Univ, Sch Med, Biol Chem & Mol Pharmacol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 2241-Pos BP 454A EP 455A PG 6 WC Biophysics SC Biophysics GA DK7YI UT WOS:000375142700210 ER PT J AU Chiara, DC Savechenkov, PY Zhou, XJ Desai, R Stern, AT Zhang, YH Forman, SA Bruzik, KS Miller, KW Cohen, JB AF Chiara, David C. Savechenkov, Pavel Y. Zhou, Xiaojuan Desai, Rooma Stern, Alex T. Zhang, Yinghui Forman, Stuart A. Bruzik, Karol S. Miller, Keith W. Cohen, Jonathan B. TI Interactions of a Photoreactive Steroid Anesthetic (F4N3-Alphaxalone) with Human alpha 1 beta 32 GABA-A Receptors SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Chiara, David C.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Neurobiol, Boston, MA USA. [Savechenkov, Pavel Y.; Bruzik, Karol S.] Univ Illinois, Med Chem & Pharmacognosy, Chicago, IL USA. [Zhou, Xiaojuan; Desai, Rooma; Stern, Alex T.; Zhang, Yinghui; Forman, Stuart A.; Miller, Keith W.] Massachusetts Gen Hosp, Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Miller, Keith W.] Harvard Univ, Sch Med, Biol Chem & Mol Pharmacol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 2242-Pos BP 455A EP 455A PG 1 WC Biophysics SC Biophysics GA DK7YI UT WOS:000375142700211 ER PT J AU Zhang, YH Sarver, JL Zhou, XJ Cafiso, DS Miller, KW AF Zhang, Yinghui Sarver, Jessica L. Zhou, Xiaojuan Cafiso, David S. Miller, Keith W. TI Pulsed Electron Paramagnetic Resonance of Spin Labeled Human GABA(A)Rs Functionally Reconstituted in Lipid Bilayers Suggests there is Space for Lipids between the Subunits SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Zhang, Yinghui; Zhou, Xiaojuan; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Sarver, Jessica L.; Cafiso, David S.] Univ Virginia, Dept Chem, Charlottesville, VA USA. [Sarver, Jessica L.; Cafiso, David S.] Univ Virginia, Ctr Membrane Biol, Charlottesville, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 2243-Pos BP 455A EP 455A PG 1 WC Biophysics SC Biophysics GA DK7YI UT WOS:000375142700212 ER PT J AU Nathwani, B Yang, D Wong, W Shih, WM AF Nathwani, Bhavik Yang, Darren Wong, Wesley Shih, William M. TI Multiplexed Mechanochemistry Assay - A Tool for Multiplexed Single Molecule Bond Rupture Force Studies SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Nathwani, Bhavik; Shih, William M.] Dana Farber Canc Inst, Canc Biol, Boston, MA 02115 USA. [Nathwani, Bhavik; Wong, Wesley; Shih, William M.] Harvard Univ, Sch Med, Biol Chem & Mol Pharmacol, Boston, MA USA. [Yang, Darren] Harvard Univ, Cambridge, MA 02138 USA. [Wong, Wesley] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 2470-Pos BP 501A EP 501A PG 1 WC Biophysics SC Biophysics GA DK7YI UT WOS:000375142700439 ER PT J AU Hardin, C Krishnan, R Del Gado, E AF Hardin, Corey Krishnan, Ramaswamy Del Gado, Emanuela TI Multi-Cellular Mechanical Regulation of Endothelial Permeability SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Hardin, Corey] Massachusetts Gen Hosp, Pulm & Critial Care, Boston, MA 02114 USA. [Krishnan, Ramaswamy] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA. [Del Gado, Emanuela] Georgetown Univ, Phys, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 3086-Pos BP 625A EP 625A PG 1 WC Biophysics SC Biophysics GA DK7YN UT WOS:000375143200148 ER PT J AU Yang, DR Ward, AR Halvorsen, K Wong, WP AF Yang, Darren Ward, Andrew R. Halvorsen, Ken Wong, Wesley P. TI Multiplexed Force Spectroscopy using DNA Nanoswitch a Centrifuge SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Yang, Darren] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Ward, Andrew R.; Wong, Wesley P.] Harvard Univ, Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ward, Andrew R.; Wong, Wesley P.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Halvorsen, Ken] SUNY Albany, RNA Inst, Albany, NY 12222 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 3135-Pos BP 635A EP 635A PG 1 WC Biophysics SC Biophysics GA DK7YN UT WOS:000375143200197 ER PT J AU Hudson, N Kim, J Springer, TA AF Hudson, Nathan Kim, Jongseong Springer, Timothy A. TI On-Rate Switching under Force Increases the Binding of von Willebrand Factor A1 to GPIb alpha SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Hudson, Nathan; Springer, Timothy A.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Hudson, Nathan; Springer, Timothy A.] Harvard Univ, Sch Med, Boston, MA USA. [Kim, Jongseong] Penn State Univ, Dept Chem, University Pk, PA USA. [Kim, Jongseong] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 3139-Pos BP 636A EP 636A PG 1 WC Biophysics SC Biophysics GA DK7YN UT WOS:000375143200201 ER PT J AU Procopio, MG Laszlo, C Dotto, GP AF Procopio, Maria-Giuseppina Laszlo, Csaba Dotto, G. Paolo TI CSL-p53: From senescence to CAF activation SO CELL CYCLE LA English DT Editorial Material DE CAF; Senescence; p53; CSL ID MULTIFOCAL EPITHELIAL TUMORS; FIELD CANCERIZATION; PRIMARY DETERMINANT; STROMA; CANCER; CSL C1 [Procopio, Maria-Giuseppina; Laszlo, Csaba; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Dotto, GP (reprint author), Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland.; Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. EM Paolo.Dotto@unil.ch NR 7 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD FEB 16 PY 2016 VL 15 IS 4 BP 485 EP 486 DI 10.1080/15384101.2015.1130091 PG 2 WC Cell Biology SC Cell Biology GA DG5ID UT WOS:000372110000004 PM 26735629 ER PT J AU Yae, T Tajima, K Maheswaran, S AF Yae, Toshifumi Tajima, Ken Maheswaran, Shyamala TI SETD1A induced miRNA network suppresses the p53 gene expression module SO CELL CYCLE LA English DT Editorial Material DE histone modification; EZH2; epigenetics; miRNA; BTG2; cancer; SETD1A; p53; cell cycle ID MECHANISMS C1 [Yae, Toshifumi; Tajima, Ken; Maheswaran, Shyamala] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc,Dept Surg, Charlestown, MA 02129 USA. [Yae, Toshifumi; Tajima, Ken; Maheswaran, Shyamala] Harvard Univ, Sch Med, Dept Surg, Charlestown, MA 02129 USA. RP Maheswaran, S (reprint author), MGH, Ctr Canc, 7214,Bldg 149,13th St, Charlestown, MA 02129 USA.; Maheswaran, S (reprint author), Harvard Univ, Sch Med, 7214,Bldg 149,13th St, Charlestown, MA 02129 USA. EM Maheswaran@helix.mgh.harvard.edu NR 7 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD FEB 16 PY 2016 VL 15 IS 4 BP 487 EP 488 DI 10.1080/15384101.2015.1130572 PG 2 WC Cell Biology SC Cell Biology GA DG5ID UT WOS:000372110000005 PM 26865005 ER PT J AU Sroubek, J Probst, V Mazzanti, A Delise, P Hevia, JC Ohkubo, K Zorzi, A Champagne, J Kostopoulou, A Yin, XY Napolitano, C Milan, DJ Wilde, A Sacher, F Borggrefe, M Ellinor, PT Theodorakis, G Nault, I Corrado, D Watanabe, I Antzelevitch, C Allocca, G Priori, SG Lubitz, SA AF Sroubek, Jakub Probst, Vincent Mazzanti, Andrea Delise, Pietro Castro Hevia, Jesus Ohkubo, Kimie Zorzi, Alessandro Champagne, Jean Kostopoulou, Anna Yin, Xiaoyan Napolitano, Carlo Milan, David J. Wilde, Arthur Sacher, Frederic Borggrefe, Martin Ellinor, Patrick T. Theodorakis, George Nault, Isabelle Corrado, Domenico Watanabe, Ichiro Antzelevitch, Charles Allocca, Giuseppe Priori, Silvia G. Lubitz, Steven A. TI Programmed Ventricular Stimulation for Risk Stratification in the Brugada Syndrome A Pooled Analysis SO CIRCULATION LA English DT Article DE death, sudden, cardiac; risk assessment; electrophysiology; arrhythmias, cardiac; Brugada syndrome ID WORLDWIDE PUBLISHED DATA; SUDDEN CARDIAC DEATH; ELECTRICAL-STIMULATION; TYPE-1 ELECTROCARDIOGRAM; CLINICAL CHARACTERISTICS; PROGNOSTIC VALUE; NATURAL-HISTORY; FIBRILLATION; METAANALYSIS; INDIVIDUALS AB Background- The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results- We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44-4.92, P < 0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05-0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01-2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58-3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98-9.58 for induced arrhythmia). Conclusions- In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features. C1 [Sroubek, Jakub] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Probst, Vincent] CHU Nantes, Hop Nord, Serv Cardiol, F-44035 Nantes 01, France. [Mazzanti, Andrea; Napolitano, Carlo; Priori, Silvia G.] IRCCS Fdn Salvatore Maugeri, Mol Cardiol, Pavia, Italy. [Priori, Silvia G.] Mol Univ Pavia, Dipartimento Med, Pavia, Italy. [Delise, Pietro] Casa Cura Pederzoli, Div Cardiol, Verona, Italy. [Castro Hevia, Jesus] Cardiovasc Surg & Cardiol Inst, Arrhythmia Unit, Havana, Cuba. [Ohkubo, Kimie; Watanabe, Ichiro] Nihon Univ, Sch Med, Dept Med, Div Cardiol, Tokyo, Japan. [Zorzi, Alessandro; Corrado, Domenico] Univ Padua, Dept Cardiac Thorac & Vasc Sci, Padua, Italy. [Champagne, Jean; Nault, Isabelle] Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Kostopoulou, Anna; Theodorakis, George] Onassis Cardiac Surg Ctr, Dept Electrophysiol & Pacing, Athens, Greece. [Yin, Xiaoyan] Boston Univ, Framingham, MA USA. [Yin, Xiaoyan] NHLBI, Framingham Heart Study, Framingham, MA USA. [Milan, David J.; Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, 55 Fruit St,GRB 109, Boston, MA 02114 USA. [Milan, David J.; Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. [Wilde, Arthur] Univ Amsterdam, Acad Med Ctr, Dept Clin & Expt Cardiol, Heart Ctr AMC, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Wilde, Arthur] Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia. [Sacher, Frederic] Bordeaux Univ Hosp, LIRYC Inst, INSERM 1045, Bordeaux, France. [Borggrefe, Martin] Univ Med Ctr Mannheim, Dept Med Cardiol 1, Mannheim, Germany. [Borggrefe, Martin] DZHK German Ctr Cardiovasc Res, Partner Site Heidelberg Mannheim, Mannheim, Germany. [Ellinor, Patrick T.; Lubitz, Steven A.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Allocca, Giuseppe] Gen Hosp Conegliano, Dept Cardiol, Treviso, Italy. [Antzelevitch, Charles] Lankenau Inst Med Res, Wynnewood, PA USA. RP Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 55 Fruit St,GRB 109, Boston, MA 02114 USA.; Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM slubitz@mgh.harvard.edu RI Napolitano, Carlo/K-4760-2016 OI Napolitano, Carlo/0000-0002-7643-4628 FU Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; National Institutes of Health/National Heart, Lung, and Blood Institute [K23HL114724, HL47678]; CARIPLO [2013-1019] FX Dr Lubitz is supported by Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 and National Institutes of Health/National Heart, Lung, and Blood Institute K23HL114724 Career Development Award. Dr Antzelevitch was supported by National Institutes of Health/National Heart, Lung, and Blood Institute HL47678. Dr Priori and Napolitano were supported by CARIPLO 2013-1019. None of the funding sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. NR 39 TC 8 Z9 8 U1 1 U2 5 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 FEB 16 PY 2016 VL 133 IS 7 BP 622 EP 630 DI 10.1161/CIRCULATIONAHA.115.017885 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DF0DV UT WOS:000371010100002 PM 26797467 ER PT J AU Hiratzka, LF Creager, MA Isselbacher, EM Svensson, LG Nishimura, RA Bonow, RO Guyton, RA Sundt, TM Halperin, JL Levine, GN Anderson, JL Albert, NM Al-Khatib, SM Birtcher, KK Bozkurt, B Brindis, RG Cigarroa, JE Curtis, LH Fleisher, LA Gentile, F Gidding, S Hlatky, MA Ikonomidis, J Joglar, J Kovacs, RJ Ohman, EM Pressler, SJ Sellke, FW Shen, WK Wijeysundera, DN AF Hiratzka, Loren F. Creager, Mark A. Isselbacher, Eric M. Svensson, Lars G. Nishimura, Rick A. Bonow, Robert O. Guyton, Robert A. Sundt, Thoralf M., III Halperin, Jonathan L. Levine, Glenn N. Anderson, Jeffrey L. Albert, Nancy M. Al-Khatib, Sana M. Birtcher, Kim K. Bozkurt, Biykem Brindis, Ralph G. Cigarroa, Joaquin E. Curtis, Lesley H. Fleisher, Lee A. Gentile, Federico Gidding, Samuel Hlatky, Mark A. Ikonomidis, John Joglar, Jose Kovacs, Richard J. Ohman, E. Magnus Pressler, Susan J. Sellke, Frank W. Shen, Win-Kuang Wijeysundera, Duminda N. CA Amer Coll Radiology Amer Assoc Thoracic Surg Amer Soc Echocardiography Amer Stroke Assoc Soc Cardiovasc Angiography & Inter Soc Vasc Med Soc CardiovascAnesthesiologists Soc Interventional Radiology Soc Thoracic Surgeons TI Surgery for Aortic Dilatation in Patients With Bicuspid Aortic Valves A Statement of Clarification From the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines SO CIRCULATION LA English DT Article DE thoracic aortic disease; heart valves; thoracic aortic aneurysm; AHA Scientific Statements; valvular heart disease; thoracic aortic dissection; anticoagulation therapy ID ASCENDING AORTA; TURNER-SYNDROME; DISSECTION; DISEASE; REPLACEMENT; DILATION AB Two guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and collaborating societies address the risk of aortic dissection in patients with bicuspid aortic valves and severe aortic enlargement: the "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease" (Circulation. 2010;121:e266-e369) and the "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease" (Circulation. 2014;129:e521-e643). However, the 2 guidelines differ with regard to the recommended threshold of aortic root or ascending aortic dilatation that would justify surgical intervention in patients with bicuspid aortic valves. The ACC and AHA therefore convened a subcommittee representing members of the 2 guideline writing committees to review the evidence, reach consensus, and draft a statement of clarification for both guidelines. This statement of clarification uses the ACC/AHA revised structure for delineating the Class of Recommendation and Level of Evidence to provide recommendations that replace those contained in Section 9.2.2.1 of the thoracic aortic disease guideline and Section 5.1.3 of the valvular heart disease guideline. C1 [Hiratzka, Loren F.] TriHlth Heart Inst, Cardiac Surg, Cincinnati, OH 45220 USA. [Nishimura, Rick A.] Mayo Clin, Div Cardiovasc Dis, Judd & Mary Morris Leighton, Med, Rochester, MN 55905 USA. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Heart & Vasc Ctr, Dartmouth, NS, Canada. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, Dartmouth, NS, Canada. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Med, Dartmouth, NS, Canada. [Guyton, Robert A.] Emory Healthcare, Div Cardiothorac Surg, Atlanta, GA USA. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [Isselbacher, Eric M.] Harvard Univ, Sch Med, Med, Cambridge, MA 02138 USA. [Svensson, Lars G.] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH USA. [Svensson, Lars G.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Surg, Cleveland, OH 44106 USA. [Bonow, Robert O.] Northwestern Univ, Feinberg Sch Med, Cardiol, Evanston, IL 60208 USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Sundt, Thoralf M., III] Harvard Univ, Sch Med, Surg, Cambridge, MA 02138 USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Med, New York, NY USA. RP Hiratzka, LF (reprint author), TriHlth Heart Inst, Cardiac Surg, Cincinnati, OH 45220 USA. EM kelle.ramsay@wolterskluwer.com NR 17 TC 4 Z9 4 U1 0 U2 6 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 FEB 16 PY 2016 VL 133 IS 7 BP 680 EP 686 DI 10.1161/CIR.0000000000000331 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DF0DV UT WOS:000371010100009 ER PT J AU Sumner, JA Kubzansky, LD Elkind, MSV Roberts, AL Agnew-Blais, J Chen, QX Cerda, M Rexrode, KM Rich-Edwards, JW Spiegelman, D Suglia, SF Rimm, EB Koenen, KC AF Sumner, Jennifer A. Kubzansky, Laura D. Elkind, Mitchell S. V. Roberts, Andrea L. Agnew-Blais, Jessica Chen, Qixuan Cerda, Magdalena Rexrode, Kathryn M. Rich-Edwards, Janet W. Spiegelman, Donna Suglia, Shakira F. Rimm, Eric B. Koenen, Karestan C. TI Response to Letter Regarding Article, "Trauma Exposure and Posttraumatic Stress Disorder Symptoms Predict Onset of Cardiovascular Events in Women" SO CIRCULATION LA English DT Letter ID DISEASE C1 [Sumner, Jennifer A.] Columbia Univ, Med Ctr, Ctr Behav Cardiovasc Hlth, New York, NY USA. [Sumner, Jennifer A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kubzansky, Laura D.; Roberts, Andrea L.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Elkind, Mitchell S. V.; Suglia, Shakira F.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Elkind, Mitchell S. V.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Agnew-Blais, Jessica] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat, London WC2R 2LS, England. [Chen, Qixuan] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Cerda, Magdalena] Univ Calif Davis, Med Ctr, Dept Emergency Med, Sacramento, CA 95817 USA. [Rexrode, Kathryn M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Rich-Edwards, Janet W.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 75 Francis St, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Dept Epidemiol, Boston, MA USA. [Rimm, Eric B.] Brigham & Womens Hosp, Harvard TH Chan Sch Publ Hlth, Dept Nutr, Dept Epidemiol,Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Rimm, Eric B.] Harvard Univ, Sch Med, Boston, MA USA. [Koenen, Karestan C.] Massachusetts Gen Hosp, Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Koenen, Karestan C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Koenen, Karestan C.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Sumner, JA (reprint author), Columbia Univ, Med Ctr, Ctr Behav Cardiovasc Hlth, New York, NY USA.; Sumner, JA (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. OI Rexrode, Kathryn/0000-0003-3387-8429 FU NCI NIH HHS [UM1 CA176726, UM1CA176726]; NHLBI NIH HHS [K01 HL130650, K01HL130650]; NIMH NIH HHS [R01 MH101269, R01MH101269-01A1] NR 5 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 16 PY 2016 VL 133 IS 7 BP E401 EP E402 DI 10.1161/CIRCULATIONAHA.115.020198 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DF0DW UT WOS:000371010200003 PM 26884627 ER PT J AU Gameiro, SR Malamas, AS Tsang, KY Ferrone, S Hodge, JW AF Gameiro, Sofia R. Malamas, Anthony S. Tsang, Kwong Y. Ferrone, Soldano Hodge, James W. TI Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells SO ONCOTARGET LA English DT Article DE vorinostat; entinostat; immunogenic modulation; antigen-processing machinery; histone deacetylases ID INDUCED IMMUNOGENIC MODULATION; SOLID TUMORS; HDAC INHIBITORS; CANCER CELLS; ENDOPLASMIC-RETICULUM; MONOCLONAL-ANTIBODIES; EPIGENETIC THERAPY; AGONIST EPITOPE; DOWN-REGULATION; FLOW-CYTOMETRY AB The clinical promise of cancer immunotherapy relies on the premise that the immune system can recognize and eliminate tumor cells identified as nonself. However, tumors can evade host immune surveillance through multiple mechanisms, including epigenetic silencing of genes involved in antigen processing and immune recognition. Hence, there is an unmet clinical need to develop effective therapeutic strategies that can restore tumor immune recognition when combined with immunotherapy, such as immune checkpoint blockade and therapeutic cancer vaccines. We sought to examine the potential of clinically relevant exposure of prostate and breast human carcinoma cells to histone deacetylase (HDAC) inhibitors to reverse tumor immune escape to T-cell mediated lysis. Here we demonstrate that prostate (LNCAP) and breast (MDA-MB-231) carcinoma cells are more sensitive to T-cell mediated lysis in vitro after clinically relevant exposure to epigenetic therapy with either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat. This pattern of immunogenic modulation was observed against a broad range of tumor-associated antigens, such as CEA, MUC1, PSA, and brachyury, and associated with augmented expression of multiple proteins involved in antigen processing and tumor immune recognition. Genetic and pharmacological inhibition studies identified HDAC1 as a key determinant in the reversal of carcinoma immune escape. Further, our findings suggest that the observed reversal of tumor immune evasion is driven by a response to cellular stress through activation of the unfolded protein response. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines. C1 [Gameiro, Sofia R.; Malamas, Anthony S.; Tsang, Kwong Y.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ferrone, Soldano] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 50 TC 4 Z9 5 U1 1 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 16 PY 2016 VL 7 IS 7 BP 7390 EP 7402 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DE0PD UT WOS:000370325900005 PM 26862729 ER PT J AU Wang, J Bi, WN Zhao, W Varghese, M Koch, RJ Walker, RH Chandraratna, RA Sanders, ME Janesick, A Blumberg, B Ward, L Ho, L Pasinetti, GM AF Wang, Jun Bi, Weina Zhao, Wei Varghese, Merina Koch, Rick J. Walker, Ruth H. Chandraratna, Roshantha A. Sanders, Martin E. Janesick, Amanda Blumberg, Bruce Ward, Libby Ho, Lap Pasinetti, Giulio M. TI Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease SO ONCOTARGET LA English DT Article DE brain bioavailable; dopaminergic; nuclear receptor related-1 protein; Parkinson's disease; retinoid X receptor; Gero-target ID CILIARY NEUROTROPHIC FACTOR; ORPHAN NUCLEAR RECEPTOR; GENE-EXPRESSION; TYROSINE-HYDROXYLASE; CANCER PREVENTION; DOPAMINE CELLS; NEURONS; TRANSCRIPTION; SURVIVAL; ACID AB Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPAR.. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) and attenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment. C1 [Wang, Jun; Bi, Weina; Zhao, Wei; Varghese, Merina; Ward, Libby; Ho, Lap; Pasinetti, Giulio M.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Wang, Jun; Pasinetti, Giulio M.] Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Koch, Rick J.; Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Chandraratna, Roshantha A.; Sanders, Martin E.] Io Therapeut Inc, Santa Ana, CA USA. [Janesick, Amanda; Blumberg, Bruce] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA USA. [Janesick, Amanda; Blumberg, Bruce] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA USA. RP Pasinetti, GM (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA.; Pasinetti, GM (reprint author), Geriatr Res Educ & Clin Ctr, Bronx, NY USA. EM giulio.pasinetti@mssm.edu OI Varghese, Merina/0000-0002-1517-3903 FU Io Therapeutics, Inc. FX This study was funded by Io Therapeutics, Inc., and we thank Drs. Chandraratna and Sanders for providing the IRX4204 compound for the study herein described. NR 46 TC 1 Z9 1 U1 2 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 16 PY 2016 VL 7 IS 7 BP 7469 EP 7479 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DE0PD UT WOS:000370325900011 PM 26862735 ER PT J AU Edderkaoui, M Xu, SP Chheda, C Morvaridi, S Hu, RW Grippo, PJ Mascarinas, E Principe, DR Knudsen, B Xue, J Habtezion, A Uyeminami, D Pinkerton, KE Pandol, SJ AF Edderkaoui, Mouad Xu, Shiping Chheda, Chintan Morvaridi, Susan Hu, Robert W. Grippo, Paul J. Mascarinas, Emman Principe, Daniel R. Knudsen, Beatrice Xue, Jing Habtezion, Aida Uyeminami, Dale Pinkerton, Kent E. Pandol, Stephen J. TI HDAC3 mediates smoking-induced pancreatic cancer SO ONCOTARGET LA English DT Article DE smoking; HDAC; pancreatic cancer ID EPITHELIAL-MESENCHYMAL TRANSITION; STELLATE CELLS; HISTONE DEACETYLASES; STEM-CELLS; T-CELLS; DIFFERENTIATION; INTERLEUKIN-6; MACROPHAGES; PROGRESSION; STATISTICS AB Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha. Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage. This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease. C1 [Edderkaoui, Mouad; Chheda, Chintan; Morvaridi, Susan; Hu, Robert W.; Knudsen, Beatrice; Pandol, Stephen J.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Edderkaoui, Mouad; Chheda, Chintan; Morvaridi, Susan; Hu, Robert W.; Knudsen, Beatrice; Pandol, Stephen J.] Cedars Sinai Med Ctr, Dept Biol Sci, Los Angeles, CA 90048 USA. [Edderkaoui, Mouad; Xu, Shiping; Pandol, Stephen J.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Edderkaoui, Mouad; Xu, Shiping; Pandol, Stephen J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Xu, Shiping] Peoples Liberat Army Gen Hosp, Nanlou Div, Dept Gastroenterol, Beijing, Peoples R China. [Grippo, Paul J.; Mascarinas, Emman; Principe, Daniel R.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Grippo, Paul J.; Mascarinas, Emman; Principe, Daniel R.] Univ Illinois, Dept Med, Chicago, IL USA. [Xue, Jing; Habtezion, Aida] Stanford Univ, Dept Med, Sch Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA. [Uyeminami, Dale; Pinkerton, Kent E.] Univ Calif Davis, Ctr Hlth & Environm, Davis, CA 95616 USA. RP Edderkaoui, M (reprint author), Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA.; Edderkaoui, M (reprint author), Cedars Sinai Med Ctr, Dept Biol Sci, Los Angeles, CA 90048 USA.; Edderkaoui, M (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA.; Edderkaoui, M (reprint author), Univ Calif Los Angeles, Los Angeles, CA USA. EM mouad.edderkaoui@cshs.org FU NIAAA [K01 AA019996, P50AA011999]; Hirshberg Foundation; NCI [P01CA163200]; Department of Veterans Affairs FX This work was supported by the NIAAA grant K01 AA019996 and the Hirshberg Foundation Award (to ME), the NCI grant P01CA163200, the NIAAA grant P50AA011999 and the Department of Veterans Affairs (to SJP). NR 41 TC 2 Z9 2 U1 2 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 16 PY 2016 VL 7 IS 7 BP 7747 EP 7760 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DE0PD UT WOS:000370325900030 PM 26745602 ER PT J AU Prasad, R Kappes, JC Katiyar, SK AF Prasad, Ram Kappes, John C. Katiyar, Santosh K. TI Inhibition of NADPH oxidase 1 activity and blocking the binding of cytosolic and membrane-bound proteins by honokiol inhibit migratory potential of melanoma cells SO ONCOTARGET LA English DT Article DE honokiol; melanoma; NADPH oxidase; cell migration; imaging ID IN-VIVO; CANCER CELLS; PHOSPHORYLATION; GROWTH; NOX1; SRC; EPIDEMIOLOGY; ACTIVATION; TRANSITION; EXPRESSION AB Overexpression of NADPH oxidase 1 (Nox1) in melanoma cells is often associated with increased migration/metastasis rate. To develop effective treatment options, we have examined the effect of honokiol, a phytochemical from Magnolia plant, on the migratory potential of human melanoma cell lines (A375, Hs294t, SK-Mel119 and SK-Mel28) and assessed whether Nox1 is the target. Using an in vitro cell migration assay, we observed that treatment of different melanoma cell lines with honokiol for 24 h resulted in a dose-dependent inhibition of cell migration that was associated with reduction in Nox1 expression and reduced levels of oxidative stress. Treatment of cells with N-acetyl-L-cysteine, an anti-oxidant, also inhibited the migration of melanoma cells. Treatment of cells with diphenyleneiodonium chloride, an inhibitor of Nox1, significantly decreased the migration ability of Hs294t and SK-Mel28 cells. Further, we examined the effect of honokiol on the levels of core proteins (p22(phox) and p47(phox)) of the NADPH oxidase complex. Treatment of Hs294t and SK-Mel28 cells with honokiol resulted in accumulation of the cytosolic p47(phox) protein and decreased levels of the membrane-bound p22(phox) protein, thus blocking their interaction and inhibiting Nox1 activation. Our in vivo bioluminescence imaging data indicate that oral administration of honokiol inhibited the migration/extravasation and growth of intravenously injected melanoma cells in internal body organs, such as liver, lung and kidney in nude mice, and that this was associated with an inhibitory effect on Nox1 activity in these internal organs/tissues. C1 [Prasad, Ram; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Environm Hlth Sci, Birmingham, AL USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Nutr Obes Res Ctr, Birmingham, AL USA. [Kappes, John C.; Katiyar, Santosh K.] Univ Alabama Birmingham, Comprehens Canc Ctr, Birmingham, AL USA. [Kappes, John C.; Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Katiyar, SK (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA.; Katiyar, SK (reprint author), Univ Alabama Birmingham, Environm Hlth Sci, Birmingham, AL USA.; Katiyar, SK (reprint author), Univ Alabama Birmingham, Nutr Obes Res Ctr, Birmingham, AL USA.; Katiyar, SK (reprint author), Univ Alabama Birmingham, Comprehens Canc Ctr, Birmingham, AL USA.; Katiyar, SK (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. EM skatiyar@uab.edu FU National Institutes of Health (NIH,) National Cancer Institute [CA166883]; Veterans Administration Merit Review Award [1I01BX001410]; Virology and Genetic Sequencing cores of the UAB Center for AIDS Research (CFAR) [P30-AI-27767] FX This work was supported by a grant from the National Institutes of Health (NIH, CA166883) National Cancer Institute (to S.K. Katiyar) and the Veterans Administration Merit Review Award (1I01BX001410) to S.K. Katiyar. The research also used the facilities supported by of the Virology and Genetic Sequencing cores of the UAB Center for AIDS Research (CFAR), P30-AI-27767. NR 31 TC 1 Z9 2 U1 2 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 16 PY 2016 VL 7 IS 7 BP 7899 EP 7912 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DE0PD UT WOS:000370325900041 PM 26760964 ER PT J AU Pfirschke, C Engblom, C Rickelt, S Cortez-Retamozo, V Garris, C Pucci, F Yamazaki, T Poirier-Colame, V Newton, A Redouane, Y Lin, YJ Wojtkiewicz, G Iwamoto, Y Mino-Kenudson, M Huynh, TG Hynes, RO Freeman, GJ Kroemer, G Zitvogel, L Weissleder, R Pittet, MJ AF Pfirschke, Christina Engblom, Camilla Rickelt, Steffen Cortez-Retamozo, Virna Garris, Christopher Pucci, Ferdinando Yamazaki, Takahiro Poirier-Colame, Vichnou Newton, Andita Redouane, Younes Lin, Yi-Jang Wojtkiewicz, Gregory Iwamoto, Yoshiko Mino-Kenudson, Mari Huynh, Tiffany G. Hynes, Richard O. Freeman, Gordon J. Kroemer, Guido Zitvogel, Laurence Weissleder, Ralph Pittet, Mikael J. TI Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy SO IMMUNITY LA English DT Article ID CANCER-THERAPY; PD-1 BLOCKADE; ANTICANCER THERAPIES; ANTITUMOR IMMUNITY; LUNG-CANCER; MOUSE MODEL; T-CELLS; IMMUNOTHERAPY; RESPONSES; MELANOMA AB Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs. C1 [Pfirschke, Christina; Engblom, Camilla; Cortez-Retamozo, Virna; Garris, Christopher; Pucci, Ferdinando; Newton, Andita; Redouane, Younes; Lin, Yi-Jang; Wojtkiewicz, Gregory; Iwamoto, Yoshiko; Weissleder, Ralph; Pittet, Mikael J.] Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA. [Pfirschke, Christina; Engblom, Camilla; Cortez-Retamozo, Virna; Garris, Christopher; Pucci, Ferdinando; Newton, Andita; Redouane, Younes; Lin, Yi-Jang; Wojtkiewicz, Gregory; Iwamoto, Yoshiko; Weissleder, Ralph; Pittet, Mikael J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Engblom, Camilla; Garris, Christopher] Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA 02115 USA. [Rickelt, Steffen; Hynes, Richard O.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Yamazaki, Takahiro; Poirier-Colame, Vichnou; Kroemer, Guido; Zitvogel, Laurence] Gustave Roussy Canc Campus, F-94805 Villejuif, France. [Mino-Kenudson, Mari; Huynh, Tiffany G.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. RP Pittet, MJ (reprint author), Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA.; Pittet, MJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu FU Samana Cay MGH Research Scholar Fund; NIH [P50-CA86355, R01-AI084880, U54-CA126515, 5U54CA163125, 5U54-CA163109]; Howard Hughes Medical Institute; Deutsche Forschungsgemeinschaft (DFG) [PF809/1-1]; Boehringer Ingelheim Fonds; DFG [RI2408/1-1] FX The authors thank the members of the Hope Babette Tang Histology Facility at the Koch Institute Swanson Biotechnology Center for technical support. This work was supported in part by the Samana Cay MGH Research Scholar Fund (to M.J.P.), NIH grants P50-CA86355 and R01-AI084880 (to M.J.P.), U54-CA126515 (to R.W.), 5U54CA163125 (to G.J.F.), and 5U54-CA163109 and the Howard Hughes Medical Institute (to R.O.H.). C.P. was supported by the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1, C.E. by the Boehringer Ingelheim Fonds, and S.R. by the DFG RI2408/1-1. NR 40 TC 30 Z9 30 U1 10 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 16 PY 2016 VL 44 IS 2 BP 343 EP 354 DI 10.1016/j.immuni.2015.11.024 PG 12 WC Immunology SC Immunology GA DE0DC UT WOS:000370294000016 PM 26872698 ER PT J AU Kuswanto, W Burzyn, D Panduro, M Wang, KK Jang, YC Wagers, AJ Benoist, C Mathis, D AF Kuswanto, Wilson Burzyn, Dalia Panduro, Marisella Wang, Kathy K. Jang, Young Charles Wagers, Amy J. Benoist, Christophe Mathis, Diane TI Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells SO IMMUNITY LA English DT Article ID FIBRO/ADIPOGENIC PROGENITORS; SATELLITE CELLS; IL-33; INFLAMMATION; REGENERATION; ALARMIN; INJURY; MACROPHAGES; POPULATION; MYOGENESIS AB Normal repair of skeletal muscle requires local expansion of a special population of Foxp3(+)CD4(+) regulatory T (Treg) cells. Such cells failed to accumulate in acutely injured muscle of old mice, known to undergo ineffectual repair. This defect reflected reduced recruitment of Treg cells to injured muscle, as well as less proliferation and retention therein. Interleukin-33 (IL-33) regulated muscle Treg cell homeostasis in young mice, and its administration to old mice ameliorated their deficits in Treg cell accumulation and muscle regeneration. The major IL-33-expressing cells in skeletal muscle displayed a constellation of markers diagnostic of fibro/adipogenic progenitor cells and were often associated with neural structures, including nerve fibers, nerve bundles, and muscle spindles, which are stretch-sensitive mechanoreceptors important for proprioception. IL-33(+) cells were more frequent after muscle injury and were reduced in old mice. IL-33 is well situated to relay signals between the nervous and immune systems within the muscle context. C1 [Kuswanto, Wilson; Burzyn, Dalia; Panduro, Marisella; Wang, Kathy K.; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Microbiol & Immunobiol, Boston, MA 02115 USA. [Jang, Young Charles; Wagers, Amy J.] Harvard Univ, Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Jang, Young Charles; Wagers, Amy J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Wagers, Amy J.] Harvard Univ, Sch Med, Paul F Glenn Ctr Biol Aging, Boston, MA 02115 USA. [Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Benoist, Christophe; Mathis, Diane] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Burzyn, Dalia] Jounce Therapeut Inc, Cambridge, MA 02138 USA. [Jang, Young Charles] Georgia Inst Technol, Atlanta, GA 30332 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Microbiol & Immunobiol, Boston, MA 02115 USA.; Mathis, D (reprint author), Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.; Mathis, D (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu FU JPB Foundation; NIH [R01DK092541, R01AG033053, U01HL100402, T32-GM007753, F30AG046045] FX We thank N. Asinovski, R. Cruse, K. Hattori, D. Jepson, A. Ortiz-Lopez, H. Paik, A. Rhoads, G. Buruzula, and J. LaVecchio for technical support; R. Lee for the ST2-flox mice; E. Estrella, and L. Kunkel for the human samples and for technical advice; and Drs. I. Chiu, A. Magnuson, J. Sanes, and B. Spiegelman for helpful discussions. This work was funded by the JPB Foundation and by NIH grants R01DK092541 to D.M. and R01AG033053 and U01HL100402 to A.J.W., who was also an Early Career Scientist at the Howard Hughes Institute. W.K. was supported by fellowships from the NIH (T32-GM007753 and F30AG046045). Cell sorting was performed under NIH P30DK036836. NR 39 TC 18 Z9 18 U1 5 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 16 PY 2016 VL 44 IS 2 BP 355 EP 367 DI 10.1016/j.immuni.2016.01.009 PG 13 WC Immunology SC Immunology GA DE0DC UT WOS:000370294000017 PM 26872699 ER PT J AU Kloverpris, HN Kazer, SW Mjosberg, J Mabuka, JM Wellmann, A Ndhlovu, Z Yadon, MC Nhamoyebonde, S Muenchhoff, M Simoni, Y Andersson, F Kuhn, W Garrett, N Burgers, WA Kamya, P Pretorius, K Dong, K Moodley, A Newell, EW Kasprowicz, V Karim, SSA Goulder, P Shalek, AK Walker, BD Ndung'u, T Leslie, A AF Kloverpris, Henrik N. Kazer, Samuel W. Mjosberg, Jenny Mabuka, Jenniffer M. Wellmann, Amanda Ndhlovu, Zaza Yadon, Marisa C. Nhamoyebonde, Shepherd Muenchhoff, Maximilian Simoni, Yannick Andersson, Frank Kuhn, Warren Garrett, Nigel Burgers, Wendy A. Kamya, Philomena Pretorius, Karyn Dong, Krista Moodley, Amber Newell, Evan W. Kasprowicz, Victoria Karim, Salim S. Abdool Goulder, Philip Shalek, Alex K. Walker, Bruce D. Ndung'u, Thumbi Leslie, Alasdair TI Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression SO IMMUNITY LA English DT Article ID SIV INFECTION; GASTROINTESTINAL-TRACT; T-CELLS; INFLAMMATION; IMMUNITY; VIRUS; ACTIVATION; FIBROSIS; DISEASE; TISSUES AB Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction. C1 [Kloverpris, Henrik N.; Mabuka, Jenniffer M.; Wellmann, Amanda; Yadon, Marisa C.; Nhamoyebonde, Shepherd; Kasprowicz, Victoria; Ndung'u, Thumbi; Leslie, Alasdair] Univ KwaZulu Natal UKZN, KwaZulu Natal Res Inst TB & HIV K RITH, ZA-4001 Durban, South Africa. [Kloverpris, Henrik N.] Univ Copenhagen, Dept Immunol & Microbiol, DK-2200 Copenhagen, Denmark. [Kazer, Samuel W.; Kamya, Philomena; Dong, Krista; Moodley, Amber; Shalek, Alex K.; Walker, Bruce D.; Ndung'u, Thumbi; Leslie, Alasdair] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. [Kazer, Samuel W.; Shalek, Alex K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Kazer, Samuel W.; Shalek, Alex K.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kazer, Samuel W.; Shalek, Alex K.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Mjosberg, Jenny] Karolinska Inst, Ctr Infect Med, S-17176 Stockholm, Sweden. [Ndhlovu, Zaza; Muenchhoff, Maximilian; Kamya, Philomena; Pretorius, Karyn; Goulder, Philip; Walker, Bruce D.; Ndung'u, Thumbi] UKZN, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4001 Durban, South Africa. [Muenchhoff, Maximilian; Goulder, Philip] Univ Oxford, Dept Paediat, Oxford OX1 3SY, England. [Simoni, Yannick; Newell, Evan W.] ASTAR, Singapore Immunol Network SIgN, Singapore 138632, Singapore. [Andersson, Frank] Inkosi Albert Luthuli Hosp, Dept Surg, ZA-4058 Durban, South Africa. [Kuhn, Warren] Stanger Hosp, ENT Dept, ZA-4450 Durban, South Africa. [Garrett, Nigel] UKZN, Dept Infect Dis, ZA-4001 Durban, South Africa. [Garrett, Nigel; Karim, Salim S. Abdool] CAPRISA, ZA-4001 Durban, South Africa. [Burgers, Wendy A.] Univ Cape Town, Div Med Virol, ZA-7925 Cape Town, South Africa. [Burgers, Wendy A.] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Karim, Salim S. Abdool] Columbia Univ, Dept Epidemiol, New York, NY 10027 USA. [Shalek, Alex K.] Harvard Univ, Sch Med, Div Hlth Sci & Technol, Cambridge, MA 02138 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. RP Kloverpris, HN (reprint author), Univ KwaZulu Natal UKZN, KwaZulu Natal Res Inst TB & HIV K RITH, ZA-4001 Durban, South Africa.; Kloverpris, HN (reprint author), Univ Copenhagen, Dept Immunol & Microbiol, DK-2200 Copenhagen, Denmark. EM henrik.kloverpris@k-rith.org FU Danish Agency for Science, Technology and Innovation [12-132295]; Lundbeck Foundation [R151-2013-14624]; MAERSK Foundation; Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation; NIH [AI067073]; Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative (IAVI) [UKZNRSA1001]; NIAID [R37AI067073]; International Early Career Scientist Award from the Howard Hughes Medical Institute; Victor Daitz Foundation; National Science Foundation Graduate Research Fellowship Program (NSF GRFP); Searle Scholars Program; South African Research Chairs Initiative FX Funding was provided by The Danish Agency for Science, Technology and Innovation (grant #12-132295), Lundbeck Foundation (grant #R151-2013-14624), and MAERSK Foundation (all to H.N.K.); by the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation and NIH grant AI067073 (both to B.D.W.); by partial support from the Bill and Melinda Gates Foundation, the International AIDS Vaccine Initiative (IAVI) (UKZNRSA1001), and the NIAID (R37AI067073); by The South African Research Chairs Initiative, an International Early Career Scientist Award from the Howard Hughes Medical Institute, and the Victor Daitz Foundation (all to T.N.); by The National Science Foundation Graduate Research Fellowship Program (NSF GRFP) (to S.W.K.); and by The Searle Scholars Program(A.K.S.). We thank Dr. HollisShen for extensive support during cell sorting; all "iThimba," "Gateway,'' "CAPRISA002/004,'' and "FRESH'' Acute Infection Study participants; the supportive role of the CAPRISA002/004 studies; Carly G.K. Ziegler and Travis K. Hughes (from the A.K.S. lab) for help on analysis of the RNA-seq data; and NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH, for alpha 4 beta 7 monoclonal antibody (cat# 11718) from Dr. A.A. Ansari. NR 39 TC 16 Z9 16 U1 4 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 16 PY 2016 VL 44 IS 2 BP 391 EP 405 DI 10.1016/j.immuni.2016.01.006 PG 15 WC Immunology SC Immunology GA DE0DC UT WOS:000370294000020 PM 26850658 ER PT J AU Putman, RK Hatabu, H Araki, T Gudmundsson, G Gao, W Nishino, M Okajima, Y Dupuis, J Latourelle, JC Cho, MH El-Chemaly, S Coxson, HO Celli, BR Fernandez, IE Zazueta, OE Ross, JC Harmouche, R Estepar, RSJ Diaz, AA Sigurdsson, S Gudmundsson, EF Eiriksdottir, G Aspelund, T Budoff, MJ Kinney, GL Hokanson, JE Williams, MC Murchison, JT MacNee, W Hoffmann, U O'Donnell, CJ Launer, LJ Harrris, TB Gudnason, V Silverman, EK O'Connor, GT Washko, GR Rosas, IO Hunninghake, GM AF Putman, Rachel K. Hatabu, Hiroto Araki, Tetsuro Gudmundsson, Gunnar Gao, Wei Nishino, Mizuki Okajima, Yuka Dupuis, Josee Latourelle, Jeanne C. Cho, Michael H. El-Chemaly, Souheil Coxson, Harvey O. Celli, Bartolome R. Fernandez, Isis E. Zazueta, Oscar E. Ross, James C. Harmouche, Rola Estepar, Raul San Jose Diaz, Alejandro A. Sigurdsson, Sigurdur Gudmundsson, Elias F. Eiriksdottir, Gudny Aspelund, Thor Budoff, Matthew J. Kinney, Gregory L. Hokanson, John E. Williams, Michelle C. Murchison, John T. MacNee, William Hoffmann, Udo O'Donnell, Christopher J. Launer, Lenore J. Harrris, Tamara B. Gudnason, Vilmundur Silverman, Edwin K. O'Connor, George T. Washko, George R. Rosas, Ivan O. Hunninghake, Gary M. CA ECLIPSE Investigator COPDGene Investigator TI Association Between Interstitial Lung Abnormalities and All-Cause Mortality SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; MUC5B PROMOTER POLYMORPHISM; EXERCISE CAPACITY; DISEASE; SUSCEPTIBILITY; EPIDEMIOLOGY; PREVALENCE AB IMPORTANCE Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. OBJECTIVE To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005 -December 2006). EXPOSURES Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1]to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1]to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation. C1 [Putman, Rachel K.; Cho, Michael H.; El-Chemaly, Souheil; Celli, Bartolome R.; Fernandez, Isis E.; Zazueta, Oscar E.; Harmouche, Rola; Diaz, Alejandro A.; Silverman, Edwin K.; Washko, George R.; Rosas, Ivan O.; Hunninghake, Gary M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Pulm & Crit Care Div, Boston, MA 02115 USA. [Hatabu, Hiroto; Nishino, Mizuki; Okajima, Yuka; Estepar, Raul San Jose] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Hatabu, Hiroto; Araki, Tetsuro; Nishino, Mizuki; Washko, George R.; Hunninghake, Gary M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Pulm Funct Imaging, Boston, MA 02115 USA. [Gudmundsson, Gunnar] Univ Iceland, Landspital Univ Hosp, Dept Resp Med & Sleep, Reykjavik, Iceland. [Gao, Wei; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Okajima, Yuka] St Lukes Int Hosp, Dept Radiol, Tokyo, Japan. [Dupuis, Josee; O'Donnell, Christopher J.; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Latourelle, Jeanne C.; O'Connor, George T.] Boston Univ, Dept Med, Ctr Pulm, Boston, MA 02215 USA. [Latourelle, Jeanne C.] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Cho, Michael H.; Ross, James C.; Silverman, Edwin K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Coxson, Harvey O.] Univ British Columbia, Dept Radiol, Vancouver, BC, Canada. [Fernandez, Isis E.] Univ Munich, Univ Hosp Grosshadern, Comprehens Pneumol Ctr, Munich, Germany. [Fernandez, Isis E.] German Ctr Lung Res, Helmholtz Zentrum Munchen, Munich, Germany. [Ross, James C.; Harmouche, Rola; Estepar, Raul San Jose] Brigham & Womens Hosp, Dept Radiol, Surg Planning Lab, 75 Francis St, Boston, MA 02115 USA. [Sigurdsson, Sigurdur; Gudmundsson, Elias F.; Eiriksdottir, Gudny; Aspelund, Thor; Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Budoff, Matthew J.] Harbor UCLA, Los Angeles Biomed Res Inst, Dept Med, Torrance, CA USA. [Kinney, Gregory L.; Hokanson, John E.] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Denver, CO USA. [Williams, Michelle C.] Univ Edinburgh, British Heart Fdn Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Murchison, John T.] Univ Edinburgh, Royal Infirm Edinburgh, Edinburgh, Midlothian, Scotland. [MacNee, William] Univ Edinburgh, Ctr Inflammat Res, Edinburgh, Midlothian, Scotland. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Cardiovasc Epidemiol & Human Genom Branch, Bethesda, MD 20892 USA. [Launer, Lenore J.; Harrris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Rosas, IO (reprint author), Brigham & Womens Hosp, Pulm & Crit Care Div, 75 Francis St, Boston, MA 02115 USA. EM irosas@rics.bwh.harvard.edu RI Coxson, Harvey/A-9861-2017; OI Coxson, Harvey/0000-0001-5750-9711; MacNee, William/0000-0002-3692-1448 FU National Institutes of Health (NIH) [T32 HL007633]; Icelandic Research Fund [141513-051]; Landspitali Scientific Fund [A-2015-030]; National Cancer Institute grant [1K23CA157631]; NIH [K08 HL097029, R01 HL113264, R21 HL119902, K25 HL104085, R01 HL116931, R01 HL116473, K01 HL118714, R01 HL089897, R01 HL089856, N01-AG-1-2100, HHSN27120120022C, P01 HL105339, P01 HL114501, R01 HL107246, R01 HL122464, R01 HL111024]; National Heart, Lung, and Blood Institute's Framingham Heart Study contract [N01-HC-2519.5]; GlaxoSmithKline [NCT00292552, 5C0104960]; National Institute on Aging (NIA) grant [27120120022C]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NIA [27120120022C] FX Dr Putman is supported by a National Institutes of Health (NIH) grant (T32 HL007633). Dr Gudmundsson is supported by a project grant from the Icelandic Research Fund (141513-051) and from the Landspitali Scientific Fund (A-2015-030). Dr Nishino is supported by a National Cancer Institute grant (1K23CA157631). Dr Cho is supported by 2 NIH grants (K08 HL097029 and R01 HL113264). Dr EI-Chemaly is supported by an NIH grant (R21 HL119902). Dr San Jose Estepar is supported by 3 NIH grants (K25 HL104085, R01 HL116931, and R01 HL116473). Dr Diaz is supported by an NIH grant (K01 HL118714). This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study contract (N01-HC-2519.5). COPDGene is supported by 2 NIH grants (R01 HL089897 and R01 HL089856). The ECLIPSE study was sponsored by GlaxoSmithKline (NCT00292552; GSK code 5C0104960). The AGES (Age, Gene/Environment Susceptibility)-Reykjavik study was supported by a National Institute on Aging (NIA) grant (27120120022C), 2 NIH contracts (N01-AG-1-2100 and HHSN27120120022C), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Dr Gudnason is supported by an NIA grant (27120120022C) and an Icelandic Research Fund project grant (141513-051). Dr Silverman is supported by 3 NIH grants (R01 HL089856, P01 HL105339, and P01 HL114501). Dr Washko is supported by 3 NIH grants (R01 HL107246, R01 HL116473, and R01 HL122464). Dr Rosas is supported by an NIH grant (P01 HL114501). Dr Hunninghake and this study are supported by 2 NIH grants (P01 HL114501 and R01 HL111024) and a project grant from the Icelandic Research Fund (141513-051). NR 34 TC 13 Z9 13 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 16 PY 2016 VL 315 IS 7 BP 672 EP 681 DI 10.1001/jama.2016.0518 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DD8JB UT WOS:000370171500013 PM 26881370 ER PT J AU Bae, E Cohen, JM Grudberg, SC AF Bae, Edward Cohen, Jeffrey M. Grudberg, Sarah C. TI Hyperpigmented Reticulated Patch in an Older Man SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ERYTHEMA-AB-IGNE; ABIGNE C1 [Bae, Edward] Boston Univ, Sch Med, Boston, MA 02118 USA. [Cohen, Jeffrey M.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Cohen, Jeffrey M.; Grudberg, Sarah C.] Harvard Univ, Sch Med, Boston, MA USA. [Grudberg, Sarah C.] Boston VA HealthCare Syst, Dept Med, 1400 Vet Foreign Wars Pkwy, Boston, MA 02132 USA. RP Grudberg, SC (reprint author), Boston VA HealthCare Syst, Dept Med, 1400 Vet Foreign Wars Pkwy, Boston, MA 02132 USA. EM sarah.grudberg@va.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 16 PY 2016 VL 315 IS 7 BP 699 EP 700 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DD8JB UT WOS:000370171500017 PM 26881374 ER PT J AU Miglioretti, DL Lange, J van den Broek, JJ Lee, CI van Ravesteyn, NT Ritley, D Kerlikowske, K Fenton, JJ Melnikow, J de Koning, HJ Hubbard, RA AF Miglioretti, Diana L. Lange, Jane van den Broek, Jeroen J. Lee, Christoph I. van Ravesteyn, Nicolien T. Ritley, Dominique Kerlikowske, Karla Fenton, Joshua J. Melnikow, Joy de Koning, Harry J. Hubbard, Rebecca A. TI Radiation-Induced Breast Cancer Incidence and Mortality From Digital Mammography Screening A Modeling Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID UNITED-STATES; TOMOSYNTHESIS; RISK; ACCURACY; OBESITY; TRIAL AB Background: Estimates of risk for radiation-induced breast cancer from mammography screening have not considered variation in dose exposure or diagnostic work-up after abnormal screening results. Objective: To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening while considering exposure from screening and diagnostic mammography and dose variation among women. Design: 2 simulation-modeling approaches. Setting: U.S. population. Patients: Women aged 40 to 74 years. Intervention: Annual or biennial digital mammography screening from age 40, 45, or 50 years until age 74 years. Measurements: Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality (harms) per 100 000 women screened. Results: Annual screening of 100 000 women aged 40 to 74 years was projected to induce 125 breast cancer cases (95% CI, 88 to 178) leading to 16 deaths (CI, 11 to 23), relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 cases of radiation-induced breast cancer leading to 32 deaths per 100 000 women. Women with large breasts requiring extra views for complete examination (8% of population) were projected to have greater radiation-induced breast cancer risk (266 cancer cases and 35 deaths per 100 000 women) than other women (113 cancer cases and 15 deaths per 100 000 women). Biennial screening starting at age 50 years reduced risk for radiation-induced cancer 5-fold. Limitation: Life-years lost from radiation-induced breast cancer could not be estimated. Conclusion: Radiation-induced breast cancer incidence and mortality from digital mammography screening are affected by dose variability from screening, resultant diagnostic work-up, initiation age, and screening frequency. Women with large breasts may have a greater risk for radiation-induced breast cancer. C1 [Miglioretti, Diana L.] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, One Shields Ave,Med Sci Bldg 1C,Room 144, Davis, CA 95616 USA. [Lange, Jane] Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. [van den Broek, Jeroen J.; van Ravesteyn, Nicolien T.; de Koning, Harry J.] Erasmus MC Univ, Med Ctr Rotterdam, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. [Lee, Christoph I.] Univ Washington, Sch Med, Dept Radiol, 825 Eastlake Ave East,G3-200, Seattle, WA 98109 USA. [Ritley, Dominique; Fenton, Joshua J.; Melnikow, Joy] Univ Calif Davis, Ctr Hlth Care Policy & Res, 2103 Stockton Blvd, Sacramento, CA 95817 USA. [Kerlikowske, Karla] San Francisco VA Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. [Hubbard, Rebecca A.] Univ Penn, Dept Biostat & Epidemiol, 604 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. RP Miglioretti, DL (reprint author), Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, One Shields Ave,Med Sci Bldg 1C,Room 144, Davis, CA 95616 USA. EM dmiglioretti@ucdavis.edu FU Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute FX Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute. NR 42 TC 8 Z9 8 U1 2 U2 6 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 FEB 16 PY 2016 VL 164 IS 4 BP 205 EP + DI 10.7326/M15-1241 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DD7WK UT WOS:000370135300011 PM 26756460 ER PT J AU Mandelblatt, JS Stout, NK Schechter, CB van den Broek, JJ Miglioretti, DL Krapcho, M Trentham-Dietz, A Munoz, D Lee, SJ Berry, DA van Ravesteyn, NT Alagoz, O Kerlikowske, K Tosteson, ANA Near, AM Hoeffken, A Chang, YJ Heijnsdijk, EA Chisholm, G Huang, XL Huang, H Ergun, MA Gangnon, R Sprague, BL Plevritis, S Feuer, E de Koning, HJ Cronin, KA AF Mandelblatt, Jeanne S. Stout, Natasha K. Schechter, Clyde B. van den Broek, Jeroen J. Miglioretti, Diana L. Krapcho, Martin Trentham-Dietz, Amy Munoz, Diego Lee, Sandra J. Berry, Donald A. van Ravesteyn, Nicolien T. Alagoz, Oguzhan Kerlikowske, Karla Tosteson, Anna N. A. Near, Aimee M. Hoeffken, Amanda Chang, Yaojen Heijnsdijk, Eveline A. Chisholm, Gary Huang, Xuelin Huang, Hui Ergun, Mehmet Ali Gangnon, Ronald Sprague, Brian L. Plevritis, Sylvia Feuer, Eric de Koning, Harry J. Cronin, Kathleen A. TI Collaborative Modeling of the Benefits and Harms Associated With Different US Breast Cancer Screening Strategies SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID AGE 40 YEARS; RANDOMIZED CONTROLLED-TRIAL; COST-EFFECTIVENESS ANALYSIS; UNITED-STATES; FOLLOW-UP; COMMUNITY PRACTICE; MENOPAUSAL STATUS; DENSE BREASTS; MAMMOGRAPHY; RISK AB Background: Controversy persists about optimal mammography screening strategies. Objective: To evaluate screening outcomes, taking into account advances in mammography and treatment of breast cancer. Design: Collaboration of 6 simulation models using national data on incidence, digital mammography performance, treatment effects, and other-cause mortality. Setting: United States. Patients: Average-risk U.S. female population and subgroups with varying risk, breast density, or comorbidity. Intervention: Eight strategies differing by age at which screening starts (40, 45, or 50 years) and screening interval (annual, biennial, and hybrid [annual for women in their 40s and biennial thereafter]). All strategies assumed 100% adherence and stopped at age 74 years. Measurements: Benefits (breast cancer-specific mortality reduction, breast cancer deaths averted, life-years, and quality adjusted life-years); number of mammograms used; harms (false-positive results, benign biopsies, and overdiagnosis); and ratios of harms (or use) and benefits (efficiency) per 1000 screens. Results: Biennial strategies were consistently the most efficient for average-risk women. Biennial screening from age 50 to 74 years avoided a median of 7 breast cancer deaths versus no screening; annual screening from age 40 to 74 years avoided an additional 3 deaths, but yielded 1988 more false-positive results and 11 more overdiagnoses per 1000 women screened. Annual screening from age 50 to 74 years was inefficient (similar benefits, but more harms than other strategies). For groups with a 2 to 4-fold increased risk, annual screening from age 40 years had similar harms and benefits as screening average-risk women biennially from 50 to 74 years. For groups with moderate or severe comorbidity, screening could stop at age 66 to 68 years. Limitation: Other imaging technologies, polygenic risk, and nonadherence were not considered. Conclusion: Biennial screening for breast cancer is efficient for average-risk populations. Decisions about starting ages and intervals will depend on population characteristics and the decision makers' weight given to the harms and benefits of screening. C1 [Mandelblatt, Jeanne S.] Lombardi Comprehens Canc Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. [Stout, Natasha K.] Harvard Univ, Sch Med, Dept Populat Med, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. [Stout, Natasha K.] Harvard Pilgrim Hlth Care Inst, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. [Schechter, Clyde B.] Albert Einstein Coll Med, Dept Family & Social Med, 1300 Morris Pk Ave,Black Bldg 406, Bronx, NY 10461 USA. [van den Broek, Jeroen J.; van Ravesteyn, Nicolien T.; Heijnsdijk, Eveline A.; de Koning, Harry J.] Univ Med Ctr Rotterdam, Erasmus MC, POB 2040, NL-3000 CA Rotterdam, Netherlands. [Miglioretti, Diana L.] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, One Shields Ave,Med Sci 1C,Room 145, Davis, CA 95616 USA. [Krapcho, Martin] Information Management Serv Inc, 3901 Calverton Blvd,Suite 200, Calverton, MD 20705 USA. [Trentham-Dietz, Amy] Univ Wisconsin, Carbone Canc Ctr, 610 Walnut St,WARE Room 307, Madison, WI 53726 USA. [Munoz, Diego] Stanford Univ, 318 Campus Dr,Room S255, Stanford, CA 94305 USA. [Lee, Sandra J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Mailstop CLS11007,450 Brookline Ave, Boston, MA 02215 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, 1400 Pressler St,4-5062 Pickens Acad Tower, Houston, TX 77030 USA. [Alagoz, Oguzhan] Univ Wisconsin, 1513 Univ Ave, Madison, WI 53706 USA. [Kerlikowske, Karla] Vet Affairs Med Ctr 111A1, 4150 Clement St, San Francisco, CA 94121 USA. [Tosteson, Anna N. A.] Geisel Sch Med Dartmouth, One Med Ctr Dr HB7505, Lebanon, NH 03756 USA. [Near, Aimee M.; Chang, Yaojen] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. [Chisholm, Gary] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Unit 1362,POB 301439, Houston, TX 77230 USA. [Huang, Xuelin] Univ Texas MD Anderson Canc Ctr, 1400 Pressler St,Unit 1411,POB 301402, Houston, TX 77230 USA. [Huang, Hui] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Ergun, Mehmet Ali] Univ Wisconsin, 3233 Mech Engn Bldg,1513 Univ Ave, Madison, WI 53706 USA. [Gangnon, Ronald] Univ Wisconsin, Dept Populat Hlth Sci, 610 Walnut St, Madison, WI 53726 USA. [Sprague, Brian L.] Univ Vermont, Off Hlth Promot Res, 1 South Prospect St, Burlington, VT 05401 USA. [Plevritis, Sylvia] Stanford Univ, James H Clark Ctr, Dept Radiol, Room S255,MC 5442,318 Campus Dr, Stanford, CA 94305 USA. [Feuer, Eric; Cronin, Kathleen A.] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9765,Room 4E534, Bethesda, MD 20892 USA. RP Mandelblatt, JS (reprint author), Lombardi Comprehens Canc Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. EM mandelbj@georgetown.edu FU National Institutes of Health FX National Institutes of Health. NR 75 TC 14 Z9 14 U1 8 U2 13 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 16 PY 2016 VL 164 IS 4 BP 215 EP + DI 10.7326/M15-1536 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA DD7WK UT WOS:000370135300012 PM 26756606 ER PT J AU Nelson, HD O'Meara, ES Kerlikowske, K Balch, S Miglioretti, D AF Nelson, Heidi D. O'Meara, Ellen S. Kerlikowske, Karla Balch, Steven Miglioretti, Diana TI Factors Associated With Rates of False-Positive and False -Negative Results From Digital Mammography Screening: An Analysis of Registry Data SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SERVICES TASK-FORCE; BREAST-CANCER RISK; UNITED-STATES; COMMUNITY PRACTICE; HORMONE-THERAPY; WOMEN; TOMOSYNTHESIS; US; DENSITY; RECOMMENDATION AB Background: Women screened with digital mammography may receive false-positive and false-negative results and subsequent imaging and biopsies. How these outcomes vary by age, time since the last screening, and individual risk factors is unclear. Objective: To determine factors associated with false-positive and false-negative digital mammography results, additional imaging, and biopsies among a general population of women screened for breast cancer. Design: Analysis of registry data. Setting: Participating facilities at 5 U.S. Breast Cancer Surveillance Consortium breast imaging registries with linkages to pathology databases and tumor registries. Patients: 405 191 women aged 40 to 89 years screened with digital mammography between 2003 and 2011. A total of 2963 were diagnosed with invasive cancer or ductal carcinoma in situ within 12 months of screening. Measurements: Rates of false-positive and false-negative results and recommendations for additional imaging and biopsies from a single screening round; comparisons by age, time since the last screening, and risk factors. Results: Rates of false-positive results (121.2 per 1000 women [95% Cl, 105.6 to 138.7]) and recommendations for additional imaging (124.9 per 1000 women [Cl, 109.3 to 142.3]) were highest among women aged 40 to 49 years and decreased with increasing age. Rates of false-negative results (1.0 to 1.5 per 1000 women) and recommendations for biopsy (15.6 to 17.5 per 1000 women) did not differ greatly by age. Results did not differ by time since the last screening. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index. Limitations: Confounding by variation in patient-level characteristics and outcomes across registries and regions may have been present. Some factors, such as numbers of first- and second-degree relatives with breast cancer and diagnoses associated with previous benign biopsy results, were not examined. Conclusion: False-positive mammography results and additional imaging are common, particularly for younger women and those with risk factors, whereas biopsies occur less often. Rates of false-negative results are low. C1 [Nelson, Heidi D.] Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code BICC, Portland, OR 97239 USA. [O'Meara, Ellen S.; Balch, Steven] Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. [Kerlikowske, Karla] VAMC 111A1, San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. [Miglioretti, Diana] Univ Calif Davis, 1 Shields Ave,Med Sci 1C,Room 145, Davis, CA 95616 USA. RP Nelson, HD (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code BICC, Portland, OR 97239 USA. EM nelsonh@ohsu.edu FU Agency for Healthcare Research and Quality; National Cancer Institute FX Agency for Healthcare Research and Quality and National Cancer Institute. NR 42 TC 10 Z9 10 U1 1 U2 8 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 16 PY 2016 VL 164 IS 4 BP 226 EP + DI 10.7326/M15-0971 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA DD7WK UT WOS:000370135300013 PM 26756902 ER PT J AU Siu, AL Bibbins-Domingo, K Grossman, DC Baumann, LC Davidson, KW Ebell, M Garcia, FAR Gillman, M Herzstein, J Kemper, AR Krist, AH Kurth, AE Owens, DK Phillips, WR Phipps, MG Pignone, MP LeFevre, M AF Siu, Albert L. Bibbins-Domingo, Kirsten Grossman, David C. Baumann, Linda Ciofu Davidson, Karina W. Ebell, Mark Garcia, Francisco A. R. Gillman, Matthew Herzstein, Jessica Kemper, Alex R. Krist, Alex H. Kurth, Ann E. Owens, Douglas K. Phillips, William R. Phipps, Maureen G. Pignone, Michael P. LeFevre, Michael CA US Preventive Serv Task Force TI Screening for Breast Cancer: US Preventive Services Task Force Recommendation Statement (Retracted article. See vol. 164, pg. 448, 2016) SO ANNALS OF INTERNAL MEDICINE LA English DT Article; Retracted Publication ID CARCINOMA IN-SITU; DIGITAL MAMMOGRAPHY; FILM MAMMOGRAPHY; TOMOSYNTHESIS; WOMEN; DENSITY; RISK; RACE; AGE; OVERDIAGNOSIS AB Description: Update of the 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for breast cancer. Methods: The USPSTF reviewed the evidence on the following: effectiveness of breast cancer screening in reducing breast cancer-specific and all-cause mortality, as well as the incidence of advanced breast cancer and treatment-related morbidity; harms of breast cancer screening; test performance characteristics of digital breast tomosynthesis as a primary screening strategy; and adjunctive screening in women with increased breast density. In addition, the USPSTF reviewed comparative decision models on optimal starting and stopping ages and intervals for screening mammography; how breast density, breast cancer risk, and comorbidity level affect the balance of benefit and harms of screening mammography; and the number of radiation-induced breast cancer cases and deaths associated with different screening mammography strategies over the course of a woman's lifetime. Population: This recommendation applies to asymptomatic women aged 40 years or older who do not have preexisting breast cancer or a previously diagnosed high-risk breast lesion and who are not at high risk for breast cancer because of a known underlying genetic mutation (such as a BRCA1 or BRCA2 gene mutation or other familial breast cancer syndrome) or a history of chest radiation at a young age. Recommendations: The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. (B recommendation) The decision to start screening mammography in women prior to age 50 years should be an individual one. Women who place a higher value on the potential benefit than the potential harms may choose to begin biennial screening between the ages of 40 and 49 years. (C recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women aged 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging (MRI), DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram. (I statement) C1 [Siu, Albert L.] Mt Sinai Sch Med, New York, NY USA. [Siu, Albert L.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grossman, David C.] Grp Hlth Res Inst, Seattle, WA USA. [Baumann, Linda Ciofu] Univ Wisconsin, Madison, WI USA. [Davidson, Karina W.] Columbia Univ, New York, NY USA. [Ebell, Mark] Univ Georgia, Athens, GA 30602 USA. [Garcia, Francisco A. R.] Pima Cty Dept Hlth, Tucson, AZ USA. [Gillman, Matthew] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gillman, Matthew] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Kemper, Alex R.] Duke Univ, Durham, NC USA. [Krist, Alex H.] Virginia Commonwealth Univ, Richmond, VA USA. [Kurth, Ann E.] NYU, New York, NY USA. [Owens, Douglas K.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Owens, Douglas K.] Stanford Univ, Stanford, CA 94305 USA. [Phillips, William R.] Univ Washington, Seattle, WA 98195 USA. [Phipps, Maureen G.] Brown Univ, Providence, RI 02912 USA. [Pignone, Michael P.] Univ N Carolina, Chapel Hill, NC USA. [LeFevre, Michael] Univ Missouri, Columbia, MO USA. RP Siu, AL (reprint author), Mt Sinai Sch Med, New York, NY USA.; Siu, AL (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY USA. FU U.S. Congress mandates that the Agency for Healthcare Research and Quality FX The USPSTF is an independent, voluntary body. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. NR 59 TC 63 Z9 64 U1 9 U2 21 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 FEB 16 PY 2016 VL 164 IS 4 BP 279 EP + DI 10.7326/M15-2886 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA DD7WK UT WOS:000370135300018 PM 26757170 ER PT J AU Heapy, AA Higgins, DM LaChappelle, KM Kirlin, J Goulet, JL Czlapinski, RA Buta, E Piette, JD Krein, SL Richardson, CR Kerns, RD AF Heapy, Alicia A. Higgins, Diana M. LaChappelle, Kathryn M. Kirlin, Joseph Goulet, Joseph L. Czlapinski, Rebecca A. Buta, Eugenia Piette, John D. Krein, Sarah L. Richardson, Caroline R. Kerns, Robert D. TI Cooperative pain education and selfmanagement (COPES): study design and protocol of a randomized non-inferiority trial of an interactive voice response-based self-management intervention for chronic low back pain SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Chronic low back pain; Clinical trial; IVR; Non-inferiority trial; CBT; Self-management ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; COGNITIVE-BEHAVIORAL TREATMENT; BECK DEPRESSION INVENTORY; DSM-IV; METAANALYSIS; MINI; TECHNOLOGY; DISABILITY; ENGAGEMENT; THERAPY AB Background: The Institute of Medicine report "Relieving Pain in America" recommends the promotion of patient self-management of pain for all people with pain. Given the high prevalence of chronic pain in the US, new strategies are needed to enhance access to cognitive behavioral therapy (CBT) and other evidencebased treatments designed to facilitate self-management of chronic pain conditions. Although CBT is efficacious, many patients have limited or no access to CBT. Technology-assisted delivery of CBT may improve access while maintaining efficacy. Methods/Design: We describe a randomized non-inferiority trial of interactive voice response (IVR)-based CBT for patients with chronic low back pain. This intervention uses daily IVR monitoring and weekly pre-recorded therapist feedback, based on patient-reported information, to provide treatment for patients at home. A total of 230 patients with chronic low back pain are being identified from a single statewide health system serving US military veterans. Participants are randomized to receive either ten weeks of in-person CBT or IVR-based CBT. The primary outcome is pain intensity as measured by the Numeric Rating Scale immediately post-treatment. Secondary outcomes include pain-related interference, emotional functioning, and quality of life measured immediately post treatment, and 6 and 9 months post recruitment. Exploratory objectives of the study are to examine: (1) potential mediators of impact on clinical outcomes (treatment retention, self-reported skill practice ratings, IVR call adherence, and treatment satisfaction); and (2) moderators of treatment engagement, adherence to therapist recommendations for pain coping skill practice, and effects on clinical outcomes. Discussion: This non-inferiority trial may identify an alternative to resource intensive in-person CBT that allows many more patients to receive care while also increasing retention of those enrolled in the program. C1 [Heapy, Alicia A.; LaChappelle, Kathryn M.; Goulet, Joseph L.; Czlapinski, Rebecca A.; Kerns, Robert D.] VA Connecticut Healthcare Syst, Pain Res Informat Multimorbid & Educ PRIME Hlth S, 11ACLGS950 Campbell Ave, West Haven, CT 06516 USA. [Heapy, Alicia A.; Goulet, Joseph L.; Buta, Eugenia; Kerns, Robert D.] Yale Univ, Sch Med, New Haven, CT USA. [Higgins, Diana M.] VA Boston Healthcare Syst, Boston, MA USA. [Higgins, Diana M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kirlin, Joseph] Widener Univ, Chester, PA 19013 USA. [Piette, John D.; Krein, Sarah L.] VA Ann Arbor Ctr Clin Management Res, Hlth Serv Res & Dev Ctr Innovat, Ann Arbor, MI USA. [Piette, John D.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Piette, John D.; Krein, Sarah L.; Richardson, Caroline R.] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Heapy, AA (reprint author), VA Connecticut Healthcare Syst, Pain Res Informat Multimorbid & Educ PRIME Hlth S, 11ACLGS950 Campbell Ave, West Haven, CT 06516 USA.; Heapy, AA (reprint author), Yale Univ, Sch Med, New Haven, CT USA. EM alicia.heapy@va.gov OI Goulet, Joseph/0000-0002-0842-804X FU Veterans Health Administration Health Services Research and Development Service Investigator Initiated Research Award [09-058] FX This project is funded through a Veterans Health Administration Health Services Research and Development Service Investigator Initiated Research Award (09-058). 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. Dr. Piette is a VA Senior Career Research Scientist. NR 39 TC 1 Z9 1 U1 7 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD FEB 16 PY 2016 VL 17 AR 85 DI 10.1186/s12891-016-0924-z PG 13 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DD7UR UT WOS:000370130700006 PM 26879051 ER PT J AU Tao, J Liu, J Egorova, N Chen, XL Sun, S Xue, XH Huang, J Zheng, GH Wang, Q Chen, LD Kong, J AF Tao, Jing Liu, Jiao Egorova, Natalia Chen, Xiangli Sun, Sharon Xue, Xiehua Huang, Jia Zheng, Guohua Wang, Qin Chen, Lidian Kong, Jian TI Increased Hippocampus-Medial Prefrontal Cortex Resting-State Functional Connectivity and Memory Function after Tai Chi chuan Practice in Elder Adults SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE Tai Chi Chuan exercise; Baduanjin exercise; memory function; aging; hippocampus; medial prefrontal cortex ID SPATIAL WORKING-MEMORY; RANDOMIZED CONTROLLED-TRIAL; HEALTHY OLDER-ADULTS; COGNITIVE IMPAIRMENT; EXERCISE INTERVENTION; THETA OSCILLATIONS; SOCIAL COGNITION; EPISODIC MEMORY; PRIOR KNOWLEDGE; BRAIN AB Previous studies provide evidence that aging is associated with the decline of memory function and alterations in the hippocampal (HPC) function, including functional connectivity to the medial prefrontal cortex (mPFC). In this study, we investigated if longitudinal (12-week) Tai Chi Chuan and Baduanjin practice can improve memory function and modulate HPC resting-state functional connectivity (rs-FC). Memory function measurements and resting-state functional magnetic resonance imaging (rs-fMRI) were applied at the beginning and the end of the experiment. The results showed that (1) the memory quotient (MQ) measured by the Wechsler Memory Scale-Chinese Revision significantly increased after Tai Chi Chuan and Baduanjin practice as compared with the control group, and no significant difference was observed in MQ between the Tai Chi Chuan and Baduanjin groups; (2) rs-FC between the bilateral hippocampus and mPFC significantly increased in the Tai Chi Chuan group compared to the control group (also in the Baduanjin group compared to the control group, albeit at a lower threshold), and no significant difference between the Tai Chi Chuan and Baduanjin groups was observed; (3) rs-FC increases between the bilateral hippocampus and mPFC were significantly associated with corresponding memory function improvement across all subjects. Similar results were observed using the left or right hippocampus as seeds. Our results suggest that both Tai Chi Chuan and Baduanjin may be effective exercises to prevent memory decline during aging. C1 [Tao, Jing; Liu, Jiao; Huang, Jia; Zheng, Guohua; Wang, Qin; Chen, Lidian] Fujian Univ Tradit Chinese Med, Coll Rehabil Med, Fuzhou, Peoples R China. [Tao, Jing; Huang, Jia; Chen, Lidian] Fujian Key Lab Rehabil Technol, Fuzhou, Peoples R China. [Tao, Jing; Egorova, Natalia; Sun, Sharon; Kong, Jian] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chen, Xiangli] Univ Edinburgh, Sch Social & Polit Sci, Edinburgh, Midlothian, Scotland. [Xue, Xiehua] Fujian Univ Tradit Chinese Med, Affiliated Rehabil Hosp, Fuzhou, Peoples R China. RP Kong, J (reprint author), Fujian Univ Tradit Chinese Med, Coll Rehabil Med, Fuzhou, Peoples R China. EM cld@fjtcm.edu.cn; kongj@nmr.mgh.harvard.edu OI Tao, Jing/0000-0001-9751-5294; Egorova, Natalia/0000-0002-9244-2900; Chen, Lidian/0000-0002-6454-7932 FU Special Scientific Research Fund of Public Welfare Profession of China [201307004]; Ministry of Science and Technology and Ministry of Finance of the People's Republic of China; National Rehabilitation Research Center of Traditional Chinese Medicine; Fujian Provincial Rehabilitation Industrial Institution; Fujian Rehabilitation Tech Co-Innovation Center [X2012007]; NIH/NCCIH [R01AT006364, R01 AT008563, R21AT008707, P01 AT006663] FX This study is supported by the Special Scientific Research Fund of Public Welfare Profession of China (Grant No. 201307004), Ministry of Science and Technology and Ministry of Finance of the People's Republic of China, National Rehabilitation Research Center of Traditional Chinese Medicine, Fujian Provincial Rehabilitation Industrial Institution, and Fujian Rehabilitation Tech Co-Innovation Center (Grant No. X2012007-Collaboration). JK is supported by R01AT006364 (NIH/NCCIH), R01 AT008563 (NIH/NCCIH), R21AT008707 (NIH/NCCIH), and P01 AT006663 (NIH/NCCIH). We thank the Joel Park from MGH for English editing. NR 74 TC 3 Z9 3 U1 14 U2 34 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD FEB 16 PY 2016 VL 8 AR 25 DI 10.3389/fnagi.2016.00025 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DD6XH UT WOS:000370067400001 PM 26909038 ER PT J AU Mullarky, E Lucki, NC Zavareh, RB Anglin, JL Gomes, AP Nicolay, BN Wong, JCY Christen, S Takahashi, H Singh, PK Blenis, J Warren, JD Fendt, SM Asara, JM DeNicola, GM Lyssiotis, CA Lairson, LL Cantley, LC AF Mullarky, Edouard Lucki, Natasha C. Zavareh, Reza Beheshti Anglin, Justin L. Gomes, Ana P. Nicolay, Brandon N. Wong, Jenny C. Y. Christen, Stefan Takahashi, Hidenori Singh, Pradeep K. Blenis, John Warren, J. David Fendt, Sarah-Maria Asara, John M. DeNicola, Gina M. Lyssiotis, Costas A. Lairson, Luke L. Cantley, Lewis C. TI Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PHGDH; inhibitor; serine; cancer metabolism ID GLUCOSE-METABOLISM; BREAST-CANCER; CELLS; GROWTH; DIFFERENTIATION; PATHWAY AB Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism. C1 [Mullarky, Edouard; Gomes, Ana P.; Wong, Jenny C. Y.; Blenis, John; DeNicola, Gina M.; Cantley, Lewis C.] Weill Cornell Med Coll, Meyer Canc Ctr, New York, NY 10065 USA. [Mullarky, Edouard; Wong, Jenny C. Y.; DeNicola, Gina M.; Cantley, Lewis C.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Mullarky, Edouard] Harvard Univ, Sch Med, Biol & Biomed Sci Grad Program, Boston, MA 02115 USA. [Lucki, Natasha C.; Zavareh, Reza Beheshti; Anglin, Justin L.; Lairson, Luke L.] Calif Inst Biomed Res, La Jolla, CA 92037 USA. [Gomes, Ana P.; Blenis, John] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Nicolay, Brandon N.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Christen, Stefan; Fendt, Sarah-Maria] Katholieke Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, B-3000 Leuven, Belgium. [Christen, Stefan; Fendt, Sarah-Maria] Vlaams Inst Biotechnol Leuven, Vesalius Res Ctr, Lab Cellular Metab & Metab Regulat, B-3000 Leuven, Belgium. [Takahashi, Hidenori] Beth Israel Deaconess Med Ctr, Dept Syst Biol, Boston, MA 02115 USA. [Takahashi, Hidenori; Asara, John M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Takahashi, Hidenori; Asara, John M.] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02115 USA. [Singh, Pradeep K.; Warren, J. David] Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA. [Singh, Pradeep K.; Warren, J. David] Weill Cornell Med Coll, Milstein Chem Core Facil, New York, NY 10065 USA. [Lyssiotis, Costas A.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Lyssiotis, Costas A.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Lairson, Luke L.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Takahashi, Hidenori] Daiichi Sankyo Co, Frontier Res Labs, Shinagawa Ku, Tokyo 1408710, Japan. RP Cantley, LC (reprint author), Weill Cornell Med Coll, Meyer Canc Ctr, New York, NY 10065 USA.; Cantley, LC (reprint author), Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA.; Lairson, LL (reprint author), Calif Inst Biomed Res, La Jolla, CA 92037 USA.; Lyssiotis, CA (reprint author), Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.; Lyssiotis, CA (reprint author), Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.; Lairson, LL (reprint author), Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. EM clyssiot@med.umich.edu; llairson@scripps.edu; lcantley@med.cornell.edu RI Cantley, Lewis/D-1800-2014; Beheshti Zavareh, Reza/D-8118-2016; Singh, Pradeep/E-6481-2010; OI Cantley, Lewis/0000-0002-1298-7653; Beheshti Zavareh, Reza/0000-0002-3345-408X; Singh, Pradeep/0000-0002-3570-1005; Fendt, Sarah-Maria/0000-0001-6018-9296 FU NIH [P01CA117969, P01CA120964]; PanCAN-AACR Pathway to Leadership Award; Damon Runyon Cancer Research Foundation [DFS-09-14]; Concern Foundation FX We thank U. Oppermann, M. G. Vander Heiden, K. R. Mattaini, and M. Yuan for technical assistance and reagents. We thank J. Johnson, Y. Zheng, H. Shim, B. D. Ngo, and other L.C.C. laboratory members for helpful discussions. L.C.C. was supported by NIH Grants P01CA117969 and P01CA120964. C.A.L. was partially supported by a PanCAN-AACR Pathway to Leadership Award and a Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation (Grant DFS-09-14). G.M.D. was supported by a PanCAN-AACR Pathway to Leadership Award. S.-M.F. was supported by a Conquer Cancer Now Award from the Concern Foundation. NR 39 TC 17 Z9 17 U1 7 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 2016 VL 113 IS 7 BP 1778 EP 1783 DI 10.1073/pnas.1521548113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD9BF UT WOS:000370220000040 PM 26831078 ER PT J AU Ramasamy, S Saez, B Mukhopadhyay, S Ding, DC Ahmed, AM Chen, X Pucci, F Yamin, R Wang, JF Pittet, MJ Kelleher, CM Scadden, DT Sweetser, DA AF Ramasamy, Selvi Saez, Borja Mukhopadhyay, Subhankar Ding, Daching Ahmed, Alwiya M. Chen, Xi Pucci, Ferdinando Yamin, Rae'e Wang, Jianfeng Pittet, Mikael J. Kelleher, Cassandra M. Scadden, David T. Sweetser, David A. TI Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-kappa B inflammatory pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TLE1; tumor suppressor; inflammation; NF-kappa B; HES1 ID TRANSDUCIN-LIKE-ENHANCER; TRANSCRIPTIONAL REPRESSION; MEDIATED TRANSCRIPTION; PULMONARY-FIBROSIS; INNATE IMMUNITY; GROUCHO; SPLIT; NOTCH; COREPRESSOR; ACTIVATION AB Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1(Delta/Delta)) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1(Delta/Delta) mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1(Delta/Delta) macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1(Delta/Delta) mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-kappa B but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1(Delta/Delta) mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression. C1 [Ramasamy, Selvi; Ding, Daching; Chen, Xi; Yamin, Rae'e; Wang, Jianfeng; Sweetser, David A.] MassGeneral Hosp Children, Ctr Human Genet Res, Div Med Genet & Pediat Hematol Oncol, Dept Pediat, Boston, MA 02114 USA. [Ramasamy, Selvi; Ding, Daching; Chen, Xi; Yamin, Rae'e; Wang, Jianfeng; Sweetser, David A.] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Saez, Borja; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Saez, Borja; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Saez, Borja; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Mukhopadhyay, Subhankar] Wellcome Trust Sanger Inst, Microbial Pathogenesis Grp, Cambridge CB10 1SA, England. [Ahmed, Alwiya M.; Kelleher, Cassandra M.] Massachusetts Gen Hosp, MassGeneral Hosp Children, Dept Pediat Surg, Boston, MA 02114 USA. [Pucci, Ferdinando; Pittet, Mikael J.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Ramasamy, S; Sweetser, DA (reprint author), MassGeneral Hosp Children, Ctr Human Genet Res, Div Med Genet & Pediat Hematol Oncol, Dept Pediat, Boston, MA 02114 USA.; Ramasamy, S; Sweetser, DA (reprint author), Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. EM sramasamy2@partners.org; dsweetser@mgh.harvard.edu FU National Institutes of Health [R01 CA115772]; Alex's Lemonade Stand Foundation; MGH Marathon Fund; Swim Across America FX The authors acknowledge Dr. Mari Mino-Kenudson of Massachusetts General Hospital, Pathology Department for help with interpreting histology slides as well as Katherine Folz-Donohue, Laura Prickett-Rice, Meredith Weglarz, and David Dombkowski for their assistance with flow cytometry. This work was supported by National Institutes of Health Grant R01 CA115772 (to S.R., D.D., X.C., and D.A.S.), Alex's Lemonade Stand Foundation (S.R.), MGH Marathon Fund (D.A.S.), and Swim Across America (D.A.S.). NR 47 TC 6 Z9 6 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 2016 VL 113 IS 7 BP 1871 EP 1876 DI 10.1073/pnas.1511380113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD9BF UT WOS:000370220000056 PM 26831087 ER PT J AU Iovino, S Burkart, AM Warren, L Patti, ME Kahn, CR AF Iovino, Salvatore Burkart, Alison M. Warren, Laura Patti, Mary Elizabeth Kahn, C. Ronald TI Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE iPS cells; insulin resistance; insulin signaling; skeletal muscle; genetic disease ID GLUCOSE-TRANSPORT; SIGNAL-TRANSDUCTION; DIABETES-MELLITUS; SKELETAL-MUSCLE; GENE-EXPRESSION; RECEPTOR; PROLIFERATION; BINDING; DEFECT; RAD AB Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient-and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut-myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance. C1 [Iovino, Salvatore; Burkart, Alison M.; Warren, Laura; Patti, Mary Elizabeth; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02215 USA. [Iovino, Salvatore; Burkart, Alison M.; Warren, Laura; Patti, Mary Elizabeth; Kahn, C. Ronald] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02215 USA.; Kahn, CR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU NIH [R01DK031036]; Novo-Nordisk Foundation; Harvard Stem Cell Institute; American Diabetes Association [T32 DK007260]; Harold Whitworth Pierce Charitable Trust Postdoctoral Fellowship FX We acknowledge the early support provided by C. Cowan and L. Daheron of HSCI iPS Core Facility for assistance with generation of human iPS cells. This work was supported by NIH R01DK031036 (to C.R.K.), funding from the Novo-Nordisk Foundation (to C.R.K. and M.E.P.), and pilot funding from the Harvard Stem Cell Institute. A.M.B. was supported by T32 DK007260, the American Diabetes Association [mentor-based fellowship award (to M.E.P.)], and the Harold Whitworth Pierce Charitable Trust Postdoctoral Fellowship. NR 35 TC 1 Z9 1 U1 0 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 FEB 16 PY 2016 VL 113 IS 7 BP 1889 EP 1894 DI 10.1073/pnas.1525665113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD9BF UT WOS:000370220000059 PM 26831110 ER PT J AU Mazzulli, JR Zunke, F Isacson, O Studer, L Krainc, D AF Mazzulli, Joseph R. Zunke, Friederike Isacson, Ole Studer, Lorenz Krainc, Dimitri TI alpha-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE synucleinopathies; protein trafficking; induced pluripotent stem cells; Parkinson's disease; long-term midbrain culture ID CHAPERONE-MEDIATED AUTOPHAGY; PARKINSONS-DISEASE; GAUCHER-DISEASE; DOPAMINE NEURONS; COPII VESICLES; MESSENGER-RNA; GLUCOCEREBROSIDASE; DEGRADATION; EXPRESSION; PATHOGENESIS AB Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of alpha-synuclein (alpha-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with alpha-syn remains unclear. Here, we find that alpha-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of alpha-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological alpha-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders. C1 [Mazzulli, Joseph R.; Krainc, Dimitri] Harvard Univ, Sch Med, MassGen Inst Neurodegenerat, Massachusetts Gen Hosp,Dept Neurol, Charlestown, MA 02129 USA. [Mazzulli, Joseph R.; Zunke, Friederike; Krainc, Dimitri] Northwestern Univ Feinberg, Sch Med, The Ken & Ruth Davee Dept Neurol, Chicago, IL 60611 USA. [Isacson, Ole] Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Inst, Belmont, MA 02478 USA. [Studer, Lorenz] Mem Sloan Kettering Canc Ctr, Ctr Stem Cell Biol, New York, NY 10065 USA. [Studer, Lorenz] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Studer, Lorenz] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, MassGen Inst Neurodegenerat, Massachusetts Gen Hosp,Dept Neurol, Charlestown, MA 02129 USA.; Krainc, D (reprint author), Northwestern Univ Feinberg, Sch Med, The Ken & Ruth Davee Dept Neurol, Chicago, IL 60611 USA. EM krainc@northwestern.edu FU Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University; NIH [P30 NS081774]; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department Biochemistry, Medical University of South Carolina [P20 RR017677]; National Institute of Neurological Disorders and Stroke [R01NS076054, R01NS092823, U24NS078338] FX We thank Jessica Sadick and Sohee Jeon for technical assistance. This work was supported in part by the Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University and NIH core support Grant P30 NS081774. Lipidomics were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department Biochemistry, Medical University of South Carolina (P20 RR017677). This research was supported by the National Institute of Neurological Disorders and Stroke Grant R01NS076054 (to D.K.), R01NS092823 (to J.R.M.), and U24NS078338 (to O.I., D.K., and L.S.). NR 39 TC 16 Z9 16 U1 6 U2 16 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 FEB 16 PY 2016 VL 113 IS 7 BP 1931 EP 1936 DI 10.1073/pnas.1520335113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD9BF UT WOS:000370220000066 PM 26839413 ER PT J AU Avnir, Y Watson, CT Glanville, J Peterson, EC Tallarico, AS Bennett, AS Qin, K Fu, Y Huang, CY Beigel, JH Breden, F Zhu, Q Marasco, WA AF Avnir, Yuval Watson, Corey T. Glanville, Jacob Peterson, Eric C. Tallarico, Aimee S. Bennett, Andrew S. Qin, Kun Fu, Ying Huang, Chiung-Yu Beigel, John H. Breden, Felix Zhu, Quan Marasco, Wayne A. TI IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity SO SCIENTIFIC REPORTS LA English DT Article ID MEMORY B-CELLS; HEMAGGLUTININ-STEM; COPY-NUMBER; INFLUENZA; VACCINE; H5N1; RECOGNITION; EXPRESSION; DIVERSITY; MULTIPLE AB IGHV polymorphism provides a rich source of humoral immune system diversity. One important example is the IGHV1-69 germline gene where the biased use of alleles that encode the critical CDR-H2 Phe54 (F-alleles) to make broadly neutralizing antibodies (HV1-69-sBnAb) to the influenza A hemagglutinin stem domain has been clearly established. However, whether IGHV1-69 polymorphism can also modulate B cell function and Ab repertoire expression through promoter and copy number (CN) variations has not been reported, nor has whether IGHV1-69 allelic distribution is impacted by ethnicity. Here we studied a cohort of NIH H5N1 vaccinees and demonstrate for the first time the influence of IGHV1-69 polymorphism on V-segment usage, somatic hypermutation and B cell expansion that elucidates the dominance of F-alleles in HV1-69-sBnAbs. We provide evidence that Phe54/Leu54 (F/L) polymorphism correlates with shifted repertoire usage of other IGHV germline genes. In addition, we analyzed ethnically diverse individuals within the 1000 genomes project and discovered marked variations in F-and L-genotypes and CN among the various ethnic groups that may impact HV169-sBnAb responses. These results have immediate implications for understanding HV1-69-sBnAb responses at the individual and population level and for the design and implementation of "universal" influenza vaccine. C1 [Avnir, Yuval; Peterson, Eric C.; Tallarico, Aimee S.; Bennett, Andrew S.; Qin, Kun; Fu, Ying; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 450 Brookline Ave, Boston, MA 02215 USA. [Avnir, Yuval; Peterson, Eric C.; Tallarico, Aimee S.; Bennett, Andrew S.; Qin, Kun; Fu, Ying; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. [Watson, Corey T.; Breden, Felix] Simon Fraser Univ, Dept Biol Sci, Burnaby, BC V5A 1S6, Canada. [Watson, Corey T.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Glanville, Jacob] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Program Computat & Syst Immunol, Stanford, CA 94305 USA. [Huang, Chiung-Yu] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Biostat & Bioinformat, 550 N Broadway,Room 1103-A, Baltimore, MD 21205 USA. [Beigel, John H.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD 21702 USA. RP Marasco, WA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 450 Brookline Ave, Boston, MA 02215 USA.; Marasco, WA (reprint author), Harvard Univ, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. EM wayne_marasco@dfci.harvard.edu FU NIH [AI074518, AI109223]; DARPA [W911NF-10-0266]; Intramural Research Programs of NIAID, National Institutes of Health; NCI, National Institutes of Health [HHSN261200800001E] FX MAb G6 was kindly provided by Dr. Roy Jefferis, University of Birmingham, Medical School, Birmingham, United Kingdom. This work was supported by the following agencies. WAM - NIH AI074518, AI109223 and DARPA W911NF-10-0266. FB - Natural Sciences and Engineering Research Council of Canada. JHB-Intramural Research Programs of NIAID, National Institutes of Health; NCI, National Institutes of Health Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 39 TC 5 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 16 PY 2016 VL 6 AR 20842 DI 10.1038/srep20842 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD8RT UT WOS:000370195300001 PM 26880249 ER PT J AU Marchlinski, FE Haffajee, CI Beshai, JF Dickfeld, TML Gonzalez, MD Hsia, HH Schuger, CD Beckman, KJ Bogun, FM Pollak, SJ Bhandari, AK AF Marchlinski, Francis E. Haffajee, Charles I. Beshai, John F. Dickfeld, Timm-Michael L. Gonzalez, Mario D. Hsia, Henry H. Schuger, Claudio D. Beckman, Karen J. Bogun, Frank M. Pollak, Scott J. Bhandari, Anil K. TI Long-Term Success of Irrigated Radiofrequency Catheter Ablation of Sustained Ventricular Tachycardia Post-Approval THERMOCOOL VT Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE catheter ablation; quality of life; radiofrequency; safety; ThermoCool; ventricular tachycardia ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; MULTICENTER; MORTALITY; THERAPY; SHOCKS; ARRHYTHMIAS; PREVENTION AB BACKGROUND Radiofrequency catheter ablation is used to treat recurrent ventricular tachycardia (VT). OBJECTIVES This study evaluated long-term safety and effectiveness of radiofrequency catheter ablation using an open-irrigated catheter. METHODS Patients with sustained monomorphic ventricular tachycardia associated with coronary disease were analyzed for cardiovascular-specific adverse events within 7 days of treatment, hospitalization duration, 6-month sustained monomorphic ventricular tachycardia recurrence, quality of life measured by the Hospital Anxiety and Depression Scale, long-term (1-, 2-, and 3-year) survival, symptomatic VT control, and amiodarone use. RESULTS Overall, 249 patients, mean age 67.4 years, were enrolled. The cardiovascular-specific adverse events rate was 3.9% (9 of 233) with no strokes. Noninducibility of targeted VT was achieved in 75.9% of patients. Post-ablation median hospitalization was 2 days. At 6 months, 62.0% (114 of 184) of patients had no sustained monomorphic ventricular tachycardia recurrence; the proportion of patients with implantable cardioverter-defibrillator shocks decreased from 81.2% to 26.8% (p < 0.0001); the frequency of VT in implantable cardioverter-defibrillator patients with recurrences was reduced by >= 50% in 63.8% of patients; and the proportion with normal Hospital Anxiety and Depression Scale scores increased from 48.8% to 69.1% (p < 0.001). Patient-reported VT remained steady for 1, 2, and 3 years at 22.7%, 29.8%, and 24.1%, respectively. Amiodarone use and hospitalization decreased from 55% and 77.2% pre-ablation to 23.3% and 30.7%, 18.5% and 36.7%, 17.7% and 31.3% at 1, 2, and 3 years, respectively. CONCLUSIONS Radiofrequency catheter ablation reduced implantable cardioverter-defibrillator shocks and VT episodes and improved quality of life at 6 months. A steady 3-year nonrecurrence rate with reduced amiodarone use and hospitalizations indicate improved long-term outcomes. (NaviStar ThermoCool Catheter for Endocardial RF Ablation in Patients With Ventricular Tachycardia [THERMOCOOL VT]; NCT00412607) (C) 2016 by the American College of Cardiology Foundation. C1 [Marchlinski, Francis E.] Hosp Univ Penn, Div Cardiovasc, 3400 Spruce St,Founders 9, Philadelphia, PA 19104 USA. [Haffajee, Charles I.] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02215 USA. [Beshai, John F.] Mayo Clin Fdn, Div Cardiovasc Dis, Phoenix, AZ USA. [Dickfeld, Timm-Michael L.] Univ Maryland, Sch Med, Div Cardiol, Baltimore, MD 21201 USA. [Gonzalez, Mario D.] Penn State Coll Med, Penn State Milton S Hershey Med Ctr, Penn State Heart & Vasc Inst, Hershey, PA USA. [Hsia, Henry H.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Cardiol, San Francisco, CA 94143 USA. [Schuger, Claudio D.] Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. [Beckman, Karen J.] Univ Oklahoma, Heart Rhythm Inst, Oklahoma City, OK USA. [Bogun, Frank M.] Univ Michigan Hlth Syst, Div Cardiol, Ann Arbor, MI USA. [Pollak, Scott J.] Florida Hosp, Cardiovas Inst, Orlando, FL USA. [Bhandari, Anil K.] Los Angeles Cardiol Associates, Los Angeles, CA USA. RP Marchlinski, FE (reprint author), Hosp Univ Penn, Div Cardiovasc, 3400 Spruce St,Founders 9, Philadelphia, PA 19104 USA. EM francis.marchlinski@uphs.upenn.edu FU F. Harlan Batrus Research Grant at the University of Pennsylvania; Biosense Webster, Inc.; Biosense Webster; St. Jude Medical; Medtronic; Biotronik; Boston Scientific; CardioInsight; Abbott Laboratories FX This paper was funded by an F. Harlan Batrus Research Grant at the University of Pennsylvania. The study was sponsored by Biosense Webster, Inc., and editorial support was funded by Biosense Webster. Dr. Marchlinski has received consulting fees and/or honorarium from Biosense Webster, St. Jude Medical, Medtronic, Biotronik, Boston Scientific, CardioInsight, and Abbott Laboratories. Dr. Dickfeld has received consulting fees and grant support from Biosense Webster. Dr. Gonzalez has received consulting fees and fellowship support from Biosense Webster. Dr. Hsia has received honorarium from Biosense Webster, Medtronic, and VytronUs. Dr. Bogun has received a research grant from Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 21 TC 6 Z9 7 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 16 PY 2016 VL 67 IS 6 BP 674 EP 683 DI 10.1016/j.jacc.2015.11.041 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DC8VF UT WOS:000369497100011 PM 26868693 ER PT J AU Hiratzka, LF Creager, MA Isselbacher, EM Svensson, LG Nishimura, RA Bonow, RO Guyton, RA Thoralf, MS Halperin, JL Levine, GN Anderson, JL Albert, NM Al-Khatib, SM Birtcher, KK Bozkurt, B Brindis, RG Cigarroa, JE Curtis, LH Fleisher, LA Gentile, F Gidding, S Hlatky, MA Ikonomidis, J Joglar, J Kovacs, RJ Ohman, EM Pressler, SJ Sellke, FW Shen, WK Wijeysundera, DN AF Hiratzka, Loren F. Creager, Mark A. Isselbacher, Eric M. Svensson, Lars G. Nishimura, Rick A. Bonow, Robert O. Guyton, Robert A. Sundt, Thoralf M., III Halperin, Jonathan L. Levine, Glenn N. Anderson, Jeffrey L. Albert, Nancy M. Al-Khatib, Sana M. Birtcher, Kim K. Bozkurt, Biykem Brindis, Ralph G. Cigarroa, Joaquin E. Curtis, Lesley H. Fleisher, Lee A. Gentile, Federico Gidding, Samuel Hlatky, Mark A. Ikonomidis, John Joglar, Jose Kovacs, Richard J. Ohman, E. Magnus Pressler, Susan J. Sellke, Frank W. Shen, Win-Kuang Wijeysundera, Duminda N. TI Surgery for Aortic Dilatation in Patients With Bicuspid Aortic Valves SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC/AHA Clinical Practice Guidelines; anticoagulation therapy; heart valves; thoracic aortic aneurysm; thoracic aortic disease; thoracic aortic dissection; valvular heart disease ID ASCENDING AORTA; TURNER-SYNDROME; DISSECTION; DISEASE; ASSOCIATION; REPLACEMENT; GUIDELINES; ANEURYSMS; DILATION AB Two guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and collaborating societies address the risk of aortic dissection in patients with bicuspid aortic valves and severe aortic enlargement: the "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease" (J Am Coll Cardiol 2010; 55:e27-130) and the "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease" (J Am Coll Cardiol 2014; 63:e57-185). However, the 2 guidelines differ with regard to the recommended threshold of aortic root or ascending aortic dilatation that would justify surgical intervention in patients with bicuspid aortic valves. The ACC and AHA therefore convened a subcommittee representing members of the 2 guideline writing committees to review the evidence, reach consensus, and draft a statement of clarification for both guidelines. This statement of clarification uses the ACC/AHA revised structure for delineating the Class of Recommendation and Level of Evidence to provide recommendations that replace those contained in Section 9.2.2.1 of the thoracic aortic disease guideline and Section 5.1.3 of the valvular heart disease guideline. C1 [Hiratzka, Loren F.] Tri Health Heart Inst Med, Cardiac Surg, Cincinnati, OH 45236 USA. [Nishimura, Rick A.] Mayo Clin, Div Cardiovasc Disease Judd & Mary Morries Leight, Med, Rochester, MN USA. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Heart & Vasc Ctr, Dartmouth, NS, Canada. [Creager, Mark A.] Geisel Sch Med, Dartmouth, NS, Canada. [Guyton, Robert A.] Emory Healthcare, Atlanta, GA USA. [Guyton, Robert A.] Div Cardiothorac Surg, New York, NY USA. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [Isselbacher, Eric M.] Harvard Univ, Sch Med, Med, Cambridge, MA 02138 USA. [Svensson, Lars G.] Inst Heart & Vasc, Cleveland Clin, Cleveland, OH USA. [Svensson, Lars G.] Case Western Reserve Univ, Cleveland Clin, Coll Med, Cleveland, OH 44106 USA. [Bonow, Robert O.] Northestern Univ Feinberg, Sch Med Goldberg, Cardiol, Chicago, IL USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sundt, Thoralf M., III] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Hiratzka, LF (reprint author), Tri Health Heart Inst Med, Cardiac Surg, Cincinnati, OH 45236 USA. NR 17 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 16 PY 2016 VL 67 IS 6 BP 724 EP 731 DI 10.1016/j.jacc.2015.11.006 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DC8VF UT WOS:000369497100014 PM 26658475 ER PT J AU Bartlett, JMS Ahmed, I Regan, MM Sestak, I Mallon, EA Dell'Orto, P Thurlimann, BJK Seynaeve, C Putter, H Brookes, CL Forbes, JF Colleoni, MA Bayani, J van de Velde, CJH Viale, G Cuzick, J Dowsett, M Rea, DW AF Bartlett, J. M. S. Ahmed, I. Regan, M. M. Sestak, I. Mallon, E. A. Dell'Orto, P. Thurlimann, B. J. K. Seynaeve, C. Putter, H. Brookes, C. L. Forbes, J. F. Colleoni, M. A. Bayani, J. van de Velde, C. J. H. Viale, G. Cuzick, J. Dowsett, M. Rea, D. W. CA Translational Aromatase Inhibitor TI HER2 status as predictive marker for Al vs Tam benefit: A TRANS-AIOG meta-analysis of 12129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2 SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Ontario Inst Canc Res, Toronto, ON, Canada. Univ Birmingham, Birmingham, W Midlands, England. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ London, London, England. Univ Glasgow, Western Infirm, Glasgow G11 6NT, Lanark, Scotland. Kantonsspital St Gallen, Breast Ctr, St Gallen, Switzerland. Erasmus MC, Inst Canc, Rotterdam, Netherlands. Leiden Univ, Med Ctr, Leiden, Netherlands. Univ Newcastle, Newcastle, NSW 2300, Australia. Univ Milan, Milan, Italy. Royal Marsden Hosp, London SW3 6JJ, England. European Inst Oncol, Milan, Italy. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S4-06 DI 10.1158/1538-7445.SABCS15-S4-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400169 ER PT J AU Connolly, R Zhao, F Miller, K Tevaarwerk, A Wagner, L Lee, M Murray, J Gray, R Piekarz, R Zujewski, JA Sparano, J AF Connolly, R. Zhao, F. Miller, K. Tevaarwerk, A. Wagner, L. Lee, M. Murray, J. Gray, R. Piekarz, R. Zujewski, J. A. Sparano, J. TI E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. Wake Forest Univ, Hlth Serv, Winston Salem, NC USA. NCI, Bethesda, MD 20892 USA. NCI, CTEP, Bethesda, MD 20892 USA. Montefiore Med Ctr, Albert Einstein Coll Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT2-01-04 DI 10.1158/1538-7445.SABCS15-OT2-01-04 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401234 ER PT J AU Denkert, C Budczies, J Regan, M Loibl, S Dell'Orto, P von Minckwitz, G Mastropasqua, M Mehta, K Muller, V Kammler, R Pfitzner, BM Fasching, PA Viale, G AF Denkert, C. Budczies, J. Regan, M. Loibl, S. Dell'Orto, P. von Minckwitz, G. Mastropasqua, M. Mehta, K. Mueller, V. Kammler, R. Pfitzner, B. M. Fasching, P. A. Viale, G. TI Systematic analysis and modulation of Ki67 interobserver variance in 9069 patients from three clinical trials How much pathologist concordance is needed for meaningful biomarker results? SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Charite, Inst Pathol, Berlin, Germany. Dana Farber Canc Inst, Boston, MA 02115 USA. German Breast Grp, Neu Isenburg, Germany. Ist Europeo Oncol, Milan, Italy. Univ Klinikum Eppendorf, Hamburg, Germany. IBCSG Coordinating Ctr, Bern, Switzerland. Univ Erlangen Nurnberg, D-91054 Erlangen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-07-02 DI 10.1158/1538-7445.SABCS15-P5-07-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400157 ER PT J AU Dieras, V Miles, D Verma, S Pegram, M Welslau, M Baselga, J Krop, I Blackwell, K Kang, B Xu, J Green, M Gianni, L AF Dieras, V. Miles, D. Verma, S. Pegram, M. Welslau, M. Baselga, J. Krop, I. Blackwell, K. Kang, B. Xu, J. Green, M. Gianni, L. TI Trastuzumab emtansine improves overall survival versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer: Final results from the phase 3 EMILIA study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Inst Curie, Paris, France. Mt Vernon Canc Ctr, Northwood, Middx, England. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Stanford Canc Inst, Palo Alto, CA USA. Med Off Hematol, Aschaffenburg, Bavaria, Germany. Mem Sloan Kettering Canc Ctr, New York, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Med Ctr, Durham, NC USA. Genentech Inc, San Francisco, CA 94080 USA. Hosp San Raffaele, I-20132 Milan, Italy. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-14-01 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401262 ER PT J AU Ferrario, C Hamilton, E Aucoin, N Falkson, CL Khan, Q Krop, IE Welch, S Bedard, PL Conlin, A Chaves, J Vo, A Walker, L Borges, V AF Ferrario, C. Hamilton, E. Aucoin, N. Falkson, C. L. Khan, Q. Krop, I. E. Welch, S. Bedard, P. L. Conlin, A. Chaves, J. Vo, A. Walker, L. Borges, V. TI A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+metastatic breast cancer (MBC) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Montreal, PQ H3T 1E2, Canada. Sarah Cannon Res Inst, Nashville, TN USA. Hop Cite Sante, Laval, PQ, Canada. Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. Univ Kansas, Med Ctr, Westwood, KS USA. Dana Farber Canc Inst, Boston, MA 02115 USA. London Hlth Sci Ctr, London Reg Canc Program, London, ON, Canada. Princess Margaret Canc Ctr, Univ Hlth Network, Toronto, ON, Canada. Eastside, Providence Oncol & Hematol Care Clin, Portland, OR USA. Northwest Med Specialties PLLC, Tacoma, WA USA. Oncothyreon Inc, Seattle, WA USA. Univ Colorado, Ctr Canc, Aurora, CO USA. Tennessee Oncol PLLC, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-14-20 DI 10.1158/1538-7445.SABCS15-P4-14-20 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400290 ER PT J AU Nguyen, M Buchwalter, G Luo, F Garraway, L Brown, M Jeselsohn, R AF Nguyen, M. Buchwalter, G. Luo, F. Garraway, L. Brown, M. Jeselsohn, R. TI Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Nguyen, M.; Buchwalter, G.; Luo, F.; Garraway, L.; Brown, M.; Jeselsohn, R.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-05-09 DI 10.1158/1538-7445.SABCS15-P3-05-09 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400243 ER PT J AU Overmoyer, B Rugo, H Schwartzberg, L Palmieri, C Taylor, R Hancock, M Small, S Johnston, MA AF Overmoyer, B. Rugo, H. Schwartzberg, L. Palmieri, C. Taylor, R. Hancock, M. Small, S. Johnston, M. A. TI Phase 2 open label, multinational, randomized, parallel design study investigating the efficacy and safety of GTx-024 on metastatic (MET) or locally advanced (LA) ER plus /AR plus breast cancer (BC) in postmenopausal (PM) women SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Inflammatory Breast Canc Program, Boston, MA 02115 USA. Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. West Clin, Memphis, TN USA. Univ Liverpool, Liverpool L69 3BX, Merseyside, England. GTx Inc, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT2-01-06 DI 10.1158/1538-7445.SABCS15-OT2-01-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401236 ER PT J AU Pagani, O Partridge, A Azim, HA Peccatori, FA Ruggeri, M Sun, Z AF Pagani, O. Partridge, A. Azim, H. A., Jr. Peccatori, F. A. Ruggeri, M. Sun, Z. TI POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Int Breast Canc Study Grp, Bern, Switzerland. Dana Farber Canc Inst, Boston, MA 02115 USA. Alliance Clin Trials Oncol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT2-01-08 DI 10.1158/1538-7445.SABCS15-OT2-01-08 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401238 ER PT J AU Pereira, ER Kedrin, D Jones, D Beech, E Taghian, A Padera, TP AF Pereira, E. R. Kedrin, D. Jones, D. Beech, E. Taghian, A. Padera, T. P. TI Sentinel lymph node metastases in breast cancer: A contributor to distant metastases? SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res 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 AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-01-22 DI 10.1158/1538-7445.SABCS15-P3-01-22 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402183 ER PT J AU Rosenberg, SM Dutton, CR Ligibel, J Barry, W Ruddy, KJ Sprunck-Harrild, K Emmons, KM Partridge, AH AF Rosenberg, S. M. Dutton, C. R. Ligibel, J. Barry, W. Ruddy, K. J. Sprunck-Harrild, K. Emmons, K. M. Partridge, A. H. TI Contraception use in young women with breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. Kaiser Fdn Res Inst, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P1-10-18 DI 10.1158/1538-7445.SABCS15-P1-10-18 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400468 ER PT J AU Rugo, H Overmoyer, B Schwartzberg, L Palmieri, C Taylor, R Hancock, M Small, S Johnston, MA AF Rugo, H. Overmoyer, B. Schwartzberg, L. Palmieri, C. Taylor, R. Hancock, M. Small, S. Johnston, M. A. TI A phase 2 open label, multi-center, multinational study investigating the efficacy and safety of GTx-024 on advanced, androgen receptor-positive triple negative breast cancer (AR plus TNBC) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Inflammatory Breast Canc Program, Boston, MA 02115 USA. West Clin, Memphis, TN USA. Univ Liverpool, Liverpool L69 3BX, Merseyside, England. GTx, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT2-01-07 DI 10.1158/1538-7445.SABCS15-OT2-01-07 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401237 ER PT J AU Rugo, HS Delord, JP Im, SA Ott, PA Piha-Paul, SA Bedard, PL Sachdev, J Le Tourneau, C van Brummelen, E Varga, A Saraf, S Pietrangelo, D Karantza, V Tan, A AF Rugo, H. S. Delord, J-P Im, S-A Ott, P. A. Piha-Paul, S. A. Bedard, P. L. Sachdev, J. Le Tourneau, C. van Brummelen, E. Varga, A. Saraf, S. Pietrangelo, D. Karantza, V. Tan, A. TI Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1 positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028 SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. Inst Univ Canc, Toulouse, France. Seoul Natl Univ Hosp, Seoul 110744, South Korea. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Princess Margaret Canc Ctr, Toronto, ON, Canada. Honor Hlth, Scottsdale, AZ USA. Inst Curie, Paris, France. Netherlands Canc Inst, Amsterdam, Netherlands. Gustave Roussy, Villejuif, France. Merck & Co Inc, Kenilworth, NJ USA. Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. NR 0 TC 3 Z9 3 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S5-07 DI 10.1158/1538-7445.SABCS15-S5-07 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400318 ER PT J AU Sagara, Y Freedman, RA Vaz-Luis, I Mallory, MA Wong, S Aydogan, F DeSantis, S Barry, WT Golshan, M AF Sagara, Y. Freedman, R. A. Vaz-Luis, I. Mallory, M. A. Wong, S. Aydogan, F. DeSantis, S. Barry, W. T. Golshan, M. TI Patient prognostic score and survival benefit offered by radiotherapy for ductal carcinoma in situ SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. McGill Univ, Ctr Hlth, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-12-02 DI 10.1158/1538-7445.SABCS15-P3-12-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400484 ER PT J AU Sestak, I Zhang, Y Schroeder, B Dowsett, M Sgroi, D Cuzick, J Schnabel, CA AF Sestak, I. Zhang, Y. Schroeder, B. Dowsett, M. Sgroi, D. Cuzick, J. Schnabel, C. A. TI Integration of tumor size and grade with the breast cancer index (BCI) for prediction of distant recurrence in hormone receptor-positive breast cancer with 1-3 positive lymph nodes SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Queen Mary Univ, Ctr Canc Prevent, London, England. BioTheranostics Inc, San Diego, CA USA. Royal Marsden Hosp, London SW3 6JJ, England. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P2-08-12 DI 10.1158/1538-7445.SABCS15-P2-08-12 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400430 ER PT J AU Sikov, WM Berry, DA Perou, CM Singh, B Cirrincione, CT Tolaney, SM Somlo, G Port, ER Qamar, R Sturtz, K Mamounas, E Golshan, M Bellon, JR Collyar, D Hahn, OM Carey, LA Hudis, CA Winer, EP AF Sikov, W. M. Berry, D. A. Perou, C. M. Singh, B. Cirrincione, C. T. Tolaney, S. M. Somlo, G. Port, E. R. Qamar, R. Sturtz, K. Mamounas, E. Golshan, M. Bellon, J. R. Collyar, D. Hahn, O. M. Carey, L. A. Hudis, C. A. Winer, E. P. TI Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC plus /- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Women & Infants Hosp Rhode Isl, Program Womens Oncol, Providence, RI 02908 USA. Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. NYU, Med Ctr, New York, NY 10016 USA. Alliance Stat Ctr, Durham, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. City Hope Comprehens Canc Ctr, Duarte, CA USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Aurora Hlth Care NCORP, Milwaukee, WI USA. Colorado Canc Res Program, Denver, CO USA. UF Hlth Canc Ctr Orlando, Orlando, FL USA. Patient Advocates Res, Danville, CA USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 4 Z9 4 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S2-05 DI 10.1158/1538-7445.SABCS15-S2-05 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400342 ER PT J AU Spring, L Gupta, A Reynolds, KL Gadd, MA Isakoff, SJ Ellisen, LW Moy, B Bardia, A AF Spring, L. Gupta, A. Reynolds, K. L. Gadd, M. A. Isakoff, S. J. Ellisen, L. W. Moy, B. Bardia, A. TI Neoadjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer: Comprehensive systematic review and meta -analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. OI Spring, Laura/0000-0001-8904-3514 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-13-02 DI 10.1158/1538-7445.SABCS15-P5-13-02 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400345 ER PT J AU Spring, L Gupta, A Reynolds, KL Gadd, MA Isakoff, SJ Ellisen, LW Moy, B Bardia, A AF Spring, L. Gupta, A. Reynolds, K. L. Gadd, M. A. Isakoff, S. J. Ellisen, L. W. Moy, B. Bardia, A. TI Neoadjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer: Comprehensive systematic review and meta-analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-13-02 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403345 ER PT J AU Stover, DG Waks, AG Erica, ML Brugge, JS Winer, EP Selfors, LM AF Stover, D. G. Waks, A. G. Erica, M. L. Brugge, J. S. Winer, E. P. Selfors, L. M. TI Immune activation signatures identify a subset of ER plus breast cancers with increased pathologic complete response to neoadjuvant chemotherapy SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-07-31 DI 10.1158/1538-7445.SABCS15-P3-07-31 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400098 ER PT J AU Telli, ML McMillan, A Ford, JM Richardson, AL Silver, DP Isakoff, SJ Kaklamani, VG Gradishar, W Stearns, V Connolly, RM Loibl, S Elkin, EP Timms, K Hartman, AR von Minckwitz, G AF Telli, M. L. McMillan, A. Ford, J. M. Richardson, A. L. Silver, D. P. Isakoff, S. J. Kaklamani, V. G. Gradishar, W. Stearns, V. Connolly, R. M. Loibl, S. Elkin, E. P. Timms, K. Hartman, A-R von Minckwitz, G. TI Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. UT Med Canc Therapy & Res Ctr, San Antonio, TX USA. Northwestern Univ, Chicago, IL 60611 USA. Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. German Breast Grp, Neu Isenburg, Germany. Myriad Genet Inc, Salt Lake City, UT USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-07-12 DI 10.1158/1538-7445.SABCS15-P3-07-12 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400080 ER PT J AU Telli, ML McMillan, A Ford, JM Richardson, AL Silver, DP Isakoff, SJ Kaklamani, VG Gradishar, W Stearns, V Connolly, RM Loibl, S Elkin, EP Timms, K Hartman, AR von Minckwitz, G AF Telli, M. L. McMillan, A. Ford, J. M. Richardson, A. L. Silver, D. P. Isakoff, S. J. Kaklamani, V. G. Gradishar, W. Stearns, V. Connolly, R. M. Loibl, S. Elkin, E. P. Timms, K. Hartman, A-R von Minckwitz, G. TI Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. UT Med Canc Therapy & Res Ctr, San Antonio, TX USA. Northwestern Univ, Chicago, IL 60611 USA. Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD, Germany. German Breast Grp, Neu Isenburg, Germany. Myriad Genet Inc, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-07-12 DI 10.1158/1538-7445.SABCS15-123-07-12 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403008 ER PT J AU Wildiers, H Kim, SB Gonzalez-Martin, A LoRusso, PM Ferrero, JM Yu, R Smitt, M Krop, I AF Wildiers, H. Kim, S-B Gonzalez-Martin, A. LoRusso, P. M. Ferrero, J-M Yu, R. Smitt, M. Krop, I. TI Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Hosp Leuven, Leuven, Belgium. Univ Ulsan, Coll Med, Seoul, South Korea. Ctr Oncol MD Anderson Int Espana, Madrid, Spain. Yale Univ, Med Ctr, Yale Canc Ctr, New Haven, CT USA. Ctr Antoine Lacassagne, F-06054 Nice, France. Genentech Inc, San Francisco, CA 94080 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S5-05 DI 10.1158/1538-7445.SABCS15-S5-05 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400301 ER PT J AU Zhang, Y Sestak, I Schroeder, BE Dowsett, M Cuzick, J Schnabel, CA Sgroi, DC AF Zhang, Y. Sestak, I. Schroeder, B. E. Dowsett, M. Cuzick, J. Schnabel, C. A. Sgroi, D. C. TI Prognostic impact of the combined risk groups by breast cancer index and HOXB13/IL17BR ratio in hormonal receptor positive, node negative breast cancer: A TransATAC study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 BioTheranostics Inc, San Diego, CA USA. Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, London, England. Royal Marsden Hosp, London SW3 6JJ, England. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-08-03 DI 10.1158/1538-7445.SABCS15-P5-08-03 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400375 ER PT J AU Adams, S Diamond, J Hamilton, E Pohlmann, P Tolaney, S Molinero, L Zou, W Liu, B Waterkamp, D Funke, R Powderly, J AF Adams, S. Diamond, J. Hamilton, E. Pohlmann, P. Tolaney, S. Molinero, L. Zou, W. Liu, B. Waterkamp, D. Funke, R. Powderly, J. TI Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 NYU, Langone Med Ctr, New York, NY USA. Univ Colorado, Anschutz Med Campus, Aurora, CO USA. Sarah Cannon Res Inst, Nashville, TN USA. Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Genentech Inc, S San Francsico, CA USA. Carolina BioOncol Inst, Huntersville, NC USA. NR 0 TC 2 Z9 2 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P2-11-06 DI 10.1158/1538-7445.SABCS15-P2-11-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400311 ER PT J AU Ahern, TP Tamimi, RM Chen, WY Garber, JE Eliassen, AH Borgquist, S AF Ahern, T. P. Tamimi, R. M. Chen, W. Y. Garber, J. E. Eliassen, A. H. Borgquist, S. TI Statin use and breast cancer incidence in the Nurses' health study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Vermont, Burlington, VT 05405 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA USA. Lund Univ, S-22100 Lund, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD1-02 DI 10.1158/1538-7445.SABCS15-PD1-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402151 ER PT J AU Ahern, TP Hertz, DL Damkier, P Ejlertsen, B Hamilton-Dutoit, SJ Rae, JM Regan, MM Thompson, AM Lash, TL Cronin-Fenton, DP AF Ahern, T. P. Hertz, D. L. Damkier, P. Ejlertsen, B. Hamilton-Dutoit, S. J. Rae, J. M. Regan, M. M. Thompson, A. M. Lash, T. L. Cronin-Fenton, D. P. TI CYP2D6 genotype and breast cancer recurrence in tamoxifen treated patients: An evaluation of the importance of loss-of-heterozygosity SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Vermont, Coll Med, Burlington, VT USA. Univ Michigan, Coll Pharm, 428 Church St, Ann Arbor, MI 48109 USA. Odense Univ Hosp, DK-5000 Odense, Denmark. Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Emory Univ, Atlanta, GA 30322 USA. Aarhus Univ, Aarhus, Denmark. NR 0 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-07-23 DI 10.1158/1538-7445.SABCS15-P3-07-23 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400090 ER PT J AU Anders, C Zielinski, C Klise, SR Wang, HT Thornton, D Tolaney, SM AF Anders, C. Zielinski, C. Klise, S. R. Wang, H. T. Thornton, D. Tolaney, S. M. TI A phase 2 study of abemaciclib in patients with brain metastases secondary to hormone receptor positive breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ N Carolina, Lineberger Canc Inst, Chapel Hill, NC USA. Med Univ, Vienna, Austria. Eli Lilly & Co, Indianapolis, IN 46285 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT1-03-04 DI 10.1158/1538-7445.SABCS15-OT1-03-04 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402020 ER PT J AU Askoxylakis, V Ferraro, G Kodack, D Badeaux, M Jain, R AF Askoxylakis, V. Ferraro, G. Kodack, D. Badeaux, M. Jain, R. TI Ado-trastuzumab emtansine (T-DM1) is effective against established HER2-positive breast cancer brain metastases in mice SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Askoxylakis, V.; Ferraro, G.; Kodack, D.; Badeaux, M.; Jain, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Labs, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-17-02 DI 10.1158/1538-7445.SABCS15-P6-17-02 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403248 ER PT J AU Bardia, A Modi, S Oliveira, M Campone, M Ma, B Dirix, L Weise, A Nardi, L Zhang, V Bhansali, SG Hewes, B Chavez-MacGregor, M AF Bardia, A. Modi, S. Oliveira, M. Campone, M. Ma, B. Dirix, L. Weise, A. Nardi, L. Zhang, V. Bhansali, S. G. Hewes, B. Chavez-MacGregor, M. TI Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2-advanced breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Vall dHebron Univ Hosp, VHIO, Barcelona, Spain. Inst Cancerol Ouest Rene Gauducheau, Ctr Rech Cancerol, Nantes, France. Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China. Sint Augustinus Hosp, Antwerp, Belgium. Barbara Ann Karmanos Canc Inst, Detroit, MI USA. Novartis Inst BioMed Res, E Hanover, NJ USA. Novartis Inst BioMed Res, Cambridge, MA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-13-01 DI 10.1158/1538-7445.SABCS15-P6-13-01 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403351 ER PT J AU Bardia, A Diamond, JR Mayer, IA Starodub, AN Moroose, RL Isakoff, SJ Ocean, AJ Guarino, MJ Berlin, JD Messersmith, WA Thomas, SS O'Shaughnessy, JA Kalinsky, K Maurer, M Chang, JC Forero, A Traina, T Gucalp, A Wilhelm, F Wegener, WA Maliakal, P Sharkey, RM Goldenberg, DM Vahdat, LT AF Bardia, A. Diamond, J. R. Mayer, I. A. Starodub, A. N. Moroose, R. L. Isakoff, S. J. Ocean, A. J. Guarino, M. J. Berlin, J. D. Messersmith, W. A. Thomas, S. S. O'Shaughnessy, J. A. Kalinsky, K. Maurer, M. Chang, J. C. Forero, A. Traina, T. Gucalp, A. Wilhelm, F. Wegener, W. A. Maliakal, P. Sharkey, R. M. Goldenberg, D. M. Vahdat, L. T. TI Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. Univ Colorado, Ctr Canc, Aurora, CO USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Indiana Univ, Hlth Ctr Canc Care, Goshen, IN USA. Univ Florida, Hlth Canc Ctr, Orlando, FL USA. Weill Cornell Med Coll, New York, NY USA. Helen Graham Canc Ctr & Res Inst, Newark, DE USA. Texas Oncol, Baylor Sammons Canc Ctr, Dallas, TX USA. Columbia Univ, Med Ctr, New York, NY USA. Houston Methodist Canc Ctr, Houston, TX USA. Univ Alabama Birmingham, Med Ctr Birmingham, Birmingham, AL USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Immunomedics Inc, Morris Plains, NJ USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD3-06 DI 10.1158/1538-7445.SABCS15-PD3-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402143 ER PT J AU Baselga, J Cortes, J De Laurentiis, M Dieras, V Harbeck, N Hsu, J Jin, H Schimmoller, F Wilson, TR Im, YH Jacot, W Krop, IE Verma, S AF Baselga, J. Cortes, J. De Laurentiis, M. Dieras, V. Harbeck, N. Hsu, J. Jin, H. Schimmoller, F. Wilson, T. R. Im, Y-H Jacot, W. Krop, I. E. Verma, S. TI SANDPIPER: Phase III study of the PI3-kinase inhibitor taselisib (GDC-0032) plus fulvestrant in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer enriched for patients with PIK3CA-mutant tumors SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Mem Hosp Canc & Allied Dis, Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Vall dHebron Univ Hosp, Barcelona, Spain. Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. Inst Curie, Paris, France. Univ Munich, Brustzentrum, Munich, Germany. Genentech Inc, San Francisco, CA 94080 USA. Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. Inst Canc Montpellier, Montpellier, France. Dana Farber Canc Inst, Boston, MA 02115 USA. Sunnybrook Odette Canc Ctr, Div Med Oncol, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT1-03-14 DI 10.1158/1538-7445.SABCS15-OT1-03-14 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402030 ER PT J AU Borgquist, S Giobbie-Hurder, A Ahern, T Garber, JE Colleoni, M Lang, I Debled, M Ejlertsen, B Coates, AS Goldhirsch, A Price, KN Gelber, RD Regan, MM Thurlimann, B AF Borgquist, S. Giobbie-Hurder, A. Ahern, T. Garber, J. E. Colleoni, M. Lang, I. Debled, M. Ejlertsen, B. Coates, A. S. Goldhirsch, A. Price, K. N. Gelber, R. D. Regan, M. M. Thurlimann, B. TI Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. BIG 1 98 Collaborat Grp, Bern, Switzerland. Int Breast Canc Study Grp, Bern, Switzerland. Univ Vermont, Coll Med, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD1-03 DI 10.1158/1538-7445.SABCS15-PD1-03 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402152 ER PT J AU Castillo, JJ Glezerman, IG Boklage, SH Lamerato, LE Chiodo, JA Tidwell, BA Schulman, KL AF Castillo, J. J. Glezerman, I. G. Boklage, S. H. Lamerato, L. E. Chiodo, J. A. Tidwell, B. A. Schulman, K. L. TI Incidence and prognostic importance of hyponatremia in a cohort of patients with breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Otsuka Amer Pharmaceut Inc, Princeton, NJ USA. Henry Ford Hlth Syst, Detroit, MI USA. Outcomes Res Solut Inc, Waltham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-08-49 DI 10.1158/1538-7445.SABCS15-P5-08-49 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400411 ER PT J AU Chan, A Delaloge, S Holmes, FA Moy, B Iwata, H Harker, G Masuda, N Konstantinovic, ZBN Petrakova, K Zotano, ALG Lannotti, N Rodriguez, GI Tassone, P von Minckwitz, G Ejlertsen, B Chia, SKL Mansi, J Barrios, CH Buyse, M Wong, A Bryce, R Ye, Y Martin, M AF Chan, A. Delaloge, S. Holmes, F. A. Moy, B. Iwata, H. Harker, G. Masuda, N. Neskovic Konstantinovic, Z. B. Petrakova, K. Guerrero Zotano, A. L. Lannotti, N. Rodriguez, G. I. Tassone, P. von Minckwitz, G. Ejlertsen, B. Chia, S. K. L. Mansi, J. Barrios, C. H. Buyse, M. Wong, A. Bryce, R. Ye, Y. Martin, M. TI Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Inst Gustave Roussy, Villejuif, France. Texas Oncol PA, Sapporo, Hokkaido, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. Aichi Canc Ctr, Nagoya, Aichi, Japan. Utah Canc Specialists, Nagoya, Aichi, Japan. Natl Hosp Org, Osaka Natl Hosp, Osaka, Japan. Inst Oncol & Radiol Serbia Pasterova 14, Belgrade, Serbia. Masarykuv Onkol Ustav, Brno, Czech Republic. Inst Valenciano Oncol, Valencia, Spain. Hematol Oncol Associates Treasure Coast, Catanzaro, Italy. STOH Res South Texas Oncol & Hematol, Milan, Italy. Tammaso Campanella Canc Ctr, Catanzaro, Italy. GBG Forsch GmbH, Neu Isenburg, Germany. Luisenkrankenhaus, Dusseldorf, Germany. Rigshosp, Copenhagen, Denmark. British Columbia Canc Agcy, Vancouver, BC, Canada. Guys Hosp, London, England. PUCRS Sch Med, Porto Alegre, RS, Brazil. IDDI & CluePoints, Madrid, Spain. Puma Biotechnol Inc, Madrid, Spain. Univ Gregorio Maranon, Gen Hosp, Madrid, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S5-02 DI 10.1158/1538-7445.SABCS15-S5-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400028 ER PT J AU Di Meglio, A Freedman, RA Lin, NU Barry, WT Metzger, O Keating, NL Winer, EP Vaz-Luis, I AF Di Meglio, A. Freedman, R. A. Lin, N. U. Barry, W. T. Metzger-Filho, O. Keating, N. L. Winer, E. P. Vaz-Luis, I. TI Time trends in incidence rates and survival for women with de novo metastatic lobular vs. ductal carcinoma, a population-based study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. IRCCS San Martino Univ Hosp, IST Natl Canc Res Inst, Genoa, Italy. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P1-07-08 DI 10.1158/1538-7445.SABCS15-P1-07-08 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402305 ER PT J AU Dieras, V Miles, D Verma, S Pegram, M Welslau, M Baselga, J Krop, I Blackwell, K Kang, B Xu, J Green, M Gianni, L AF Dieras, V. Miles, D. Verma, S. Pegram, M. Welslau, M. Baselga, J. Krop, I. Blackwell, K. Kang, B. Xu, J. Green, M. Gianni, L. TI Trastuzumab emtansine improves overall survival versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer: Final results from the phase 3 EMILIA study SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Inst Curie, Paris, France. Mt Vernon Canc Ctr, Northwood, Middx, England. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Stanford Canc Inst, Palo Alto, CA USA. Med Off Hematol, Aschaffenburg, Bavaria, Germany. Mem Sloan Kettering Canc Ctr, New York, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Med Ctr, Durham, NC USA. Genentech Inc, San Francisco, CA 94080 USA. Hosp San Raffaele, I-20132 Milan, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-14-01 DI 10.1158/1538-7445.SABCS15-P4-14-01 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400273 ER PT J AU Emens, L Adams, S Loi, S Schmid, P Schneeweiss, A Rugo, H Chui, S Winer, E AF Emens, L. Adams, S. Loi, S. Schmid, P. Schneeweiss, A. Rugo, H. Chui, S. Winer, E. TI A phase Ill randomized trial of atezolizumab in combination with nab-paclitaxel as first line therapy for patients with metastatic triple-negative breast cancer (mTNBC) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NYU, Sch Med, New York, NY USA. Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. Queen Mary Univ London, Barts Canc Inst, London, England. Univ Heidelberg Hosp, Heidelberg, Germany. Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Genentech Inc, San Francisco, CA 94080 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT1-01-06 DI 10.1158/1538-7445.SABCS15-OT1-01-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401307 ER PT J AU Fairweather, M Jiang, W Keating, NL Freedman, RA Nakhlis, F AF Fairweather, M. Jiang, W. Keating, N. L. Freedman, R. A. Nakhlis, F. TI Morbidity of primary local therapy for locally advanced metastatic breast cancer: An analysis of the surveillance, epidemiology and end results (SEER) medicare registry SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P1-16-01 DI 10.1158/1538-7445.SABCS15-P1-16-01 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403449 ER PT J AU Garber, JE Tung, NM Elkin, EP Allen, BA Singh, NU Wenstrup, R Hartman, AR Winer, EP Lin, NU AF Garber, J. E. Tung, N. M. Elkin, E. P. Allen, B. A. Singh, N. U. Wenstrup, R. Hartman, A-R Winer, E. P. Lin, N. U. TI Predisposing germline mutations in a clinic based breast cancer (BC) population SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Myriad Genet Labs, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P1-08-07 DI 10.1158/1538-7445.SABCS15-P1-08-07 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402293 ER PT J AU Goetz, MP Beeram, M Beck, T Conlin, AK Dees, EC Dickler, MN Helsten, TL Conkling, PR Edenfield, WJ Richards, DA Turner, PK Cai, N Chan, EM Pant, S Becerra, CH Kalinsky, K Puhalla, SL Rexer, BN Burris, HA Tolaney, SM AF Goetz, M. P. Beeram, M. Beck, T. Conlin, A. K. Dees, E. C. Dickler, M. N. Helsten, T. L. Conkling, P. R. Edenfield, W. J. Richards, D. A. Turner, P. K. Cai, N. Chan, E. M. Pant, S. Becerra, C. H. Kalinsky, K. Puhalla, S. L. Rexer, B. N. Burris, H. A. Tolaney, S. M. TI Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Mayo Clin, Rochester, MN USA. START Ctr Canc Care, San Antonio, TX USA. Highlands Oncol Grp, Rogers, AR USA. Providence Canc Ctr, Oncol & Hematol Care Clin, Portland, OR USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. Virginia Oncol Associates, Norfolk, VA USA. Greenville Hosp Syst, Clin Res Unit, Inst Translat Oncol Res, Greenville, SC USA. Texas Oncol Tyler Canc Ctr, Tyler, TX USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Univ Oklahoma, Hlth Sci Ctr, Peggy & Charles Stephenson Oklahoma Canc Ctr, Oklahoma City, OK USA. Texas Oncol Baylor Sammons Canc Ctr, Dallas, TX USA. Columbia Univ, Med Ctr, New York, NY USA. Univ Pittsburgh, Magee Womens Hosp, Med Ctr, Pittsburgh, PA 15213 USA. Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN USA. Sarah Cannon Res Inst SCRI, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-13-25 DI 10.1158/1538-7445.SABCS15-P4-13-25 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400061 ER PT J AU Harris, JR AF Harris, J. R. TI Critical Decision Making in Radiation Therapy for Breast Cancer in 2015 SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Harris, J. R.] Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PL1 DI 10.1158/1538-7445.SABCS15-PL1 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401167 ER PT J AU Hassett, MJ Cronin, AM Carroll, NM Uno, H Hornbrook, MC Ritzwoller, D AF Hassett, M. J. Cronin, A. M. Carroll, N. M. Uno, H. Hornbrook, M. C. Ritzwoller, D. TI The incidence of and survival after breast cancer recurrence SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Kaiser Permanente Colorado, Denver, CO USA. Kaiser Permanente Northwest, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P1-07-07 DI 10.1158/1538-7445.SABCS15-P1-07-07 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402304 ER PT J AU Hazra, A Warren, L Nakhlis, F Bellon, JR Hirshfield-Bartek, J Jacene, H Yeh, ED Dominici, L Schlosnagle, E Hirko, K Overmoyer, B AF Hazra, A. Warren, L. Nakhlis, F. Bellon, J. R. Hirshfield-Bartek, J. Jacene, H. Yeh, E. D. Dominici, L. Schlosnagle, E. Hirko, K. Overmoyer, B. TI Tumor profiling of inflammatory breast cancer: Advancing the tools needed for precision medicine SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-18-03 DI 10.1158/1538-7445.SABCS15-P6-18-03 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403318 ER PT J AU Hyman, DM Piha-Paul, SA Rodon, J Saura, C Puzanov, I Shapiro, GI Loi, S Joensuu, H Hanrahan, AJ Modi, S Lalani, AS Xu, F Garza, SJ Cutler, RE Bryce, R Meric-Bernstam, F Baselga, J Solit, DB AF Hyman, D. M. Piha-Paul, S. A. Rodon, J. Saura, C. Puzanov, I. Shapiro, G. I. Loi, S. Joensuu, H. Hanrahan, A. J. Modi, S. Lalani, A. S. Xu, F. Garza, S. J. Cutler, R. E. Bryce, R. Meric-Bernstam, F. Baselga, J. Solit, D. B. TI Neratinib for ERBB2 mutant, HER2 non-amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Mem Sloan Kettering Canc Ctr, New York, NY USA. MD Anderson Canc Ctr, Houston, TX USA. Vall dHebron Univ Hosp, Barcelona, Spain. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA USA. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. Puma Biotechnol Inc, Los Angeles, CA USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD5-05 DI 10.1158/1538-7445.SABCS15-PD5-05 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401290 ER PT J AU Hyslop, T Alvarado, M Forero, A Golshan, M Hieken, T Horton, J Hudis, C McGuire, K Meric-Bernstam, F Nanda, R Zagar, T Hwang, S AF Hyslop, T. Alvarado, M. Forero, A. Golshan, M. Hieken, T. Horton, J. Hudis, C. McGuire, K. Meric-Bernstam, F. Nanda, R. Zagar, T. Hwang, S. TI Treatment outcomes in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast MR imaging: Results of a secondary analysis of TBCRC 017 SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Alabama Birmingham, Birmingham, AL USA. Duke Canc Inst, Durham, NC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. Duke Univ, Sch Med, Durham, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Chicago Med, Chicago, IL USA. Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S3-06 DI 10.1158/1538-7445.SABCS15-S3-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400450 ER PT J AU Juric, D Ismail-Khan, R Campone, M Garcia-Estevez, L Becerra, C De Boer, R Hamilton, E Mayer, IA Hui, R Lathrop, KI Pagani, O Asano, S Bhansali, SG Zhang, V Hewes, B Munster, P AF Juric, D. Ismail-Khan, R. Campone, M. Garcia-Estevez, L. Becerra, C. De Boer, R. Hamilton, E. Mayer, I. A. Hui, R. Lathrop, K. I. Pagani, O. Asano, S. Bhansali, S. G. Zhang, V. Hewes, B. Munster, P. TI Phase Ib/Il study of ribociclib and alpelisib and letrozole in ER+, HER2-breast cancer: Safety, preliminary efficacy and molecular analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Inst Cancerol Ouest Rene Gauducheau, St Herblain, France. Hosp San Chinarro, Madrid, Spain. Texas Oncol, Baylor Charles Sammons Canc Ctr, Dallas, TX USA. Royal Melbourne Hosp, Melbourne, Vic, Australia. Sarah Cannon Res Inst, Nashville, TN USA. Tennessee Oncol, Nashville, TN USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Univ Sydney, Westmead Hosp, Sydney, NSW 2006, Australia. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Osped San Giovanni Bellinzona, Breast Unit, Bellinzona, Switzerland. Osped San Giovanni Bellinzona, Oncol Inst Southern Switzerland, Bellinzona, Switzerland. Novartis Inst BioMed Res, Cambridge, MA USA. Novartis Pharmaceut, E Hanover, NJ USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-14-01 DI 10.1158/1538-7445.SABCS15-P3-14-01 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402148 ER PT J AU Kidwell, KM Hertz, DL Leyland-Jones, B Regan, MM Dowsett, M Rae, JM AF Kidwell, K. M. Hertz, D. L. Leyland-Jones, B. Regan, M. M. Dowsett, M. Rae, J. M. TI Analysis of the International tamoxifen pharmacogenomics consortium (ITPC) dataset shows that genotyping DNA derived from tumor does not introduce CYP2D6 genotyping error or mask an association with tamoxifen efficacy SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Michigan, Ann Arbor, MI 48109 USA. Avera Canc Inst, Sioux Falls, SD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Royal Marsden Hosp, London SW3 6JJ, England. NR 0 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-09-02 DI 10.1158/1538-7445.SABCS15-P6-09-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402393 ER PT J AU Kimmick, G Pitcher, B Mandelblatt, J Clapp, J Balman, K Barginear, M Freedman, R Artz, A Klepin, H Lafky, J Hopkins, J Winer, E Hudis, C Muss, H Cohen, H Jatoi, A Hurria, A AF Kimmick, G. Pitcher, B. Mandelblatt, J. Clapp, J. Balman, K. Barginear, M. Freedman, R. Artz, A. Klepin, H. Lafky, J. Hopkins, J. Winer, E. Hudis, C. Muss, H. Cohen, H. Jatoi, A. Hurria, A. TI All-cause survival estimates compared to observed survival in older women with breast cancer in CALGB 49907 and 369901 (Alliance A151503) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Duke Univ, Med Ctr, Durham, NC USA. Georgetown Univ, Washington, DC 20057 USA. North Shore Hlth Syst, New York, NY USA. Dana Farber Canc Inst, Boston, MA USA. Univ Chicago, Chicago, IL 60637 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Mayo Clin, Jacksonville, FL USA. Forsyth Reg Canc Ctr, New York, NY USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-09-10 DI 10.1158/1538-7445.SABCS15-P6-09-10 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402398 ER PT J AU Le, X Luo, F Treacy, D Wulf, G Garraway, L AF Le, X. Luo, F. Treacy, D. Wulf, G. Garraway, L. TI Understanding resistance mechanisms of PIK3a inhibition in breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-06-11 DI 10.1158/1538-7445.SABCS15-P3-06-11 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622404004 ER PT J AU Lin, NU Pegram, MD Lai, C Lacasia, A Stein, A Yoo, B Perez, EA AF Lin, N. U. Pegram, M. D. Lai, C. Lacasia, A. Stein, A. Yoo, B. Perez, E. A. TI An open-label, single-arm, phase II study of pertuzumab with high-dose trastuzumab for the treatment of central nervous system progression post-radiotherapy in patients with HER2-positive metastatic breast cancer (PATRICIA) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Stanford Canc Inst, Stanford, CA USA. Genentech Inc, San Francisco, CA 94080 USA. Mayo Clin, Jacksonville, FL 32224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT3-01-04 DI 10.1158/1538-7445.SABCS15-OT3-01-04 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401252 ER PT J AU Loi, S Drubay, D Adams, S Francis, PA Joensuu, H Dieci, MV Badve, S Demaria, S Gray, R Piccart, MJ Kellokumpa-Lehtinen, PL Andre, F Dufaure-Gare, I Denkert, C Salgado, R Michiels, S AF Loi, S. Drubay, D. Adams, S. Francis, P. A. Joensuu, H. Dieci, M. V. Badve, S. Demaria, S. Gray, R. Piccart, M. J. Kellokumpa-Lehtinen, P-L Andre, F. Dufaure-Gare, I. Denkert, C. Salgado, R. Michiels, S. TI Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. Gustave Roussy, Villejuif, France. NYU, Sch Med, New York, NY 10003 USA. Univ Helsinki, Cent Hosp, Helsinki, Finland. Univ Padua, Padua, Italy. Indiana Univ, Indianapolis, IN 46204 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Inst Jules Bordet, B-1000 Brussels, Belgium. Tampere Univ Hosp, Tampere, Finland. Charite, Berlin, Germany. RI dieci, maria vittoria/K-6645-2016 NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA S1-03 DI 10.1158/1538-7445.SABCS15-S1-03 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400449 ER PT J AU Losk, K Luis, IVD Camuso, K Lloyd, M Kadish, S Hirshfield-Bartek, J Cutone, L Golshan, M Lin, N Bunnell, C AF Losk, K. Luis, I. Vaz Duarte Camuso, K. Lloyd, M. Kadish, S. Hirshfield-Bartek, J. Cutone, L. Golshan, M. Lin, N. Bunnell, C. TI Factors associated with delays in chemotherapy initiation among patients with breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Losk, K.; Luis, I. Vaz Duarte; Camuso, K.; Lloyd, M.; Kadish, S.; Hirshfield-Bartek, J.; Cutone, L.; Golshan, M.; Lin, N.; Bunnell, C.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P1-12-08 DI 10.1158/1538-7445.SABCS15-P1-12-08 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400008 ER PT J AU Luis, IV O'Neill, A Sepucha, K Miller, KD Baker, E Dang, CT Northfelt, DW Winer, EP Sledge, GW Schneider, BP Partridge, A AF Luis, I. Vaz O'Neill, A. Sepucha, K. Miller, K. D. Baker, E. Dang, C. T. Northfelt, D. W. Winer, E. P. Sledge, G. W. Schneider, B. P. Partridge, A. TI Survival benefit needed to undergo chemotherapy: Patients and physicians preferences SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Mayo Clin, Scottsdale, AR USA. Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-11-02 DI 10.1158/1538-7445.SABCS15-P5-11-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403088 ER PT J AU Luo, F Le, X Jeselsohn, R Brown, M Garraway, L AF Luo, F. Le, X. Jeselsohn, R. Brown, M. Garraway, L. TI Estrogen-independent growth of ESR1-mutant breast cancer cells requires CDK4/6 SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. Broad Inst, Cambridge, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-05-13 DI 10.1158/1538-7445.SABCS15-P3-05-13 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400238 ER PT J AU Martens, JWM Smid, M Rodriguez-Gonzalez, G Sieuwerts, AM Prager-Van der Smissen, WJC Van der Vlugt-Daane, MV Van Galen, A Nik-Zainal, S Staaf, J Brinkman, AB Van de Vijver, MJ Richardson, AL Berentsen, K Caldas, C Butler, A Martin, S Davies, HD Debets, R Meijer-Van Gelder, ME Van Deurzen, CHM Ramakrishna, MR Ringner, M Viari, A Birney, E Borresen-Dale, AL Stunnenberg, HG Stratton, M Foekens, JA AF Martens, J. W. M. Smid, M. Rodriguez-Gonzalez, G. Sieuwerts, A. M. Prager-Van der Smissen, W. J. C. Van der Vlugt-Daane, M. Van Galen, A. Nik-Zainal, S. Staaf, J. Brinkman, A. B. Van de Vijver, M. J. Richardson, A. L. Berentsen, K. Caldas, C. Butler, A. Martin, S. Davies, H. D. Debets, R. Meijer-Van Gelder, M. E. Van Deurzen, C. H. M. Ramakrishna, M. R. Ringner, M. Viari, A. Birney, E. Borresen-Dale, A-L Stunnenberg, H. G. Stratton, M. Foekens, J. A. TI Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res ID BLOCKADE C1 Erasmus MC, Rotterdam, Netherlands. Wellcome Trust Sanger Inst, Hinxton, England. Lund Univ, Lund, Sweden. Radboud Univ Nijmegen, NL-6525 ED Nijmegen, Netherlands. Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Cambridge, Cambridge, England. Synergie Lyon Canc, Lyon, France. European Bioinformat Inst, Hinxton, England. Univ Oslo, Oslo, Norway. NR 5 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-08-10 DI 10.1158/1538-7445.SABCS15-P6-08-10 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622404184 ER PT J AU Mayer, E DeMichele, A Dubsky, P Barry, W Metzger, O Symmans, WF Burstein, H Miller, K Wolff, A Rastogi, P Loibl, S von Minckwitz, G Goulioti, T Zardavas, D Fesl, C Koehler, M Bartlett, CH Chen, L Piccart, M Winer, E Gnant, M AF Mayer, E. DeMichele, A. Dubsky, P. Barry, W. Metzger, O. Symmans, W. F. Burstein, H. Miller, K. Wolff, A. Rastogi, P. Loibl, S. von Minckwitz, G. Goulioti, T. Zardavas, D. Fesl, C. Koehler, M. Bartlett, C. Huang Chen, L. Piccart, M. Winer, E. Gnant, M. TI PALLAS: PAlbociclib Collaborative Adjuvant Study: A randomized phase 3 trial of palbociclib with adjuvant endocrine therapy versus endocrine therapy alone for HR+/HER2-early breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Alliance Clin Trials Oncol Fdn, Chicago, IL USA. PrECOG, Philadelphia, PA USA. Austrian Breast & Colorectal Canc Study Grp, Vienna, Austria. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NSABP Fdn, Pittsburgh, PA USA. German Breast Grp, Neu Isenburg, Germany. Pfizer Inc, New York, NY USA. Breast Int Grp, Brussels, Belgium. Inst Jules Bordet, B-1000 Brussels, Belgium. NR 0 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT1-03-21 DI 10.1158/1538-7445.SABCS15-OT1-03-21 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402037 ER PT J AU Miller, K Cortes, J Hurvitz, SA Krop, IE Tripathy, D Verma, S Riahi, K Reynolds, JG Wickham, T Molnar, I Yardley, DA AF Miller, K. Cortes, J. Hurvitz, S. A. Krop, I. E. Tripathy, D. Verma, S. Riahi, K. Reynolds, J. G. Wickham, T. Molnar, I. Yardley, D. A. TI HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. VHIO, Barcelona, Spain. Univ Calif Los Angeles, Los Angeles, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Merrimack Pharmaceut Inc, Cambridge, MA USA. Sarah Cannon Res Inst, Nashville, TN USA. Tennessee Oncol PLLC, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT3-01-01 DI 10.1158/1538-7445.SABCS15-OT3-01-01 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401249 ER PT J AU Miller, K Krop, I Schwartzberg, L Abramson, V Garcia-Estevez, L Eakle, J Nanda, R Yardley, D Ademuyiwa, F Chan, S Crown, J Danso, M Gelmon, K Ma, L Martinez-Janez, N Gradishar, W Steinberg, J Tudor, IC Uppal, H Paton, VE Parker, J Hudis, CA Traina, TA AF Miller, K. Krop, I. Schwartzberg, L. Abramson, V. Garcia-Estevez, L. Eakle, J. Nanda, R. Yardley, D. Ademuyiwa, F. Chan, S. Crown, J. Danso, M. Gelmon, K. Ma, L. Martinez-Janez, N. Gradishar, W. Steinberg, J. Tudor, I. C. Uppal, H. Paton, V. E. Parker, J. Hudis, C. A. Traina, T. A. TI Improved clinical outcomes on enzalutamide observed in patients with PREDICT AR plus triple-negative breast cancer: prognosis or prediction? SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Comprehens Canc Ctr Clara Campal, Madrid, Spain. Florida Canc Specialists, Sarasota, FL USA. Univ Chicago Med, Chicago, IL USA. Tennessee Oncol PLCC, Nashville, TN USA. Washington Univ, Sch Med, St Louis, MO USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. All Ireland Cooperat Oncol Res Grp, Dublin, Ireland. Virginia Oncol, Norfolk, VA USA. BC Canc Agcy, Vancouver, BC, Canada. Rocky Mt Canc Ctr, Lakewood, CO USA. Hosp Madrid Norte Sanchinarro, Madrid, Spain. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Astellas Pharma Global Dev Inc, Northbrook, IL USA. Medivation Inc, San Francisco, CA USA. Univ N Carolina, Chapel Hill, NC USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P3-07-25 DI 10.1158/1538-7445.SABCS15-P3-07-25 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400092 ER PT J AU Nakhlis, F Regan, M Chun, YS Dominici, LS Jacene, HA Yeh, ED Bellon, JR Warren, LE Hirko, K Hirshfield-Bartek, J Hazra, A Overmoyer, BA AF Nakhlis, F. Regan, M. Chun, Y. S. Dominici, L. S. Jacene, H. A. Yeh, E. D. Bellon, J. R. Warren, L. E. Hirko, K. Hirshfield-Bartek, J. Hazra, A. Overmoyer, B. A. TI Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P6-18-02 DI 10.1158/1538-7445.SABCS15-P6-18-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403317 ER PT J AU Nelson, SH Marinac, CR Patterson, RE Nachuta, SJ Caan, BJ Chen, WY Shu, XO Pierce, JP AF Nelson, S. H. Marinac, C. R. Patterson, R. E. Nachuta, S. J. Caan, B. J. Chen, W. Y. Shu, X-O Pierce, J. P. TI Post-diagnosis physical activity and comorbidities, not BMI, explain mortality risk in the after breast cancer pooling project SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Univ Calif San Diego, Canc Prevent & Control Program, Moores UCSD Canc Ctr, La Jolla, CA 92093 USA. Vanderbilt Univ, Sch Med, Div Epidemiol, Nashville, TN 37212 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD4-08 DI 10.1158/1538-7445.SABCS15-PD4-08 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402053 ER PT J AU Oliveira, M de Azambuja, E Saura, C Dubsky, P Zardavas, D Fesl, C Bardia, A Soberino, J Gil, EC Ng, V Fredrickson, J Stout, TJ Singel, SM Hsu, JY Piccart, M Gnant, M Baselga, J AF Oliveira, M. de Azambuja, E. Saura, C. Dubsky, P. Zardavas, D. Fesl, C. Bardia, A. Soberino, J. Gil, E. Ciruelos Ng, V. Fredrickson, J. Stout, T. J. Singel, S. M. Hsu, J. Y. Piccart, M. Gnant, M. Baselga, J. TI LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early-stage breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Vall dHebron Univ Hosp, VHIO, Barcelona, Spain. SOLTI Breast Canc Res Grp, Barcelona, Spain. Inst Jules Bordet, B-1000 Brussels, Belgium. Breast Data Ctr, Brussels, Belgium. Med Univ Vienna, Vienna, Austria. ABCSG Austrian Breast & Colorectal Canc Study Grp, Vienna, Austria. Breast Int Grp BIG Aisbl, Brussels, Belgium. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. 12 Octubre Univ Hosp, Madrid, Spain. Genentech Inc, San Francisco, CA 94080 USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT1-03-06 DI 10.1158/1538-7445.SABCS15-OT1-03-06 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402022 ER PT J AU Partridge, AH Rosenberg, SM Rajagopal, PS Ruddy, KJ Tamimi, RM Schapira, L Come, S Borges, V Gelber, S AF Partridge, A. H. Rosenberg, S. M. Rajagopal, P. S. Ruddy, K. J. Tamimi, R. M. Schapira, L. Come, S. Borges, V. Gelber, S. TI Employment trends in young women following a breast cancer diagnosis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. Mayo Clin, Rochester, MN USA. Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-10-04 DI 10.1158/1538-7445.SABCS15-P4-10-04 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403156 ER PT J AU Partridge, AH Fasse, K Stanton, AL Jones, A Bright, E Petrie, KJ AF Partridge, A. H. Fasse, K. Stanton, A. L. Jones, A. Bright, E. Petrie, K. J. TI What goes through your mind when you think about your medication? Thoughts about endocrine medication and treatment adherence SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Auckland, Auckland 1, New Zealand. Univ Calif Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P5-12-13 DI 10.1158/1538-7445.SABCS15-P5-12-13 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400023 ER PT J AU Pruneri, G Gray, KP Vingiani, A Viale, G Curigliano, G Criscitiello, C Lang, I Thurlimann, B Goldhirsch, A Price, KN Cancello, G Munzone, E Gelber, RD Regan, MM Colleoni, M AF Pruneri, G. Gray, K. P. Vingiani, A. Viale, G. Curigliano, G. Criscitiello, C. Lang, I. Thurlimann, B. Goldhirsch, A. Price, K. N. Cancello, G. Munzone, E. Gelber, R. D. Regan, M. M. Colleoni, M. TI Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple negative breast cancer treated by induction chemotherapy with or without oral low dose cyclophosphamide-methotrexate maintenance chemotherapy (CMM) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 European Inst Oncol, Milan, Italy. Dana Farber Canc Inst, Ctr Stat, Int Breast Canc Study Grp, Boston, MA 02115 USA. Natl Inst Oncol, Budapest, Hungary. Kantonsspital, St Gallen, Switzerland. Swiss Grp Clin Canc Res SAKK, St Gallen, Switzerland. NR 0 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P2-08-02 DI 10.1158/1538-7445.SABCS15-P2-08-02 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400421 ER PT J AU Ruddy, KJ Rack, B Schwitulla, J Lambrechts, D Haeberle, L Schramm, A Trapp, E Scholz, C Beutler, AS Ginsburg, E Couch, F Partridge, AH Wang, L Weinshilboum, RM Janni, W Vachon, C Fasching, P AF Ruddy, K. J. Rack, B. Schwitulla, J. Lambrechts, D. Haeberle, L. Schramm, A. Trapp, E. Scholz, C. Beutler, A. S. Ginsburg, E. Couch, F. Partridge, A. H. Wang, L. Weinshilboum, R. M. Janni, W. Vachon, C. Fasching, P. TI Genetic predictors of chemotherapy-related amenorrhea SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Mayo Clin, Rochester, MN USA. Univ Munich, Munich, Germany. Univ Erlangen Nurnberg, Ernlagen, Germany. Univ Leuven, Leuven, Belgium. Univ Hosp Erlangen, Erlangen, Germany. Univ Ulm, D-89069 Ulm, Germany. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-10-07 DI 10.1158/1538-7445.SABCS15-P4-10-07 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622403158 ER PT J AU Sajjadi, AY Singh, B Deng, B Boas, DA Moy, B Schapira, L Bardia, A Specht, MC Carp, SA Isakoff, SJ AF Sajjadi, A. Y. Singh, B. Deng, B. Boas, D. A. Moy, B. Schapira, L. Bardia, A. Specht, M. C. Carp, S. A. Isakoff, S. J. TI Dynamic tomographic optical breast imaging (TOBI) for neoadjuvant chemotherapy monitoring SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Sajjadi, A. Y.; Singh, B.; Deng, B.; Boas, D. A.; Moy, B.; Schapira, L.; Bardia, A.; Specht, M. C.; Carp, S. A.; Isakoff, S. J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-03-04 DI 10.1158/1538-7445.SABCS15-P4-03-04 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402210 ER PT J AU Saura, C Isakoff, SJ Calvo, I Patt, D Andersen, J Gonzalez-Martin, A Fisher, J Ciruelos, E Gil-Gil, M De la Pena, L Choi, Y Jia, S Singel, S Patel, PH Baselga, J Oliveira, M AF Saura, C. Isakoff, S. J. Calvo, I. Patt, D. Andersen, J. Gonzalez-Martin, A. Fisher, J. Ciruelos, E. Gil-Gil, M. De la Pena, L. Choi, Y. Jia, S. Singel, S. Patel, P. H. Baselga, J. Oliveira, M. TI FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (Ipat, GDC-0068) in combination with paclitaxel (Pac) as neoadjuvant treatment for early stage triple negative breast cancer (TNBC) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 VHIO, Barcelona, Spain. SOLTI Breast Canc Res Grp, Barcelona, Spain. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Ctr Integral Oncol Clara Campal, Barcelona, Spain. Texas Oncol Ctr, Dallas, TX USA. Compass Oncol, Dallas, TX USA. MD Anderson Canc Ctr, Houston, TX USA. Carolinas Healthcare Syst, Dallas, TX USA. Hosp Univ 12 Octubre, Madrid, Spain. ICO Hosp, Barcelona, Spain. Genentech Inc, San Francisco, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT1-03-09 DI 10.1158/1538-7445.SABCS15-OT1-03-09 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402025 ER PT J AU Shapiro, G AF Shapiro, G. TI Beyond CDK 4/6: Targeting additional cell cycle and transcriptional CDKs in breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Shapiro, G.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA MS1-1 DI 10.1158/1538-7445.SABCS15-MS1-1 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622401163 ER PT J AU Smith, SG Sestak, I Forster, A Partridge, A Side, L Horne, R Wardle, J Cuzick, J AF Smith, S. G. Sestak, I. Forster, A. Partridge, A. Side, L. Horne, R. Wardle, J. Cuzick, J. TI Factors affecting uptake and adherence to breast cancer chemoprevention: A systematic review and meta-analysis SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Queen Mary Univ London, London, England. UCL, London, England. Dana Farber Canc Ctr, Boston, MA USA. Univ Coll London Hosp, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD1-08 DI 10.1158/1538-7445.SABCS15-PD1-08 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402157 ER PT J AU Sparano, JA Gray, RJ Makower, DF Pritchard, KI Albain, KS Hayes, DF Geyer, CE Dees, EC Perez, EA Olson, JA Zujweski, J Keane, MM Moreno, HLG Reddi, RP Goggins, TF Mayer, IA Brufsky, AM Toppmeyer, DL Kaklamani, VG Atkins, JN Berenberg, JL Sledge, GW AF Sparano, J. A. Gray, R. J. Makower, D. F. Pritchard, K. I. Albain, K. S. Hayes, D. F. Geyer, C. E., Jr. Dees, E. C. Perez, E. A. Olson, J. A., Jr. Zujweski, J. Keane, M. M. Moreno, H. L. Gomez Reddi, R. P. Goggins, T. F. Mayer, I. A. Brufsky, A. M. Toppmeyer, D. L. Kaklamani, V. G. Atkins, J. N. Berenberg, J. L. Sledge, G. W., Jr. TI Prospective trial of endocrine therapy alone in patients with estrogen receptor positive, HER2-negative, node-negative breast cancer: Results of the TAILORx low risk registry SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Sunnybrook Res Inst, Toronto, ON, Canada. Loyola Univ, Med Ctr, 2160 S 1st Ave, Maywood, IL 60153 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. Virginia Commonwealth Univ, Med Coll Virginia, Massey Canc Ctr, Richmond, VA 23298 USA. Univ N Carolina, Chapel Hill, NC USA. Mayo Clin, Jacksonville, FL 32224 USA. Duke Univ, Med Ctr, Durham, NC USA. NCI, Bethesda, MD 20892 USA. Univ Coll Hosp, Galway, Ireland. Oncosalud SAC, Lima, Peru. Via Christi Reg Med Ctr, Wichita, KS USA. Fox Valley Hematol & Oncol, Appleton, WI USA. Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. Univ Pittsburgh, Pittsburgh, PA USA. Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. Northwestern Univ, Chicago, IL 60611 USA. Southeast Clin Oncol Res Consortium, Goldsboro, NC USA. Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P2-08-01 DI 10.1158/1538-7445.SABCS15-P2-08-01 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400420 ER PT J AU Spoerke, J Gendreau, S Johnston, S Schmid, P Krop, I Qui, J Derynck, M Chan, I Walter, K Amler, L Hampton, G Lackner, M AF Spoerke, J. Gendreau, S. Johnston, S. Schmid, P. Krop, I. Qui, J. Derynck, M. Chan, I. Walter, K. Amler, L. Hampton, G. Lackner, M. TI High prevalence and clonal heterogeneity of ESR1 mutations (mt) in circulating tumor DNA (ctDNA) from patients (pts) enrolled in FERGI, a randomized phase II study testing pictilisib (GDC-0941) in combination with fulvestrant (F) in pts that failed a prior aromatase inhibitor (AI) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Genentech Inc, San Francisco, CA 94080 USA. Royal Marsden Hosp, London SW3 6JJ, England. Queen Mary Univ London, Barts Canc Inst, London, England. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA PD6-03 DI 10.1158/1538-7445.SABCS15-PD6-03 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400266 ER PT J AU Wagle, N Painter, CA Ilzarbe, M Van Allen, EM Frank, E Oh, C Krevalin, M Lloyd, M Anderka, K Kryukov, G Boehm, JS Winer, E Lander, ES Golub, TR AF Wagle, N. Painter, C. A. Ilzarbe, M. Van Allen, E. M. Frank, E. Oh, C. Krevalin, M. Lloyd, M. Anderka, K. Kryukov, G. Boehm, J. S. Winer, E. Lander, E. S. Golub, T. R. TI The metastatic breast cancer project: A national direct-to-patient research initiative to accelerate genomics research SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Broad Inst, Cambridge, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA OT2-05-03 DI 10.1158/1538-7445.SABCS15-OT2-05-03 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400247 ER PT J AU Yeh, E Rives, A Guo, H Regan, M Birdwell, R Nakhlis, F Bellon, J Warren, L Hirshfield-Bartek, J Jacene, H Dominici, L Overmoyer, B AF Yeh, E. Rives, A. Guo, H. Regan, M. Birdwell, R. Nakhlis, F. Bellon, J. Warren, L. Hirshfield-Bartek, J. Jacene, H. Dominici, L. Overmoyer, B. TI MRI changes in breast skin following preoperative therapy for inflammatory breast cancer (IBC) SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA P4-02-08 DI 10.1158/1538-7445.SABCS15-P4-02-08 PG 2 WC Oncology SC Oncology GA DL4QN UT WOS:000375622402206 ER PT J AU Abrahamse, H Hamblin, MR AF Abrahamse, Heidi Hamblin, Michael R. TI New photosensitizers for photodynamic therapy SO BIOCHEMICAL JOURNAL LA English DT Review DE naturally occurring photosensitizers; photochemical mechanisms; photodynamic therapy; photosensitizers; synthetic dyes; tetrapyrroles ID CHLOROALUMINUM SULFONATED PHTHALOCYANINE; SELECTIVE ANTIMICROBIAL PHOTOSENSITIZERS; GENETICALLY ENCODED PHOTOSENSITIZER; RESISTANT STAPHYLOCOCCUS-AUREUS; SINGLET OXYGEN GENERATION; NEAR-INFRARED LIGHT; IN-VIVO; PHOTOCHEMICAL INTERNALIZATION; CANCER-CELLS; QUANTUM DOTS AB Photodynamic therapy (PDT) was discoveredmore than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochemical reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compounds have received clinical approval. Other molecular structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnology has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochemical internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound. C1 [Abrahamse, Heidi] Univ Johannesburg, Fac Hlth Sci, Laser Res Ctr, ZA-2028 Doornfontein, South Africa. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA.; Hamblin, MR (reprint author), Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM Hamblin@helix.mgh.harvard.edu FU National Institutes of Health [R01AI050875] FX This work was supported by the National Institutes of Health [grant number R01AI050875 (to M.R.H.)]. NR 161 TC 23 Z9 24 U1 123 U2 323 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2016 VL 473 BP 347 EP 364 DI 10.1042/BJ20150942 PN 4 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2ZR UT WOS:000374785000001 PM 26862179 ER PT J AU Riddler, SA Aga, E Bosch, RJ Bastow, B Bedison, M Vagratian, D Vaida, F Eron, JJ Gandhi, RT Mellors, JW AF Riddler, Sharon A. Aga, Evgenia Bosch, Ronald J. Bastow, Barbara Bedison, Margaret Vagratian, David Vaida, Florin Eron, Joseph J. Gandhi, Rajesh T. Mellors, John W. CA ACTG A5276S Protocol Team TI Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1-Infected Adults Receiving Long-term Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV/AIDS; residual viremia; viral decay; single-copy assay; CD4/CD8 ratio ID CD4(+) T-CELLS; PERSISTENCE; HIV-1; INFECTION AB We measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of >= 1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8(+) T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4-12 of suppressive ART. C1 [Riddler, Sharon A.; Bedison, Margaret; Vagratian, David; Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Aga, Evgenia; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Cambridge, MA 02138 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Ragon Inst, Cambridge, MA USA. [Bastow, Barbara] Social & Sci Syst, Silver Spring, MD USA. [Vaida, Florin] Univ Calif San Diego, La Jolla, CA 92093 USA. [Eron, Joseph J.] Univ N Carolina Chapel Hill, Chapel Hill, NC USA. RP Riddler, SA (reprint author), Univ Pittsburgh, Sch Med, Dept Med, 3520 Fifth Ave,Ste 510, Pittsburgh, PA 15213 USA. EM riddler@pitt.edu FU National Institute of Allergy and Infectious Diseases [UM1 AI068634, UM1 AI068636, UM1 AI106701, AI038858, AI038855]; National Institutes of Health (NIH) [AI069494, AI069432, AI069415, AI069428, AI069439, TR000445, AI069452, AI069423, TR001111, AI50410, AI069511, TR000042, AI069481, AI068636, AI069501, TR001082, AI069532, AI069556, AI069471, AI069472, A1069424, TR000124, AI069496, AI069419, TR000457, AI069418, TR0000454, AI 50409] FX This work was supported by the National Institute of Allergy and Infectious Diseases (awards UM1 AI068634, UM1 AI068636, and UM1 AI106701, for current work; and awards AI038858 and AI038855, for past work), National Institutes of Health (NIH) (grants AI069494, AI069432, AI069415, AI069428, AI069439, TR000445, AI069501, AI069452, AI069423, TR001111, AI50410, AI069511, TR000042, AI069481, AI068636, AI069501, AI069439, AI069471, AI069432, TR001082, AI069532, AI069556, AI069471, AI069472, A1069424, TR000124, AI069496, AI069419, TR000457, AI069418, TR0000454, and AI 50409). NR 15 TC 3 Z9 3 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2016 VL 213 IS 4 BP 556 EP 560 DI 10.1093/infdis/jiv433 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG9XS UT WOS:000372437700009 PM 26333941 ER PT J AU Nabavi, S Schmolze, D Maitituoheti, M Malladi, S Beck, AH AF Nabavi, Sheida Schmolze, Daniel Maitituoheti, Mayinuer Malladi, Sadhika Beck, Andrew H. TI EMDomics: a robust and powerful method for the identification of genes differentially expressed between heterogeneous classes SO BIOINFORMATICS LA English DT Article ID WNT/BETA-CATENIN PATHWAY; OVARIAN-CANCER; CARCINOMA; CELL AB Motivation: A major goal of biomedical research is to identify molecular features associated with a biological or clinical class of interest. Differential expression analysis has long been used for this purpose; however, conventional methods perform poorly when applied to data with high within class heterogeneity. Results: To address this challenge, we developed EMDomics, a new method that uses the Earth mover's distance to measure the overall difference between the distributions of a gene's expression in two classes of samples and uses permutations to obtain q-values for each gene. We applied EMDomics to the challenging problem of identifying genes associated with drug resistance in ovarian cancer. We also used simulated data to evaluate the performance of EMDomics, in terms of sensitivity and specificity for identifying differentially expressed gene in classes with high within class heterogeneity. In both the simulated and real biological data, EMDomics outperformed competing approaches for the identification of differentially expressed genes, and EMDomics was significantly more powerful than conventional methods for the identification of drug resistance-associated gene sets. EMDomics represents a new approach for the identification of genes differentially expressed between heterogeneous classes and has utility in a wide range of complex biomedical conditions in which sample classes show within class heterogeneity. C1 [Nabavi, Sheida] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Schmolze, Daniel; Malladi, Sadhika; Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Schmolze, Daniel; Malladi, Sadhika; Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA. [Schmolze, Daniel; Maitituoheti, Mayinuer; Malladi, Sadhika; Beck, Andrew H.] Harvard Univ, Sch Med, Boston, MA USA. [Maitituoheti, Mayinuer] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Malladi, Sadhika] Harker Sch, San Jose, CA USA. RP Beck, AH (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA.; Beck, AH (reprint author), Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA.; Beck, AH (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM abeck2@bidmc.harvard.edu FU National Library Of Medicine of the National Institutes of Health [K22LM011931, K99LM011595] FX Research reported in this publication was supported by the National Library Of Medicine of the National Institutes of Health under Award Number K22LM011931 (A.H.B.) and K99LM011595 (S.N.). NR 40 TC 1 Z9 1 U1 1 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 FEB 15 PY 2016 VL 32 IS 4 BP 533 EP 541 DI 10.1093/bioinformatics/btv634 PG 9 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 DF9PO UT WOS:000371693700008 PM 26515818 ER PT J AU Belperio, J Horwich, T Abraham, WT Fonarow, GC Gorcsan, J Bersohn, MM Singh, JP Sonel, A Lee, LY Halilovic, J Kadish, A Shalaby, AA AF Belperio, John Horwich, Tamara Abraham, William T. Fonarow, Gregg C. Gorcsan, John, III Bersohn, Malcolm M. Singh, Jagmeet P. Sonel, Ali Lee, Li-Yin Halilovic, Jasmina Kadish, Alan Shalaby, Alaa A. TI Inflammatory Mediators and Clinical Outcome in Patients With Advanced Heart Failure Receiving Cardiac Resynchronization Therapy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID GROWTH-FACTORS; FIBROBLAST PROLIFERATION; PLEURAL FIBROSIS; CYTOKINES; INJURY; ASSOCIATION; ACTIVATION; MICE AB Expression of different cytokines and growth factors after " myocardial injury has been associated with fibroplasia and dilatation versus reverse remodeling and myocardial repair. Specifically, the proinflammatory/fibrotic mediators: interleukin (IL)-6, epidermal growth factor, and fibroblast growth factor (FGF)-2 cause fibroplasia, whereas reparative cytokines including: IL-1 alpha, IL-1 beta, IL-4, and IL-13 can limit fibrosis. In appropriate patients, cardiac resynchronization therapy (CRT) reverses cardiomyopathy and improves outcome. However, a significant proportion will not respond to this therapy. We conducted this study to assess the association of proinflammatory/fibrotic and/or reparative immune response mediators at baseline with outcome after CRT. In the multicenter RISK study, plasma samples were collected prospectively before CRT implantation. Plasma IL-6, epidermal growth factor, FGF-2, IL-1 alpha, IL-1 beta, IL-4, and IL-13 were evaluated by Luminex technology. The primary outcome was predefined as freedom from heart failure hospitalization or death and a decrease in echocardiographic end-systolic volume of >15% at 12 months. To determine associations with the outcome, multivariate logistic regression models including baseline clinical characteristics and the specific cytokines and growth factors were constructed. On multivariate analysis of 257 patients, detectable reparative cytokine IL-13 was significantly associated with the primary outcome (odds ratio 3.79; 95% CI 2.10 to 6.82, p <0.0001). In contrast, detectable proinflammatory/fibrotic growth factor FGF-2 was negatively associated (odds ratio 0.31; 95% CI, 0.14 to 0.68; p = 0.004). In conclusion, in CRT recipients, baseline levels of inflammatory mediators affecting cardiac fibrosis versus repair were associated with subsequent clinical outcome. Published by Elsevier Inc. C1 [Belperio, John; Horwich, Tamara; Fonarow, Gregg C.; Bersohn, Malcolm M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Abraham, William T.] Ohio State Univ, Columbus, OH 43210 USA. [Gorcsan, John, III; Sonel, Ali; Shalaby, Alaa A.] Univ Pittsburgh, Pittsburgh, PA USA. [Bersohn, Malcolm M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Singh, Jagmeet P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sonel, Ali] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Lee, Li-Yin; Halilovic, Jasmina] St Jude Med, Sylmar, CA USA. [Shalaby, Alaa A.] New York Med Coll, Valhalla, NY 10595 USA. RP Shalaby, AA (reprint author), Univ Pittsburgh, Pittsburgh, PA USA.; Shalaby, AA (reprint author), New York Med Coll, Valhalla, NY 10595 USA. EM Alaa.Shalaby@va.gov FU St. Jude Medical, Sylmar, California, CRM FX Study sponsored by St. Jude Medical, Sylmar, California, CRM. NR 26 TC 2 Z9 2 U1 0 U2 3 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 FEB 15 PY 2016 VL 117 IS 4 BP 617 EP 625 DI 10.1016/j.amjcard.2015.11.049 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DE1NQ UT WOS:000370394100020 PM 26832186 ER PT J AU Valim, C Ahmad, R Lanaspa, M Tan, Y Acacio, S Gillette, MA Almendinger, KD Milner, DA Madrid, L Pelle, K Harezlak, J Silterra, J Alonso, PL Carr, SA Mesirov, JP Wirth, DF Wiegand, RC Bassat, Q AF Valim, Clarissa Ahmad, Rushdy Lanaspa, Miguel Tan, Yan Acacio, Sozinho Gillette, Michael A. Almendinger, Katherine D. Milner, Danny A., Jr. Madrid, Lola Pelle, Karell Harezlak, Jaroslaw Silterra, Jacob Alonso, Pedro L. Carr, Steven A. Mesirov, Jill P. Wirth, Dyann F. Wiegand, Roger C. Bassat, Quique TI Responses to Bacteria, Virus, and Malaria Distinguish the Etiology of Pediatric Clinical Pneumonia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE biomarkers; pneumonia; immunoassay; bacteria ID COMMUNITY-ACQUIRED PNEUMONIA; RESPIRATORY-TRACT INFECTIONS; GERMAN COMPETENCE NETWORK; TUMOR-NECROSIS-FACTOR; HEALTH-CARE SETTINGS; C-REACTIVE PROTEIN; PNEUMOCOCCAL PNEUMONIA; CHEST RADIOGRAPHS; AFRICAN CHILDREN; YOUNG-CHILDREN AB Rationale: Plasma-detectable biomarkers that rapidly and accurately diagnose bacterial infections in children with suspected pneumonia could reduce the morbidity of respiratory disease and decrease the unnecessary use of antibiotic therapy. Objectives: Using 56 markers measured in a multiplexed immunoassay, we sought to identify proteins and protein combinations that could discriminate bacterial from viral or malarial diagnoses. Methods: We selected 80 patients with clinically diagnosed pneumonia (as defined by the World Health Organization) who also met criteria for bacterial, viral, or malarial infection based on clinical, radiographic, and laboratory results. Ten healthy community control subjects were enrolled to assess marker reliability. Patients were subdivided into two sets: one for identifying potential markers and another for validating them. Measurements and Main Results:. Three proteins (haptoglobin, tumor necrosis factor receptor 2 or IL-10, and tissue inhibitor of metalloproteinases 1) were identified that, when combined through a classification tree signature, accurately classified patients into bacterial, malarial, and viral etiologies and misclassified only one patient with bacterial pneumonia from the validation set. The overall sensitivity and specificity of this signature for the bacterial diagnosis were 96 and 86%, respectively. Alternative combinations of markers with comparable accuracy were selected by support vector machine and regression models and included haptoglobin, IL-10, and creatine kinase MB. Conclusions: Combinations of plasma proteins accurately identified children with a respiratory syndrome who were likely to have bacterial infections and who would benefit from antibiotic therapy. When used in conjunction with malaria diagnostic tests, they may improve diagnostic specificity and simplify treatment decisions for clinicians. C1 [Valim, Clarissa; Milner, Danny A., Jr.; Pelle, Karell; Wirth, Dyann F.] Harvard Univ, Dept Immunol & Infect Dis, TH Chan Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Valim, Clarissa; Ahmad, Rushdy; Tan, Yan; Gillette, Michael A.; Almendinger, Katherine D.; Milner, Danny A., Jr.; Pelle, Karell; Silterra, Jacob; Carr, Steven A.; Mesirov, Jill P.; Wirth, Dyann F.; Wiegand, Roger C.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Lanaspa, Miguel; Madrid, Lola; Alonso, Pedro L.; Bassat, Quique] Barcelona Ctr Int Hlth Res, Barcelona Inst Global Hlth, Barcelona, Spain. [Lanaspa, Miguel; Madrid, Lola; Alonso, Pedro L.; Bassat, Quique] Hosp Clin Univ Barcelona, Barcelona, Spain. [Lanaspa, Miguel; Acacio, Sozinho; Madrid, Lola; Alonso, Pedro L.; Bassat, Quique] Ctr Invest Saude Manhica, Maputo, Mozambique. [Tan, Yan; Mesirov, Jill P.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Acacio, Sozinho] Minist Hlth, Natl Inst Hlth, Maputo, Mozambique. [Gillette, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gillette, Michael A.; Milner, Danny A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Milner, Danny A., Jr.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Harezlak, Jaroslaw] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA. [Harezlak, Jaroslaw] Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. RP Wirth, DF (reprint author), Harvard Univ, Dept Immunol & Infect Dis, TH Chan Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM dfwirth@hsph.harvard.edu RI Bassat, Quique/P-2341-2016 OI Bassat, Quique/0000-0003-0875-7596 FU Bill and Melinda Gates Foundation [OPP50092]; program Miguel Servet of the ISCIII (Plan Nacional de I+D+I) [CP11/00269]; program Rio Hortega of the ISCIII [CM13/00260] FX Supported by the Bill and Melinda Gates Foundation (grant OPP50092). Q.B. has a fellowship from the program Miguel Servet of the ISCIII (Plan Nacional de I+D+I 2008-2011, grant CP11/00269). L.M. has a fellowship from the program Rio Hortega of the ISCIII (CM13/00260). The funders had no role in the study design, collection, analysis, interpretation of data, writing of the manuscript, or in the decision to submit the manuscript for publication. NR 54 TC 5 Z9 5 U1 2 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2016 VL 193 IS 4 BP 448 EP 459 DI 10.1164/rccm.201506-1100OC PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DE1MW UT WOS:000370392100017 PM 26469764 ER PT J AU Dudley, JC Lin, MT Le, DT Eshleman, JR AF Dudley, Jonathan C. Lin, Ming-Tseh Le, Dung T. Eshleman, James R. TI Microsatellite Instability as a Biomarker for PD-1 Blockade SO CLINICAL CANCER RESEARCH LA English DT Review ID NONPOLYPOSIS COLORECTAL-CANCER; MISMATCH-REPAIR DEFICIENCY; COMPREHENSIVE MOLECULAR CHARACTERIZATION; CELL LUNG-CANCER; LYNCH-SYNDROME; COLON-CANCER; MUTATION CARRIERS; ENDOMETRIAL CANCER; PROGNOSTIC-SIGNIFICANCE; GENETIC INSTABILITY AB Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%-33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%-2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine. (C) 2016 AACR. C1 [Dudley, Jonathan C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lin, Ming-Tseh; Eshleman, James R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Le, Dung T.; Eshleman, James R.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Eshleman, JR (reprint author), Johns Hopkins Univ, Sch Med, Suite 344,Canc Res Bldg 2,1550 Orleans St, Baltimore, MD 21231 USA. EM jeshlem@jhmi.edu NR 100 TC 26 Z9 28 U1 16 U2 36 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2016 VL 22 IS 4 BP 813 EP 820 DI 10.1158/1078-0432.CCR-15-1678 PG 8 WC Oncology SC Oncology GA DD7TY UT WOS:000370128500006 PM 26880610 ER PT J AU Kenkre, VP Hong, FX Cerhan, JR Lewis, M Sullivan, L Williams, ME Gascoyne, RD Horning, SJ Kahl, BS AF Kenkre, Vaishalee P. Hong, Fangxin Cerhan, James R. Lewis, Marcia Sullivan, Leslie Williams, Michael E. Gascoyne, Randy D. Horning, Sandra J. Kahl, Brad S. TI Fc Gamma Receptor 3A and 2A Polymorphisms Do Not Predict Response to Rituximab in Follicular Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTI-CD20 MONOCLONAL-ANTIBODY; LOW-TUMOR-BURDEN; RANDOMIZED CONTROLLED-TRIAL; NON-HODGKINS-LYMPHOMA; ADVANCED-STAGE; CELL LYMPHOMA; PHASE-II; IN-VIVO; THERAPY; RIIIA AB Purpose: Preclinical studies suggest that SNPs in the Fc gamma receptor (FCGR) genes influence response to rituximab, but the clinical relevance of this is uncertain. Experimental Design: We prospectively obtained specimens for genotyping in the rituximab extended schedule or re-treatment trial (RESORT) study, in which 408 previously untreated, low tumor burden follicular lymphoma (FL) patients were treated with single agent rituximab. Patients received rituximab in 4 weekly doses and responders were randomized to rituximab retreatment (RR) upon progression versus maintenance rituximab (MR). SNP genotyping was performed in 321 consenting patients. Results: Response rates to initial therapy and response duration were correlated with the FCGR3A SNP at position 158 (rs396991) and the FCGR2A SNP at position 131 (rs1801274). The response rate to initial rituximab was 71%. No FCGR genotypes or grouping of genotypes were predictive of initial response. A total of 289 patients were randomized to RR (n = 143) or to MR (n = 146). With a median follow-up of 5.5 years, the 3-year response duration in the RR arm and the MR arm was 50% and 78%, respectively. Genotyping was available in 235 of 289 randomized patients. In patients receiving RR (n = 115) or MR (n = 120), response duration was not associated with any FCGR genotypes or genotype combinations. Conclusions: Based on this analysis of treatment-naive, low tumor burden FL, we conclude that the FCGR3A and FCGR2A SNPs do not confer differential responsiveness to rituximab. (C) 2015 AACR. C1 [Kenkre, Vaishalee P.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cerhan, James R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lewis, Marcia; Sullivan, Leslie] Transgenomic Inc, Omaha, NE USA. [Williams, Michael E.] Univ Virginia, Sch Med, Dept Med, Charlottesville, VA 22908 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Gascoyne, Randy D.] Ctr Lymphoid Canc, Vancouver, BC, Canada. [Horning, Sandra J.] Genentech Roche Inc, San Francisco, CA USA. [Kahl, Brad S.] Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA. RP Kahl, BS (reprint author), Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA. EM bkahl@dom.wustl.edu FU Public Health Service Grants [CA180820, CA180794, CA180799, CA180790, CA180847, CA180816]; NCI, NIH; Department of Health and Human Services; Lymphoma Research Foundation; University of Wisconsin Forward Lymphoma Fund FX This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD, and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA180799, CA180790, CA180847, CA180816 and from the NCI, NIH, and the Department of Health and Human Services. This work was supported by a grant from the Lymphoma Research Foundation and the University of Wisconsin Forward Lymphoma Fund. NR 27 TC 3 Z9 3 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 FEB 15 PY 2016 VL 22 IS 4 BP 821 EP 826 DI 10.1158/1078-0432.CCR-15-1848 PG 6 WC Oncology SC Oncology GA DD7TY UT WOS:000370128500007 PM 26510856 ER PT J AU Sarantopoulos, J Shapiro, GI Cohen, RB Clark, JW Kauh, JS Weiss, GJ Cleary, JM Mahalingam, D Pickard, MD Faessel, HM Berger, AJ Burke, K Mulligan, G Dezube, BJ Harvey, RD AF Sarantopoulos, John Shapiro, Geoffrey I. Cohen, Roger B. Clark, Jeffrey W. Kauh, John S. Weiss, Glen J. Cleary, James M. Mahalingam, Devalingam Pickard, Michael D. Faessel, Helene M. Berger, Allison J. Burke, Kristine Mulligan, George Dezube, Bruce J. Harvey, R. Donald TI Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID CONTINUAL REASSESSMENT METHOD; UBIQUITIN-PROTEASOME SYSTEM; ACUTE MYELOID-LEUKEMIA; ANTICANCER THERAPIES; PROTEIN-DEGRADATION; OVARIAN-CANCER; S-PHASE; MLN4924; CELLS; APOPTOSIS AB Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. Results: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade >= 3 treatmentrelated serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with anMTDbetween 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. (C) 2015 AACR. C1 [Sarantopoulos, John; Mahalingam, Devalingam] Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Shapiro, Geoffrey I.; Cleary, James M.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Cohen, Roger B.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Clark, Jeffrey W.] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Kauh, John S.; Harvey, R. Donald] Emory Univ, Winship Canc Inst, Hematol & Med Oncol, Atlanta, GA 30322 USA. [Weiss, Glen J.] Scottsdale Healthcare, Virginia G Piper Canc Ctr, Scottsdale, AZ USA. [Pickard, Michael D.; Faessel, Helene M.; Berger, Allison J.; Burke, Kristine; Mulligan, George; Dezube, Bruce J.] Millennium Pharmaceut Inc, Cambridge, MA USA. RP Sarantopoulos, J (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. EM Sarantopoulo@uthscsa.edu FU Millennium Pharmaceuticals, Inc.; Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio: Cancer Center Support Grant [P30CA054174]; University of Pennsylvania, Philadelphia, PA FX This work was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; The Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio: Cancer Center Support Grant (P30CA054174); and University of Pennsylvania, Philadelphia, PA. NR 45 TC 11 Z9 11 U1 1 U2 4 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 FEB 15 PY 2016 VL 22 IS 4 BP 847 EP 857 DI 10.1158/1078-0432.CCR-15-1338 PG 11 WC Oncology SC Oncology GA DD7TY UT WOS:000370128500010 PM 26423795 ER PT J AU Paweletz, CP Sacher, AG Raymond, CK Alden, RS O'Connell, A Mach, SL Kuang, YA Gandhi, L Kirschmeier, P English, JM Lim, LP Janne, PA Oxnard, GR AF Paweletz, Cloud P. Sacher, Adrian G. Raymond, Chris K. Alden, Ryan S. O'Connell, Allison Mach, Stacy L. Kuang, Yanan Gandhi, Leena Kirschmeier, Paul English, Jessie M. Lim, Lee P. Jaenne, Pasi A. Oxnard, Geoffrey R. TI Bias-Corrected Targeted Next-Generation Sequencing for Rapid, Multiplexed Detection of Actionable Alterations in Cell-Free DNA from Advanced Lung Cancer Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID CIRCULATING FREE DNA; MUTATION STATUS; TUMOR-DNA; GEFITINIB; THERAPY; PLASMA; NSCLC AB Purpose: Tumor genotyping is a powerful tool for guiding non-small cell lung cancer (NSCLC) care; however, comprehensive tumor genotyping can be logistically cumbersome. To facilitate genotyping, we developed a next-generation sequencing (NGS) assay using a desktop sequencer to detect actionable mutations and rearrangements in cell-free plasma DNA (cfDNA). Experimental Design: An NGS panel was developed targeting 11 driver oncogenes found in NSCLC. Targeted NGS was performed using a novel methodology that maximizes on-target reads, and minimizes artifact, and was validated on DNA dilutions derived from cell lines. Plasma NGS was then blindly performed on 48 patients with advanced, progressive NSCLC and a known tumor genotype, and explored in two patients with incomplete tumor genotyping. Results: NGS could identify mutations present in DNA dilutions at >= 0.4% allelic frequency with 100% sensitivity/specificity. Plasma NGS detected a broad range of driver and resistance mutations, including ALK, ROS1, and RET rearrangements, HER2 insertions, and MET amplification, with 100% specificity. Sensitivity was 77% across 62 known driver and resistance mutations from the 48 cases; in 29 cases with common EGFR and KRAS mutations, sensitivity was similar to droplet digital PCR. In two cases with incomplete tumor genotyping, plasma NGS rapidly identified a novel EGFR exon 19 deletion and a missed case of MET amplification. Conclusions: Blinded to tumor genotype, this plasma NGS approach detected a broad range of targetable genomic alterations in NSCLC with no false positives including complex mutations like rearrangements and unexpected resistance mutations such as EGFR C797S. Through use of widely available vacutainers and a desktop sequencing platform, this assay has the potential to be implemented broadly for patient care and translational research. (C) 2015 AACR. C1 [Paweletz, Cloud P.; O'Connell, Allison; Kuang, Yanan; Kirschmeier, Paul; English, Jessie M.; Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA. [Sacher, Adrian G.; Alden, Ryan S.; Mach, Stacy L.; Gandhi, Leena; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Raymond, Chris K.; Lim, Lee P.] Resolut Biosci, Bellevue, WA USA. RP Oxnard, GR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM geoffrey_oxnard@dfci.harvard.edu RI Sacher, Adrian/I-8080-2016; OI Sacher, Adrian/0000-0001-7865-2701; Gandhi, Leena/0000-0002-2398-9179 FU Department of Defense; Conquer Cancer Foundation of ASCO; Phi Beta Psi Sorority; Stading-Younger Cancer Research Foundation; Expect Miracles Foundation; Harold and Gail Kirstein Lung Cancer Research Fund; US National Institutes of Health [R01CA135257] FX This work was supported in part by the Department of Defense, Conquer Cancer Foundation of ASCO, Phi Beta Psi Sorority, Stading-Younger Cancer Research Foundation, Expect Miracles Foundation, Harold and Gail Kirstein Lung Cancer Research Fund, and US National Institutes of Health grant R01CA135257 (P.A. Janne). NR 26 TC 25 Z9 26 U1 6 U2 18 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 FEB 15 PY 2016 VL 22 IS 4 BP 915 EP 922 DI 10.1158/1078-0432.CCR-15-1627-T PG 8 WC Oncology SC Oncology GA DD7TY UT WOS:000370128500017 PM 26459174 ER PT J AU Hecht, VC Sullivan, LB Kimmerling, RJ Kim, DH Hosios, AM Stockslager, MA Stevens, MM Kang, JH Wirtz, D Vander Heiden, MG Manalis, SR AF Hecht, Vivian C. Sullivan, Lucas B. Kimmerling, Robert J. Kim, Dong-Hwee Hosios, Aaron M. Stockslager, Max A. Stevens, Mark M. Kang, Joon Ho Wirtz, Denis Vander Heiden, Matthew G. Manalis, Scott R. TI Biophysical changes reduce energetic demand in growth factor-deprived lymphocytes SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CD8(+) T-CELLS; SURVIVAL; MEMORY; AUTOPHAGY; DENSITY; PROLIFERATION; BCL-2; SIZE; MAINTAINS; NAIVE AB Cytokine regulation of lymphocyte growth and proliferation is essential for matching nutrient consumption with cell state. Here, we examine how cellular biophysical changes that occur immediately after growth factor depletion promote adaptation to reduced nutrient uptake. After growth factor withdrawal, nutrient uptake decreases, leading to apoptosis. Bcl-xL expression prevents cell death, with autophagy facilitating long-term cell survival. However, autophagy induction is slow relative to the reduction of nutrient uptake, suggesting that cells must engage additional adaptive mechanisms to respond initially to growth factor depletion. We describe an acute biophysical response to growth factor withdrawal, characterized by a simultaneous decrease in cell volume and increase in cell density, which occurs before autophagy initiation and is observed in both FL5.12 Bcl-xL cells depleted of IL-3 and primary CD8(+) T cells depleted of IL-2 that are differentiating toward memory cells. The response reduces cell surface area to minimize energy expenditure while conserving biomass, suggesting that the biophysical properties of cells can be regulated to promote survival under conditions of nutrient stress. C1 [Hecht, Vivian C.; Kimmerling, Robert J.; Manalis, Scott R.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Hecht, Vivian C.; Sullivan, Lucas B.; Kimmerling, Robert J.; Hosios, Aaron M.; Stevens, Mark M.; Kang, Joon Ho; Vander Heiden, Matthew G.; Manalis, Scott R.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Sullivan, Lucas B.; Hosios, Aaron M.; Stevens, Mark M.; Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kang, Joon Ho] MIT, Dept Phys, Cambridge, MA 02139 USA. [Stockslager, Max A.; Manalis, Scott R.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Kim, Dong-Hwee; Wirtz, Denis] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD 21218 USA. [Kim, Dong-Hwee; Wirtz, Denis] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Kim, Dong-Hwee; Wirtz, Denis] Johns Hopkins Sch Med, Dept Pathol & Oncol, Baltimore, MD 21205 USA. [Kim, Dong-Hwee; Wirtz, Denis] Johns Hopkins Sch Med, Sydney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kim, Dong-Hwee] Korea Univ, KU KIST Grad Sch Converging Sci & Technol, Seoul 02841, South Korea. RP Manalis, SR (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG; Manalis, SR (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Manalis, SR (reprint author), MIT, Dept Mech Engn, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mvh@mit.edu; srm@mit.edu FU Koch Institute Support (core) grant from the National Cancer Institute [P30-CA14051]; Physical Sciences Oncology Center [U54CA143874]; Burrough's Wellcome Foundation; Ludwig Center at the Massachusetts Institute of Technology; Damon Runyon Cancer Research Foundation; American Cancer Society [PF-15-096-01-TBE] FX This work was supported by a Koch Institute Support (core) grant from the National Cancer Institute (P30-CA14051), Physical Sciences Oncology Center (U54CA143874), Burrough's Wellcome Foundation, the Ludwig Center at the Massachusetts Institute of Technology, and the Damon Runyon Cancer Research Foundation. Lucas B. Sullivan was supported by a postdoctoral fellowship from the American Cancer Society (PF-15-096-01-TBE). NR 49 TC 1 Z9 1 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 15 PY 2016 VL 212 IS 4 BP 439 EP 447 DI 10.1083/jcb.201506118 PG 9 WC Cell Biology SC Cell Biology GA DE2WS UT WOS:000370488700009 PM 26880201 ER PT J AU Hon, YY Lin, EE Tian, X Yang, Y Sun, H Swenson, ER Taveira-Dasilva, AM Gladwin, MT Machado, RF AF Hon, Yuen Yi Lin, Elaina E. Tian, Xin Yang, Yang Sun, He Swenson, Erik R. Taveira-Dasilva, Angelo M. Gladwin, Mark T. Machado, Roberto F. TI Increased consumption and vasodilatory effect of nitrite during exercise SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE nitrite store; incremental exercise test; pharmacokinetics; hemodynamics; vasodilation ID DIETARY NITRATE SUPPLEMENTATION; OXIDE PRODUCTION; BLOOD-FLOW; MITOCHONDRIAL RESPIRATION; XANTHINE-OXIDASE; OXYGEN-UPTAKE; O-2 COST; L-NAME; CAPACITY; HUMANS AB This study investigated the effects of aerobic-to-anaerobic exercise on nitrite stores in the human circulation and evaluated the effects of systemic nitrite infusion on aerobic and anaerobic exercise capacity and hemodynamics. Six healthy volunteers were randomized to receive sodium nitrite or saline for 70 min in two separate occasions in an exercise study. Subjects cycled on an upright electronically braked cycle ergometer 30 min into the infusion according to a ramp protocol designed to attain exhaustion in 10 min. They were allowed to recover for 30 min thereafter. The changes of whole blood nitrite concentrations over the 70-min study period were analyzed by pharmacokinetic modeling. Longitudinal measurements of hemodynamic and clinical variables were analyzed by fitting nonparametric regression spline models. During exercise, nitrite consumption/elimination rate was increased by similar to 137%. Cardiac output (CO), mean arterial pressure (MAP), and pulmonary artery pressure (PAP) were increased, but smaller elevation of MAP and larger increases of CO and PAP were found during nitrite infusion compared with placebo control. The higher CO and lower MAP during nitrite infusion were likely attributed to vasodilation and a trend toward decrease in systemic vascular resistance. In contrast, there were no significant changes in mean pulmonary artery pressures and pulmonary vascular resistance. These findings, together with the increased consumption of nitrite and production of iron-nitrosyl-hemoglobin during exercise, support the notion of nitrite conversion to release NO resulting in systemic vasodilatation. However, at the dosing used in this protocol achieving micromolar plasma concentrations of nitrite, exercise capacity was not enhanced, as opposed to other reports using lower dosing. C1 [Hon, Yuen Yi] Clin Ctr Pharm Dept, NIH, Bethesda, MD USA. [Lin, Elaina E.; Gladwin, Mark T.; Machado, Roberto F.] NHLBI, Vasc Med Branch, Bldg 10, Bethesda, MD 20892 USA. [Tian, Xin; Yang, Yang] NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. [Sun, He] Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin 300072, Peoples R China. [Swenson, Erik R.] Univ Washington, VA Puget Sound Hlth Care Syst, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Taveira-Dasilva, Angelo M.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. RP Machado, RF (reprint author), Univ Illinois, Sect Pulm Crit Care Med Sleep & Allergy, 840 S Wood St,Rm 920-N,Clin Sci Bldg,MC 719, Chicago, IL 60612 USA. EM machador@uic.edu FU Intramural Research Program of Clinical Center Pharmacy Department; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of Clinical Center Pharmacy Department and the National Heart, Lung, and Blood Institute, National Institutes of Health. There was no commercial sponsorship. NR 43 TC 2 Z9 2 U1 5 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD FEB 15 PY 2016 VL 310 IS 4 BP 1354 EP 1364 DI 10.1152/ajplung.00081.2015 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA DD7DU UT WOS:000370084700006 ER PT J AU Bychkovsky, BL Ferreyra, ME Strasser-Weippl, K Herold, CI Lopes, GD Dizon, DS Schmeler, KM Del Carmen, M Randall, TC Nogueira-Rodrigues, A Calabrich, AFD Louis, JS Vail, CM Goss, PE AF Bychkovsky, Brittany L. Ferreyra, Mayra E. Strasser-Weippl, Kathrin Herold, Christina I. Lopes, Gilberto de Lima, Jr. Dizon, Don S. Schmeler, Kathleen M. Del Carmen, Marcela Randall, Tom C. Nogueira-Rodrigues, Angelica de Carvalho Calabrich, Aknar Freire Louis, Jessica St. Vail, Caroline M. Goss, Paul E. TI Cervical cancer control in Latin America: A call to action SO CANCER LA English DT Review DE cervical cancer; human papillomavirus (HPV); Latin America; screening; vaccination ID HUMAN-PAPILLOMAVIRUS VACCINATION; HPV VACCINATION; COST-EFFECTIVENESS; INTRAEPITHELIAL NEOPLASIA; QUADRIVALENT VACCINE; SURVIVAL ANALYSIS; PROGRAM; WOMEN; PREVENTION; HEALTH AB Cervical cancer (CC) is second most common cause of cancer in Latin America and is a leading cause of cancer mortality among women. In 2015, an estimated 74,488 women will be diagnosed with CC in Latin America and 31,303 will die of the disease. CC mortality is projected to increase by 45% by 2030 despite human papillomavirus (HPV) vaccination and screening efforts. In this setting, the goal was of the current study was to examine CC control efforts in Latin America and identify deficiencies in these efforts that could be addressed to reduce CC incidence and mortality. The authors found that HPV vaccination has been introduced in the majority of Latin American countries, and there is now a need to monitor the success (or shortcomings) of these programs and to ensure that these programs are sustainable. This topic was also reviewed in light of emerging data demonstrating that visual inspection with acetic acid and HPV DNA testing without Papanicolaou tests have efficacy from a screening perspective and are good alternatives to cytology-based screening programs. Overall, there is a need to build capacity for CC control in Latin America and the best strategy will depend on the country/region and must be tailored to meet the needs of the population as well as available resources. Cancer 2016;122:502-514. (c) 2015 American Cancer Society. C1 [Bychkovsky, Brittany L.; Herold, Christina I.] Dana Farber Canc Inst, Dept Breast Oncol, Boston, MA 02115 USA. [Bychkovsky, Brittany L.; Herold, Christina I.; Goss, Paul E.] Harvard Univ, Sch Med, Boston, MA USA. [Ferreyra, Mayra E.] Maria Curie Hosp, Dept Oncol, Buenos Aires, DF, Argentina. [Strasser-Weippl, Kathrin] Wilhelminen Hosp, Ctr Oncol & Hematol, Vienna, Austria. [Lopes, Gilberto de Lima, Jr.] Canc Inst Sao Paulo State, Clin Oncol, Sao Paulo, Brazil. [Lopes, Gilberto de Lima, Jr.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Dizon, Don S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Schmeler, Kathleen M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Del Carmen, Marcela] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol, Boston, MA USA. [Randall, Tom C.] Dana Farber Harvard Canc Ctr, Global Oncol Initiat, Boston, MA USA. [Randall, Tom C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Nogueira-Rodrigues, Angelica] Univ Fed Minas Gerais, Brazilian Gynecol Oncol Grp, Belo Horizonte, MG, Brazil. [de Carvalho Calabrich, Aknar Freire] Clin AMO, Salvador, BA, Brazil. [Louis, Jessica St.; Vail, Caroline M.; Goss, Paul E.] Global Canc Inst, Boston, MA USA. [Louis, Jessica St.; Vail, Caroline M.; Goss, Paul E.] Massachusetts Gen Hosp, Avon Int Breast Canc Res Program, 55 Fruit St,Lawrence House,LRH 302, Boston, MA 02114 USA. [Vail, Caroline M.] Univ New England, Biddeford, ME USA. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Avon Breast Canc Ctr Excellence, 55 Fruit St,Lawrence House,LRH-302, Boston, MA 02114 USA.; Goss, PE (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Goss, PE (reprint author), Global Canc Inst, Boston, MA USA.; Goss, PE (reprint author), Massachusetts Gen Hosp, Avon Int Breast Canc Res Program, 55 Fruit St,Lawrence House,LRH 302, Boston, MA 02114 USA. EM pgoss@partners.org FU Avon Foundation; World Health Organization; Pfizer; Eli Lilly; Sanofi Aventis; Boehringer Ingelheim; Astra Zeneca; Roche; Merck-Serono; Merck Sharp; Dhome; Fresenius Kabi; Bristol-Myers Squibb; government of Brazil; government of United States; government of Singapore FX Mayra E. Ferreyra, Jessica St. Louis, Caroline M. Vail, and Paul E. Goss are supported by the Avon Foundation. Gilberto de Lima Lopes Jr. has received nonfinancial support and travel fees from the World Health Organization; grants and personal fees from Pfizer, Eli Lilly, Sanofi Aventis, Boehringer Ingelheim, Astra Zeneca, Roche, Merck-Serono, Merck Sharp and Dhome, Fresenius Kabi, and Bristol-Myers Squibb; and grants from the governments of Brazil, Singapore, and the United States for work performed outside of the current study. Tom C. Randall has acted as a consultant for the National Cancer Institute Center for Global Health. NR 106 TC 1 Z9 1 U1 3 U2 9 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 FEB 15 PY 2016 VL 122 IS 4 BP 502 EP 514 DI 10.1002/cncr.29813 PG 13 WC Oncology SC Oncology GA DD5YA UT WOS:000369999600005 PM 26670695 ER PT J AU Landsburg, DJ Petrich, AM Abramson, JS Sohani, AR Press, O Cassaday, R Chavez, JC Song, K Zelenetz, AD Gandhi, M Shah, N Fenske, TS Jaso, J Medeiros, LJ Yang, DT Nabhan, C AF Landsburg, Daniel J. Petrich, Adam M. Abramson, Jeremy S. Sohani, Aliyah R. Press, Oliver Cassaday, Ryan Chavez, Julio C. Song, Kevin Zelenetz, Andrew D. Gandhi, Mitul Shah, Namrata Fenske, Timothy S. Jaso, Jesse Medeiros, L. Jeffrey Yang, David T. Nabhan, Chadi TI Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma SO CANCER LA English DT Article DE BCL2 (B-cell lymphoma 2); BCL6 (B-cell lymphoma 6); gene rearrangement; MYC; non-Hodgkin lymphoma ID B-CELL LYMPHOMA; RITUXIMAB PLUS CYCLOPHOSPHAMIDE; IN-VIVO EFFICACY; MYC; BCL6; TRANSLOCATIONS; VINCRISTINE; DOXORUBICIN; PREDNISONE; EXPRESSION AB BACKGROUNDDouble-hit lymphomas (DHLs) are collectively defined as B-cell non-Hodgkin lymphomas harboring rearrangements of MYC as well as B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6). To the authors' knowledge, the impact of specific oncogene rearrangements on outcomes of patients with DHL who are treated with immunochemotherapy has not been previously described. METHODSThe authors identified patients whose diagnostic tissue specimens underwent metaphase karyotyping or fluorescence in situ hybridization for MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (-) of rearrangements: MYC+/BCL2+/BCL6- (BCL2-DHL), MYC+/BCL2-/BCL6+ (BCL6-DHL), and MYC+/BCL2+/BCL6+ (triple-hit lymphoma; THL). RESULTSA total of 117 patients were included in the current analysis (76 BCL2-DHL patients, 16 BCL6-DHL patients, and 25 THL patients). Compared with patients with BCL2-DHL, those with BCL6-DHL were more likely to be classified as having a non-germinal center cell of origin, presented with extranodal disease, and appeared to achieve higher rates of complete response despite receiving intensive induction therapy less frequently. However, patients with BCL6-DHL experienced a shorter median overall survival if achieving an initial complete response compared with patients with BCL2-DHL. Patients with THL experienced survival outcomes similar to those of patients with BCL2-DHL. CONCLUSIONSRecognition of the specific oncogene rearrangements may be of prognostic value and potentially guide future therapeutic strategies for patients with DHL. Cancer 2016;122:559-564. (c) 2015 American Cancer Society. C1 [Landsburg, Daniel J.] Hosp Univ Penn, Div Hematol Oncol, 3400 Civic Ctr Blvd,PCAM 2 South, Philadelphia, PA 19104 USA. [Petrich, Adam M.; Gandhi, Mitul] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Boston, MA USA. [Press, Oliver; Cassaday, Ryan] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Chavez, Julio C.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Malignant Hematol, Tampa, FL 33682 USA. [Song, Kevin] British Columbia Canc Agcy, Leukemia BMT Program British Columbia, Vancouver, BC V5Z 4E6, Canada. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Gandhi, Mitul] Virginia Canc Specialists, Fairfax, VA USA. [Shah, Namrata; Fenske, Timothy S.] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Jaso, Jesse; Medeiros, L. Jeffrey] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Yang, David T.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Nabhan, Chadi] Univ Chicago, Dept Med, Sect Hematol & Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Landsburg, DJ (reprint author), Hosp Univ Penn, Div Hematol Oncol, 3400 Civic Ctr Blvd,PCAM 2 South, Philadelphia, PA 19104 USA. EM daniel.landsburg@uphs.upenn.edu FU Genentech/Roche; Roche; Gilead; GlaxoSmithKline; Janssen; Celgene; Hospira; Amgen; Medscape; Bristol-Myers Squibb FX Jeremy S. Abramson has acted as a paid member of the Scientific Advisory Boards for Incyte, Gilead, Pharmacyclics, Millennium, Amgen, and Seattle Genetics for work performed outside of the current study. Aliyah R. Sohani has received honorarium from Seattle Genetics for a speech given to company employees outside of the current study. Oliver Press has acted as a paid advisor or in an advisory role for BIND Biosciences, Algeta ASA, and PhaseRx and has received grants and fees as part of clinical trial funding/iDSMB membership from Genentech/Roche for work performed outside of the current study. He also owns stock in Emergent BioSolutions and has stock options in Adaptive Biotechnologies, which is not publically traded. Andrew D. Zelenetz has received research and consulting fees from Roche, Gilead, GlaxoSmithKline, and Janssen; consulting fees from Celgene, Hospira, Amgen, and Medscape; and research fees from Bristol-Myers Squibb for work performed outside of the current study. NR 21 TC 8 Z9 8 U1 1 U2 3 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 FEB 15 PY 2016 VL 122 IS 4 BP 559 EP 564 DI 10.1002/cncr.29781 PG 6 WC Oncology SC Oncology GA DD5YA UT WOS:000369999600010 PM 26565895 ER PT J AU Schiff, D Desjardins, A Cloughesy, T Mikkelsen, T Glantz, M Chamberlain, MC Reardon, DA Wen, PY AF Schiff, David Desjardins, Annick Cloughesy, Timothy Mikkelsen, Thomas Glantz, Michael Chamberlain, Marc C. Reardon, David A. Wen, Patrick Y. TI Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas SO CANCER LA English DT Article DE antiangiogenic therapy; cabozantinib; glioblastoma; high-grade glioma; signal transduction inhibitors ID C-MET; GROWTH-FACTOR; KINASE INHIBITOR; POOR-PROGNOSIS; THYROID-CANCER; GLIOBLASTOMA; BEVACIZUMAB; CELLS; EXPRESSION; INVASION AB BACKGROUNDCabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma. METHODSCabozantinib doses of 40mg and 60mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and 1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21). RESULTSA total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60mg daily was the maximum administered dose and a dose of 40mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONSCabozantinib at a dose of 40mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma. (c) 2015 American Cancer Society. C1 [Schiff, David] Univ Virginia, Med Ctr, Neurooncol Ctr, Dept Neurol, Box 800432, Charlottesville, VA 22908 USA. [Desjardins, Annick; Reardon, David A.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC USA. [Cloughesy, Timothy] Univ Calif Los Angeles, Ctr Oncol, Neurooncol Program, Los Angeles, CA USA. [Mikkelsen, Thomas] Henry Ford Hlth Syst, Dept Neurosurg, Div Neurooncol, Detroit, MI USA. [Glantz, Michael] Pennsylvania State Coll Med, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA USA. [Chamberlain, Marc C.] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Neurooncol, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Reardon, David A.; Wen, Patrick Y.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Schiff, D (reprint author), Univ Virginia, Neurooncol Ctr, Dept Neurol, Box 800432, Charlottesville, VA 22908 USA.; Schiff, D (reprint author), Univ Virginia, Med Ctr, Neurooncol Ctr, Dept Neurol, Box 800432, Charlottesville, VA 22908 USA. EM davidschiff@virginia.edu FU Exelixis Inc. FX Funded by Exelixis Inc. NR 20 TC 3 Z9 3 U1 1 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 FEB 15 PY 2016 VL 122 IS 4 BP 582 EP 587 DI 10.1002/cncr.29798 PG 6 WC Oncology SC Oncology GA DD5YA UT WOS:000369999600013 PM 26588662 ER PT J AU Filson, CP Shelton, JB Tan, HJ Kwan, L Skolarus, TA Saigal, CS Litwin, MS AF Filson, Christopher P. Shelton, Jeremy B. Tan, Hung-Jui Kwan, Lorna Skolarus, Ted A. Saigal, Christopher S. Litwin, Mark S. TI Expectant management of veterans with early-stage prostate cancer SO CANCER LA English DT Article DE active surveillance; expectant management; prostate cancer; veterans' health; watchful waiting ID POPULATION-BASED COHORT; LOW-RISK; RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; TRENDS; MEN; RECOMMENDATIONS; PREFERENCES; COMORBIDITY; SURVIVAL AB BACKGROUNDFor certain men with low-risk prostate cancer, aggressive treatment results in marginal survival benefits while exposing them to urinary and sexual side effects. Nevertheless, expectant management has been underused. In the current study, the authors evaluated the association between various factors and expectant management use among veterans diagnosed with prostate cancer. METHODSThe authors identified men diagnosed with prostate cancer in 2008. The outcome of interest was use of expectant management, based on documentation captured through an in-depth chart review. Multivariable regression models were fit to examine associations between use of expectant management and patient demographics, cancer severity, and facility characteristics. The authors assessed variation across 21 tertiary care regions and 52 facilities by generating predicted probabilities for receipt of expectant management. RESULTSExpectant management was more common among patients aged 75 years (40% vs 27% for those aged<55 years; odds ratio, 2.57) and those with low-risk tumors (49% vs 20% for patients with high-risk tumors; odds ratio, 5.35). There was no association noted between patient comorbidity and receipt of expectant management (P=.90). There were also no associations found between facility factors and use of expectant management (all P>.05). Among ideal candidates for expectant management, receipt of expectant management varied considerably across individual facilities (0%-85%; P<.001). CONCLUSIONSPatient age and tumor risk were found to be more strongly associated with use of expectant management than patient comorbidity. Although use of expectant management appears broadly appropriate, there was variation in expectant management noted between hospitals that was apparently not attributable to facility factors. Research determining the basis of this variation, with a focus on providers, will be critical to help optimize prostate cancer treatment for veterans. (c) 2015 American Cancer Society. C1 [Filson, Christopher P.] Emory Univ, Sch Med, Dept Urol, 1365 Clifton Rd NE,Bldg B,1st Fl,Ste 1400, Atlanta, GA 30322 USA. [Filson, Christopher P.; Shelton, Jeremy B.; Tan, Hung-Jui; Kwan, Lorna; Saigal, Christopher S.; Litwin, Mark S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Filson, Christopher P.] Vet Affairs Atlanta Healthcare Syst, Decatur, GA USA. [Shelton, Jeremy B.; Skolarus, Ted A.; Saigal, Christopher S.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Shelton, Jeremy B.; Saigal, Christopher S.] Vet Affairs Ann Arbor Healthcare Syst, Hlth Serv Res & Dev Serv, Ctr Clin Management Res, Ann Arbor, MI USA. [Skolarus, Ted A.] Univ Michigan, Dept Urol, Dow Div Hlth Serv Res, Ann Arbor, MI 48109 USA. [Litwin, Mark S.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. RP Filson, CP (reprint author), Emory Univ, Sch Med, Dept Urol, 1365 Clifton Rd NE,Bldg B,1st Fl,Ste 1400, Atlanta, GA 30322 USA. EM cfilson@emory.edu FU American Cancer Society [PF-14-161-01-CPHPS]; Urology Care Foundation Research Scholars Program FX Christopher P. Filson was supported in part by postdoctoral fellowships from the American Cancer Society (PF-14-161-01-CPHPS) and the Urology Care Foundation Research Scholars Program for work performed as part of the current study. NR 27 TC 2 Z9 2 U1 0 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 FEB 15 PY 2016 VL 122 IS 4 BP 626 EP 633 DI 10.1002/cncr.29785 PG 8 WC Oncology SC Oncology GA DD5YA UT WOS:000369999600018 PM 26540451 ER PT J AU Kim, TH Shivdasani, RA AF Kim, Tae-Hee Shivdasani, Ramesh A. TI Stomach development, stem cells and disease SO DEVELOPMENT LA English DT Review DE Epithelial-mesenchymal interactions; Organogenesis; Transcriptional control of development ID HYPERTROPHIC PYLORIC-STENOSIS; POLYPEPTIDE-EXPRESSING METAPLASIA; ENTERIC NERVOUS-SYSTEM; JUNCTIONAL EPIDERMOLYSIS-BULLOSA; TRANSCRIPTION FACTOR BARX1; MOUSE GASTRIC EPITHELIUM; SURFACE MUCOUS CELLS; INTESTINAL METAPLASIA; HELICOBACTER-PYLORI; SMOOTH-MUSCLE AB The stomach, an organ derived from foregut endoderm, secretes acid and enzymes and plays a key role in digestion. During development, mesenchymal-epithelial interactions drive stomach specification, patterning, differentiation and growth through selected signaling pathways and transcription factors. After birth, the gastric epithelium is maintained by the activity of stem cells. Developmental signals are aberrantly activated and stem cell functions are disrupted in gastric cancer and other disorders. Therefore, a better understanding of stomach development and stem cells can inform approaches to treating these conditions. This Review highlights the molecular mechanisms of stomach development and discusses recent findings regarding stomach stem cells and organoid cultures, and their roles in investigating disease mechanisms. C1 [Kim, Tae-Hee] Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 0A4, Canada. [Kim, Tae-Hee] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Kim, TH (reprint author), Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 0A4, Canada.; Kim, TH (reprint author), Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.; Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. EM tae-hee.kim@sickkids.ca; ramesh_shivdasani@dfci.harvard.edu FU National Institutes of Health [R01DK081113]; Hospital for Sick Children (SickKids) Foundation; Catalyst Scholar Award in Regenerative Medicine FX Our research is funded by the National Institutes of Health [R01DK081113 to R.A.S.]; The Hospital for Sick Children (SickKids) Foundation and Catalyst Scholar Award in Regenerative Medicine (to T.-H.K.). Deposited in PMC for release after 12 months. NR 141 TC 3 Z9 3 U1 1 U2 13 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD FEB 15 PY 2016 VL 143 IS 4 BP 554 EP 565 DI 10.1242/dev.124891 PG 12 WC Developmental Biology SC Developmental Biology GA DD7VQ UT WOS:000370133200002 PM 26884394 ER PT J AU Liu, LY Alexa, K Cortes, M Schatzman-Bone, S Kim, AJ Mukhopadhyay, B Cinar, R Kunos, G North, TE Goessling, W AF Liu, Leah Y. Alexa, Kristen Cortes, Mauricio Schatzman-Bone, Stephanie Kim, Andrew J. Mukhopadhyay, Bani Cinar, Resat Kunos, George North, Trista E. Goessling, Wolfram TI Cannabinoid receptor signaling regulates liver development and metabolism SO DEVELOPMENT LA English DT Article DE Cannabinoid receptor; Liver development; Methionine; Zebrafish; Mouse ID S-ADENOSYLHOMOCYSTEINE-HYDROLASE; ENDOCANNABINOID SYSTEM; METHIONINE METABOLISM; TARGETED DISRUPTION; HEPATIC STEATOSIS; LIPID-METABOLISM; CB1 RECEPTORS; ZEBRAFISH; MICE; EXPRESSION AB Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function. C1 [Liu, Leah Y.; Alexa, Kristen; Schatzman-Bone, Stephanie; Kim, Andrew J.; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Cortes, Mauricio; North, Trista E.] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Mukhopadhyay, Bani; Cinar, Resat; Kunos, George] NIAAA, Lab Physiol Studies, Bethesda, MD 20982 USA. [North, Trista E.; Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Goessling, Wolfram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Goessling, Wolfram] Dana Farber Canc Inst, Boston, MA 02215 USA. [Goessling, Wolfram] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Goessling, W (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA.; Goessling, W (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Goessling, W (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA.; Goessling, W (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA.; Goessling, W (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM wgoessling@partners.org OI Goessling, Wolfram/0000-0001-9972-1569; CINAR, RESAT/0000-0002-8597-7253 FU National Institutes of Health NIAAA [F31AA022548]; NIDDK [R03096156, R01DK090311]; Harvard Stem Cell Institute; Biomedical Sciences FX This work was supported by National Institutes of Health NIAAA [F31AA022548 to L.Y.L.] and NIDDK [R03096156 to T.E.N. and R01DK090311 to W.G.], and by the Harvard Stem Cell Institute [to T.E.N. and W.G.]. W.G. is a Pew Scholar in the Biomedical Sciences. Deposited in PMC for release after 12 months. NR 60 TC 1 Z9 1 U1 2 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD FEB 15 PY 2016 VL 143 IS 4 BP 609 EP 622 DI 10.1242/dev.121731 PG 14 WC Developmental Biology SC Developmental Biology GA DD7VQ UT WOS:000370133200008 PM 26884397 ER PT J AU Cunningham, MA Wirth, JR Scott, JL Eudaly, J Collins, EL Gilkeson, GS AF Cunningham, Melissa A. Wirth, Jena R. Scott, Jennifer L. Eudaly, Jackie Collins, Erin L. Gilkeson, Gary S. TI Early Ovariectomy Results in Reduced Numbers of CD11c+/CD11b+Spleen Cells and Impacts Disease Expression in Murine Lupus SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE systemic lupus erythematosus; mouse models; estrogen; ovariectomy; dendritic cells ID ESTROGEN-RECEPTOR-ALPHA; DENDRITIC CELLS; AUTOIMMUNE-DISEASE; B-CELLS; SEX-HORMONES; NITRIC-OXIDE; 17-BETA-ESTRADIOL; ERYTHEMATOSUS; DIFFERENTIATION; MACROPHAGES AB Ninety percent of those diagnosed with systemic lupus erythematosus are female, with peak incidence between the ages of 15 and 45, when women are most hormonally active. Despite significant research effort, the mechanisms underlying this sex bias remain unclear. We previously showed that a functional knockout of estrogen receptor alpha (ER alpha) resulted in significantly reduced renal disease and increased survival in murine lupus. Dendritic cell (DC) development, which requires both estrogen and ER alpha, is impacted, as is activation status and cytokine production. Since both estrogen and testosterone levels have immunomodulating effects, we presently studied the phenotype of NZM2410 lupus-prone mice following post- and prepubertal ovariectomy (OVX) +/- estradiol (E2) replacement to determine the impact of hormonal status on disease expression and DC development in these mice. We observed a trend toward survival benefit in addition to decreased proteinuria and improved renal histology in the early OVX, but not late OVX- or E2-repleted WT mice. Interestingly, there was also a significant difference in splenic DC subsets by flow cytometry. Spleens from NZM mice OVX'd early had a significant decrease in proinflammatory CD11c+CD11b+ DCs (vs. unmanipulated WTs, late OVX- and E2-repleted mice). These early OVX'd animals also had a significant increase in tolerogenic CD11c+CD8a+ DCs vs. WT. These data join a growing body of evidence that supports a role for hormone modulation of DCs that likely impacts the penetrance and severity of autoimmune diseases, such as lupus. C1 [Cunningham, Melissa A.; Wirth, Jena R.; Scott, Jennifer L.; Eudaly, Jackie; Collins, Erin L.; Gilkeson, Gary S.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Hosp, Div Rheumatol & Immunol, Charleston, SC 29425 USA. RP Cunningham, MA (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Affairs Hosp, Div Rheumatol & Immunol, Charleston, SC 29425 USA. EM cunnima@musc.edu OI Cunningham, Melissa/0000-0002-9207-1986 FU South Carolina Clinical & Translational Research (SCTR) Institute; NUI/NCRR [UR1 RR029880, UL1 RR029882]; VA Medical Research Service Merit Award [1I01BX000470-01] FX This publication was supported by The South Carolina Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, NUI/NCRR Grant number UR1 RR029880 and UL1 RR029882; and a VA Medical Research Service Merit Award 1I01BX000470-01. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCRR. NR 46 TC 0 Z9 0 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD FEB 15 PY 2016 VL 7 AR 31 DI 10.3389/fimmu.2016.00031 PG 10 WC Immunology SC Immunology GA DD7RW UT WOS:000370122800001 PM 26913030 ER PT J AU Ying, HQ Dey, P Yao, WT Kimmelman, AC Draetta, GF Maitra, A DePinho, RA AF Ying, Haoqiang Dey, Prasenjit Yao, Wantong Kimmelman, Alec C. Draetta, Giulio F. Maitra, Anirban DePinho, Ronald A. TI Genetics and biology of pancreatic ductal adenocarcinoma SO GENES & DEVELOPMENT LA English DT Review DE KRAS; cancer metabolism; pancreatic cancer; tumor immune modulation ID REGULATORY T-CELLS; MYELOID SUPPRESSOR-CELLS; CANCER STEM-CELLS; TUMOR-INFILTRATING MACROPHAGES; PAPILLARY MUCINOUS NEOPLASMS; CHIMERIC ANTIGEN RECEPTORS; COLONY-STIMULATING FACTOR; RAS-DRIVEN TUMORIGENESIS; DNA-DAMAGE RESPONSE; K-RAS AB With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. C1 [Ying, Haoqiang; Draetta, Giulio F.] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Dey, Prasenjit; DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Yao, Wantong; Draetta, Giulio F.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Div Genom Stabil & DNA Repair, Dept Radiat Oncol, Boston, MA 02115 USA. [Draetta, Giulio F.] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Dept Pathol & Translat Mol Pathol, Houston, TX 77030 USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Sheikh Ahmed Pancreat Canc Res Ctr, Houston, TX 77030 USA. RP Ying, HQ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.; DePinho, RA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. EM hying@mdanderson.org; rdepinho@mdanderson.org FU Sheikh Ahmed Center for Pancreatic Cancer Research and Pancreatic Cancer Moon Shot at the University of Texas MD Anderson Cancer Center; University of Texas Star Award; Department of Defense [W81XWH-14-1-0429, W81XWH-11-1-0418]; Odyssey Fellowship; Anne Eastland Spears Fellowship in GI Cancer Research at the University of Texas MD Anderson Cancer Center; American Cancer Society [RSG-13-298-01-TBG]; National Institutes of Health [R01GM095567, R01CA157490, R01CA188048, U01DK108328, U01CA196403, P01CA117969]; American Association for Cancer Research [14-90-25-DRAE] FX We thank Alan Wang and Denise Spring for critical reading of the manuscript and insightful comments. H.Y. and G.F.D. are supported by the Sheikh Ahmed Center for Pancreatic Cancer Research and Pancreatic Cancer Moon Shot at the University of Texas MD Anderson Cancer Center. H.Y. is also supported by University of Texas Star Award. P.D. is supported by W81XWH-14-1-0429 (Department of Defense). W.Y. is supported by an Odyssey Fellowship and the Anne Eastland Spears Fellowship in GI Cancer Research at the University of Texas MD Anderson Cancer Center. A.C.K. is supported by RSG-13-298-01-TBG (American Cancer Society), R01GM095567, R01CA157490, and R01CA188048 (National Institutes of Health). G.F.D. is supported by 14-90-25-DRAE (American Association for Cancer Research) and W81XWH-11-1-0418 (Department of Defense). A.M. is supported by U01DK108328 and U01CA196403 (National Institutes of Health). R.A.D is supported by P01CA117969 (National Institutes of Health). NR 393 TC 20 Z9 20 U1 7 U2 40 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 FEB 15 PY 2016 VL 30 IS 4 BP 355 EP 385 DI 10.1101/gad.275776.115 PG 31 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DD7UZ UT WOS:000370131500001 PM 26883357 ER PT J AU Koerte, IK Hufschmidt, J Muehlmann, M Tripodis, Y Stamm, JM Pasternak, O Giwerc, MY Coleman, MJ Baugh, CM Fritts, NG Heinen, F Lin, A Stern, RA Shenton, ME AF Koerte, Inga K. Hufschmidt, Jakob Muehlmann, Marc Tripodis, Yorghos Stamm, Julie M. Pasternak, Ofer Giwerc, Michelle Y. Coleman, Michael J. Baugh, Christine M. Fritts, Nathan G. Heinen, Florian Lin, Alexander Stern, Robert A. Shenton, Martha E. TI Cavum Septi Pellucidi in Symptomatic Former Professional Football Players SO JOURNAL OF NEUROTRAUMA LA English DT Article DE biomarkers; head trauma; MRI; neurodegenerative disorders; traumatic brain injury ID CHRONIC TRAUMATIC ENCEPHALOPATHY; REPETITIVE BRAIN TRAUMA; MRI FINDINGS; SCHIZOPHRENIA; INJURY; DEMENTIA; DISORDER; DISEASE; BOXERS; IMPACT AB Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho=0.98; Intraclass Correlation Coefficient [ICC] 0.99; p<0.0001; septum length: rho=0.93; ICC 0.96; p<0.0001). For presence versus absence of CSP, there was high agreement (Cohen kappa=0.83, p<0.0001). A higher rate of CSP, a greater length of CSP, as well as a greater ratio of CSP length to septum length was found in symptomatic former professional football players compared with athlete controls. In addition, a greater length of CSP was associated with decreased performance on a list learning task (Neuropsychological Assessment Battery List A Immediate Recall, p=0.04) and decreased test scores on a measure of estimate verbal intelligence (Wide Range Achievement Test Fourth Edition Reading Test, p=0.02). Given the high prevalence of CSP in neuropathologically confirmed CTE in addition to the results of this study, CSP may serve as a potential early in vivo imaging marker to identify those at high risk for CTE. Future research is needed to investigate the pathomechanism underlying the development of CSP after repetitive head impacts, and its potential association with neuropathologically confirmed CTE. C1 [Koerte, Inga K.; Hufschmidt, Jakob; Muehlmann, Marc; Stamm, Julie M.; Pasternak, Ofer; Giwerc, Michelle Y.; Coleman, Michael J.; Lin, Alexander; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02115 USA. [Koerte, Inga K.; Muehlmann, Marc] Univ Munich, Dept Child & Adolescent Psychiat Psychosomat & Ps, Munich, Germany. [Hufschmidt, Jakob; Heinen, Florian] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat Neurol, Munich, Germany. [Tripodis, Yorghos] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tripodis, Yorghos; Stamm, Julie M.; Baugh, Christine M.; Fritts, Nathan G.; Stern, Robert A.] Boston Univ, Sch Med, CTE Ctr, Boston, MA 02118 USA. [Tripodis, Yorghos; Stern, Robert A.] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Stamm, Julie M.; Stern, Robert A.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Baugh, Christine M.] Harvard Univ, Interfac Initiat Hlth Policy, Cambridge, MA 02138 USA. [Lin, Alexander; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Lin, Alexander] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Clin Spect,Dept Radiol, Boston, MA 02115 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Brockton Div, Brockton, MA USA. RP Koerte, IK (reprint author), Brigham & Womens Hosp, Psychiat Neuroimaging Lab, 1249 Boylston St, Boston, MA 02215 USA. EM ikoerte@bwh.harvard.edu OI Tripodis, Yorghos/0000-0003-2190-7608 FU NCATS NIH HHS [UL1-TR000157]; NIA NIH HHS [P30 AG13846]; NIMH NIH HHS [T32 MH019733]; NINDS NIH HHS [F31 NS 081957, R01 NS078337] NR 39 TC 3 Z9 3 U1 3 U2 14 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 FEB 15 PY 2016 VL 33 IS 4 BP 346 EP 353 DI 10.1089/neu.2015.3880 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DD2NH UT WOS:000369758800004 PM 26414478 ER PT J AU Tisdall, MD Reuter, M Qureshi, A Buckner, RL Fischl, B Kouwe, AJW AF Tisdall, M. Dylan Reuter, Martin Qureshi, Abid Buckner, Randy L. Fischl, Bruce van der Kouwe, Andre J. W. TI Prospective motion correction with volumetric navigators (vNavs) reduces the bias and variance in brain morphometry induced by subject motion SO NEUROIMAGE LA English DT Article DE Head motion; Motion correction; Bias; MRI; Cortical gray matter estimates; Volume; Thickness; Quality control ID FUNCTIONAL CONNECTIVITY MRI; IMAGE-BASED TRACKING; HEAD MOTION; COORDINATE SYSTEM; CORTICAL SURFACE; THICKNESS; CHILDREN; ARTIFACT; IMPACT; FMRI AB Recent work has demonstrated that subject motion produces systematic biases in the metrics computed by widely used morphometry software packages, even when the motion is too small to produce noticeable image artifacts. In the common situation where the control population exhibits different behaviors in the scanner when compared to the experimental population, these systematic measurement biases may produce significant confounds for between-group analyses, leading to erroneous conclusions about group differences. While previous work has shown that prospective motion correction can improve perceived image quality, here we demonstrate that, in healthy subjects performing a variety of directed motions, the use of the volumetric navigator (vNav) prospective motion correction system significantly reduces the motion-induced bias and variance in morphometry. (C) 2015 Elsevier Inc. All rights reserved. C1 [Tisdall, M. Dylan; Reuter, Martin; Buckner, Randy L.; Fischl, Bruce; van der Kouwe, Andre J. W.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Res, Charlestown, MA 02129 USA. [Tisdall, M. Dylan; Reuter, Martin; Buckner, Randy L.; Fischl, Bruce; van der Kouwe, Andre J. W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Tisdall, M. Dylan; Fischl, Bruce; van der Kouwe, Andre J. W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Tisdall, M. Dylan; Reuter, Martin; Qureshi, Abid; Buckner, Randy L.; Fischl, Bruce; van der Kouwe, Andre J. W.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Reuter, Martin; Qureshi, Abid] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Reuter, Martin; Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. RP Tisdall, MD (reprint author), AA Martinos Ctr Biomed Imaging, Room 2301,149 13th St, Charlestown, MA 02141 USA. EM tisdall@nmr.mgh.harvard.edu FU National Cancer Institute [1K25-CA181632-01]; NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01-HD071664, 4R00-HD074649-03]; National Institute of Mental Health [R21-MH096559]; National Center for Research Resources [P41-RR014075, U24-RR021382, 1UL1-RR025758-01, 1S10-RR023401, 1S10-RR019307, 1S10-RR023043]; National Institute for Biomedical Imaging and Bioengineering [8P41-EB015896-15]; National Institute on Aging [5R01-AG008122-23, 2R01- AG016495, R21-AG046657]; National Institute for Neurological Disorders and Stroke [5R21-NS072652-02, 5R01-NS070963-03, 1R01-NS083534]; Simons Foundation; CorticoMetrics FX Support for this research was provided in part by the National Cancer Institute (1K25-CA181632-01), NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD071664, 4R00-HD074649-03), the National Institute of Mental Health (R21-MH096559), the National Center for Research Resources (P41-RR014075, U24-RR021382, 1UL1-RR025758-01, 1S10-RR023401, 1S10-RR019307, 1S10-RR023043), the National Institute for Biomedical Imaging and Bioengineering (8P41-EB015896-15), the National Institute on Aging (5R01-AG008122-23, 2R01- AG016495, R21-AG046657), the National Institute for Neurological Disorders and Stroke (5R21-NS072652-02, 5R01-NS070963-03, 1R01-NS083534), and the Simons Foundation. In addition, BF has a financial interest in CorticoMetrics, a company whose medical pursuits focus on brain imaging and measurement technologies. BF's interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. MR and MDT had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 42 TC 7 Z9 7 U1 0 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 FEB 15 PY 2016 VL 127 BP 11 EP 22 DI 10.1016/j.neuroimage.2015.11.054 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DD5HE UT WOS:000369952900002 PM 26654788 ER PT J AU Opitz, A Fox, MD Craddock, RC Colcombe, S Milham, MP AF Opitz, Alexander Fox, Michael D. Craddock, R. Cameron Colcombe, Stan Milham, Michael P. TI An integrated framework for targeting functional networks via transcranial magnetic stimulation SO NEUROIMAGE LA English DT Article ID HUMAN MOTOR CORTEX; DEEP BRAIN-STIMULATION; ELECTRIC-FIELD; COIL ORIENTATION; INTERINDIVIDUAL VARIABILITY; SUBGENUAL CINGULATE; CEREBRAL-CORTEX; CONNECTIVITY; TMS; DEPRESSION AB Transcranial magnetic stimulation (TMS) is a powerful investigational tool for in vivomanipulation of regional or network activity, with a growing number of potential clinical applications. Unfortunately, the vast majority of targeting strategies remain limited by their reliance on non-realistic brain models and assumptions that anatomo-functional relationships are 1: 1. Here, we present an integrated framework that combines anatomically realistic finite element models of the human head with resting functional MRI to predict functional networks targeted via TMS at a given coil location and orientation. Using data from the Human Connectome Project, we provide an example implementation focused on dorsolateral prefrontal cortex (DLPFC). Three distinct DLPFC stimulation zones were identified, differing with respect to the network to be affected (default, frontoparietal) and sensitivity to coil orientation. Network profiles generated for DLPFC targets previously published for treating depression revealed substantial variability across studies, highlighting a potentially critical technical issue. (C) 2015 Elsevier Inc. All rights reserved. C1 [Opitz, Alexander; Craddock, R. Cameron; Colcombe, Stan; Milham, Michael P.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Opitz, Alexander; Craddock, R. Cameron; Milham, Michael P.] Child Mind Inst, Ctr Developing Brain, New York, NY USA. [Fox, Michael D.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol,Berenson Allen Ctr Noninvas Brain Sti, Boston, MA 02215 USA. [Fox, Michael D.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fox, Michael D.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. RP Opitz, A; Milham, MP (reprint author), Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. EM aopitz@nki.rfmh.org; michael.milham@childmind.org OI Craddock, Cameron/0000-0002-4950-1303 FU NIH [U01MH099059, K23 NS083741, R21 MH099196]; Child Mind Institute [1FDN2012-1]; Sidney Baer Foundation FX This work was supported in part by grants from NIH (U01MH099059) and the Child Mind Institute (1FDN2012-1) to Michael P. Milham, and gifts to the Child Mind Institute (Michael P. Milham) from Phyllis Green, Randolph Cowen, and Joseph P. Healey. Michael D. Fox was supported in part from NIH grants K23 NS083741 and R21 MH099196, and the Sidney Baer Foundation. NR 45 TC 4 Z9 4 U1 6 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2016 VL 127 BP 86 EP 96 DI 10.1016/j.neuroimage.2015.11.040 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DD5HE UT WOS:000369952900009 PM 26608241 ER PT J AU Doshi, J Erus, G Ou, YM Resnick, SM Gur, RC Gur, RE Satterthwaite, TD Furth, S Davatzikos, C AF Doshi, Jimit Erus, Guray Ou, Yangming Resnick, Susan M. Gur, Ruben C. Gur, Raquel E. Satterthwaite, Theodore D. Furth, Susan Davatzikos, Christos CA Alzheimer's Neuroimaging TI MUSE: MUlti-atlas region Segmentation utilizing Ensembles of registration algorithms and parameters, and locally optimal atlas selection SO NEUROIMAGE LA English DT Article DE MRI; Multi-atlas segmentation; Registration; Label fusion; ROI ID IMAGE SEGMENTATION; LABEL FUSION; OLDER-ADULTS; DEFORMABLE REGISTRATION; ALZHEIMERS-DISEASE; HUMAN BRAIN; MRI; HIPPOCAMPUS; VALIDATION; CHILDREN AB Atlas-based automated anatomical labeling is a fundamental tool in medical image segmentation, as it defines regions of interest for subsequent analysis of structural and functional image data. The extensive investigation of multi-atlas warping and fusion techniques over the past 5 or more years has clearly demonstrated the advantages of consensus-based segmentation. However, the common approach is to use multiple atlases with a single registration method and parameter set, which is not necessarily optimal for every individual scan, anatomical region, and problem/data-type. Different registration criteria and parameter sets yield different solutions, each providing complementary information. Herein, we present a consensus labeling framework that generates a broad ensemble of labeled atlases in target image space via the use of several warping algorithms, regularization parameters, and atlases. The label fusion integrates two complementary sources of information: a local similarity ranking to select locally optimal atlases and a boundary modulation term to refine the segmentation consistently with the target image's intensity profile. The ensemble approach consistently outperforms segmentations using individual warping methods alone, achieving high accuracy on several benchmark datasets. The MUSE methodology has been used for processing thousands of scans from various datasets, producing robust and consistent results. MUSE is publicly available both as a downloadable software package, and as an application that can be run on the CBICA Image Processing Portal (https://ipp.cbica.upenn.edu), a web based platform for remote processing of medical images. (C) 2015 Elsevier Inc. All rights reserved. C1 [Doshi, Jimit; Erus, Guray; Ou, Yangming; Davatzikos, Christos] Univ Penn, Ctr Biomed Image Comp & Analyt CBICA, Philadelphia, PA 19104 USA. [Ou, Yangming] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Biomed Imaging Ctr, Boston, MA 02129 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Gur, Ruben C.; Gur, Raquel E.; Satterthwaite, Theodore D.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Furth, Susan] Childrens Hosp Philadelphia, Div Nephrol, Philadelphia, PA 19104 USA. RP Erus, G (reprint author), Univ Penn, Ctr Biomed Image Comp & Analyt CBICA, Philadelphia, PA 19104 USA.; Erus, G (reprint author), Univ Penn, Richards Bldg,3700 Hamilton Walk,7th Floor, Philadelphia, PA 19104 USA. EM jimit.doshi@uphs.upenn.edu FU Intramural Research Program, National Institute on Aging, NIH; National Institutes of Health [R01-AG014971]; [HHSN271201300284] FX This work was partially supported by the Intramural Research Program, National Institute on Aging, NIH. This work is also supported in part by the National Institutes of Health grant number R01-AG014971, and by contract HHSN271201300284. NR 52 TC 8 Z9 8 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2016 VL 127 BP 186 EP 195 DI 10.1016/j.neuroimage.2015.11.073 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DD5HE UT WOS:000369952900017 PM 26679328 ER PT J AU Yendiki, A Reuter, M Wilkens, P Rosas, HD Fischl, B AF Yendiki, Anastasia Reuter, Martin Wilkens, Paul Rosas, H. Diana Fischl, Bruce TI Joint reconstruction of white-matter pathways from longitudinal diffusion MRI data with anatomical priors SO NEUROIMAGE LA English DT Article DE Diffusion MRI; Tractography; Longitudinal data analysis ID HUNTINGTONS-DISEASE; TRACTOGRAPHY; MOTION; REGISTRATION; STATISTICS; FRAMEWORK; ACCURATE; ROBUST; BRAIN; SEGMENTATION AB We consider the problem of reconstructing white-matter pathways in a longitudinal study, where diffusion-weighted and T-1-weighted MR images have been acquired at multiple time points for the same subject. We propose a method for joint reconstruction of a subject's pathways at all time points given the subject's entire set of longitudinal data. We apply a method for unbiased within-subject registration to generate a within-subject template from the T-1-weighted images of the subject at all time points. We follow a global probabilistic tractography approach, where the unknown pathway is represented in the space of this within-subject template and propagated to the native space of the diffusion-weighted images at all time points to compute its posterior probability given the images. This ensures spatial correspondence of the reconstructed pathway among time points, which in turn allows longitudinal changes in diffusion measures to be estimated consistently along the pathway. We evaluate the reliability of the proposed method on data from healthy controls scanned twice within a month, where no changes in white-matter microstructure are expected between scans. We evaluate the sensitivity of the method on data from Huntington's disease patients scanned repeatedly over the course of several months, where changes are expected between scans. We show that reconstructing white-matter pathways jointly using the data from all time points leads to improved reliability and sensitivity, when compared to reconstructing the pathways at each time point independently. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yendiki, Anastasia; Reuter, Martin; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Yendiki, Anastasia; Reuter, Martin; Wilkens, Paul; Rosas, H. Diana; Fischl, Bruce] Harvard Univ, Sch Med, Boston, MA USA. [Wilkens, Paul; Rosas, H. Diana] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Yendiki, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA.; Yendiki, A (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM ayendiki@nmr.mgh.harvard.edu FU National Institute for Biomedical Imaging and Bioengineering [K99/R00-EB008129, R01-EB006758]; National Cancer Institute [K25-CA181632]; National Center for Research Resources [P41-RR14075, U24-RR021382]; National Institute on Aging [AG022381, 5R01-AG008122-22]; National Center for Alternative Medicine [RC1-AT005728-01]; National Institute for Neurological Disorders and Stroke [R01-NS052585-01, 1R21-NS072652-01, 1R01-NS070963]; Shared Instrumentation Grants [1S10RR023401, 1S10RR019307, 1S10RR023043]; National Institutes of Health Blueprint for Neuroscience Research, part of the multi-institutional Human Connectome Project [5U01-MH093765] FX Support for this research was provided in part by the National Institute for Biomedical Imaging and Bioengineering (Pathway to Independence award K99/R00-EB008129, R01-EB006758), the National Cancer Institute (K25-CA181632), the National Center for Research Resources (P41-RR14075, U24-RR021382), the National Institute on Aging (AG022381, 5R01-AG008122-22), the National Center for Alternative Medicine (RC1-AT005728-01), the National Institute for Neurological Disorders and Stroke (R01-NS052585-01, 1R21-NS072652-01, 1R01-NS070963), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by the National Institutes of Health Blueprint for Neuroscience Research (5U01-MH093765), part of the multi-institutional Human Connectome Project. In addition, B.F. has a financial interest in CorticoMetrics, a company whose medical pursuits focus on brain imaging and measurement technologies. B.F.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 36 TC 4 Z9 4 U1 0 U2 3 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 FEB 15 PY 2016 VL 127 BP 277 EP 286 DI 10.1016/j.neuroimage.2015.12.003 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DD5HE UT WOS:000369952900025 PM 26717853 ER PT J AU Blank, I Balewski, Z Mahowald, K Fedorenko, E AF Blank, Idan Balewski, Zuzanna Mahowald, Kyle Fedorenko, Evelina TI Syntactic processing is distributed across the language system SO NEUROIMAGE LA English DT Article DE Functional MRI; Language; Syntactic processing; Syntactic complexity ID ANTERIOR TEMPORAL-LOBE; OBJECT RELATIVE CLAUSES; AUDITORY SENTENCE COMPREHENSION; FUNCTIONAL CONNECTIVITY MRI; WORKING-MEMORY RESOURCES; EVENT-RELATED FMRI; BROCAS AREA; NEURAL BASIS; HUMAN BRAIN; CORTICAL REPRESENTATION AB Language comprehension recruits an extended set of regions in the human brain. Is syntactic processing localized to a particular region or regions within this system, or is it distributed across the entire ensemble of brain regions that support high-level linguistic processing? Evidence from aphasic patients is more consistent with the latter possibility: damage to many different language regions and to white-matter tracts connecting them has been shown to lead to similar syntactic comprehension deficits. However, brain imaging investigations of syntactic processing continue to focus on particular regions within the language system, often parts of Broca's area and regions in the posterior temporal cortex. We hypothesized that, whereas the entire language system is in fact sensitive to syntactic complexity, the effects in some regions may be difficult to detect because of the overall lower response to language stimuli. Using an individual-subjects approach to localizing the language system, shown in prior work to be more sensitive than traditional group analyses, we indeed find responses to syntactic complexity throughout this system, consistent with the findings from the neuropsychological patient literature. We speculate that such distributed nature of syntactic processing could perhaps imply that syntax is inseparable from other aspects of language comprehension (e.g., lexico-semantic processing), in line with current linguistic and psycholinguistic theories and evidence. Neuroimaging investigations of syntactic processing thus need to expand their scope to include the entire system of high-level language processing regions in order to fully understand how syntax is instantiated in the human brain. (C) 2015 Elsevier Inc. All rights reserved. C1 [Blank, Idan; Balewski, Zuzanna; Mahowald, Kyle] MIT, Dept Brain & Cognit Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Blank, Idan] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Fedorenko, Evelina] Massachusetts Gen Hosp, Dept Psychiat, East 13th St, Charlestown, MA 02129 USA. RP Blank, I (reprint author), MIT, Brain & Cognit Sci Dept, 46-4141f,43 Vassar St, Cambridge, MA 02139 USA.; Fedorenko, E (reprint author), MGH, Dept Psychiat, Bldg 149,Room 2624,East 13th St, Charlestown, MA 02129 USA. EM iblank@mit.edu; evelina.fedorenko@mgh.harvard.edu FU NICHD [HD 057522]; National Defense Science and Engineering Graduate (NDSEG) Fellowship FX We thank Nancy Kanwisher and Ted Gibson for many helpful discussions of this work. We thank Melissa Kline for recording the sentences. For comments on the earlier drafts of the manuscript we are grateful to Adele Goldberg, Marina Bedny, David Caplan, Nancy Kanwisher, and especially Ted Gibson, who read and commented on multiple versions. This work was supported by a K99/R00 award HD 057522 to E.F. from NICHD. K.M. was supported by a National Defense Science and Engineering Graduate (NDSEG) Fellowship. NR 195 TC 7 Z9 7 U1 11 U2 18 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 FEB 15 PY 2016 VL 127 BP 307 EP 323 DI 10.1016/j.neuroimage.2015.11.069 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DD5HE UT WOS:000369952900028 PM 26666896 ER PT J AU Wong, KHK Sandlin, RD Carey, TR Miller, KL Shank, AT Oklu, R Maheswaran, S Haber, DA Irimia, D Stott, SL Toner, M AF Wong, Keith H. K. Sandlin, Rebecca D. Carey, Thomas R. Miller, Kathleen L. Shank, Aaron T. Oklu, Rahmi Maheswaran, Shyamala Haber, Daniel A. Irimia, Daniel Stott, Shannon L. Toner, Mehmet TI The Role of Physical Stabilization in Whole Blood Preservation SO SCIENTIFIC REPORTS LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; CIRCULATING TUMOR-CELLS; T-CELL; MICROAGGREGATE FORMATION; PLATELET-AGGREGATION; PERIPHERAL-BLOOD; DNA TRAPS; RED; AGITATION; CANCER AB The rapid degradation of blood ex vivo imposes logistical limitations on the utilization of blood-borne cells in medical diagnostics and scientific investigations. A fundamental but overlooked aspect in the storage of this fluid tissue is blood settling, which induces physical stress and compaction, aggregates blood cells, and causes collateral damage due to leukocyte activation. Here we show that the polymer Ficoll 70 kDa stabilized blood samples and prevented blood settling over the course of 72 hours, primarily by inhibiting depletion-mediated red blood cell aggregation. Physical stabilization decreased echinocyte formation, improved leukocyte viability, and inhibited the release of neutrophil elastase-a marker of neutrophil extracellular trap formation. In addition, Ficoll-stabilized blood was compatible with common leukocyte enrichment techniques including red blood cell lysis and immunomagnetic purification. This study showed for the first time that blood settling can be prevented using polymers and has implications in diagnostics. C1 [Wong, Keith H. K.; Sandlin, Rebecca D.; Carey, Thomas R.; Miller, Kathleen L.; Shank, Aaron T.; Irimia, Daniel; Stott, Shannon L.; Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr,Ctr Engn Med, Boston, MA 02114 USA. [Wong, Keith H. K.; Sandlin, Rebecca D.; Carey, Thomas R.; Miller, Kathleen L.; Shank, Aaron T.; Irimia, Daniel; Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Oklu, Rahmi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Oklu, Rahmi] Mayo Clin, Div Intervent Radiol, Scottsdale, AZ 85259 USA. [Maheswaran, Shyamala; Haber, Daniel A.; Stott, Shannon L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Maheswaran, Shyamala] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Haber, Daniel A.; Stott, Shannon L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Toner, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr,Ctr Engn Med, Boston, MA 02114 USA.; Toner, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM mtoner@hms.harvard.edu RI Wong, Keith/J-6857-2012 OI Wong, Keith/0000-0002-6578-0373 FU US National Institutes of Health (NIH) P41 BioMEMS Resource Center award [EB002503]; NIH National Institute of Biomedical Imaging and Bioengineering award [EB012493]; Howard Hughes Medical Institute FX We thank Octavio Hurtado and Alexander Aranyosi for technical assistance, John Walsh, Linda Nieman, and Joseph Martel for helpful suggestions and assistance in microscopy, and healthy volunteers who contributed blood samples. We also thank Bjorn Neu for discussions regarding molecular depletion interaction. This work was supported by funding from the US National Institutes of Health (NIH) P41 BioMEMS Resource Center award EB002503 (M.T.), NIH National Institute of Biomedical Imaging and Bioengineering award EB012493 (M.T.), and the Howard Hughes Medical Institute (D.A.H.). NR 38 TC 1 Z9 1 U1 3 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 FEB 15 PY 2016 VL 6 AR 21023 DI 10.1038/srep21023 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6TV UT WOS:000370058300001 PM 26876805 ER PT J AU Ghosh, B Zhao, WN Reis, SA Patnaik, D Fass, DM Tsai, LH Mazitschek, R Haggarty, SJ AF Ghosh, Balaram Zhao, Wen-Ning Reis, Surya A. Patnaik, Debasis Fass, Daniel M. Tsai, Li-Huei Mazitschek, Ralph Haggarty, Stephen J. TI Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Cognitive enhancer; Nootropic; Histone deacetylases; Epigenetic; Chromatin; Acetylation; CREB; Neuroepigenetic ID HISTONE DEACETYLASE INHIBITORS; EPIGENETIC MECHANISMS; COGNITIVE ENHANCERS; MEMORY FORMATION; NEUROPLASTICITY; DISORDERS; MOUSE AB Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A.; Patnaik, Debasis; Fass, Daniel M.; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Chem Neurobiol Lab, 185 Cambridge St, Boston, MA 02114 USA. [Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A.; Patnaik, Debasis; Fass, Daniel M.; Haggarty, Stephen J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A.; Patnaik, Debasis; Fass, Daniel M.; Haggarty, Stephen J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A.; Patnaik, Debasis; Fass, Daniel M.; Haggarty, Stephen J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. [Ghosh, Balaram] Birla Inst Technol & Sci, Dept Pharm, Hyderabad Campus, Pilani 500078, Rajasthan, India. RP Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Chem Neurobiol Lab, 185 Cambridge St, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM shaggarty@mgh.harvard.edu OI Patnaik, Debasis/0000-0002-9829-3352; Haggarty, Stephen J./0000-0002-7872-168X FU NIH [R01DA028301, R01DA030321, P50CA086355]; Tau Consortium; Consortium for Frontotemporal Dementia Research (Bluefield Foundation) FX We would like to thank Dr. Florence F. Wagner for helpful discussions and critical reading of the manuscript. S.J.H. was supported through funding from the NIH (R01DA028301, R01DA030321), Tau Consortium, and the Consortium for Frontotemporal Dementia Research (Bluefield Foundation). R.M. was supported through funding from the NIH (P50CA086355). NR 28 TC 0 Z9 0 U1 3 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 15 PY 2016 VL 26 IS 4 BP 1265 EP 1271 DI 10.1016/j.bmcl.2016.01.022 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DC7CZ UT WOS:000369377700033 PM 26804233 ER PT J AU Carreno, FR Frazer, A AF Carreno, Flavia R. Frazer, Alan TI The Allure of Transcutaneous Vagus Nerve Stimulation as a Novel Therapeutic Modality SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID TREATMENT-RESISTANT DEPRESSION; DELTA-FOSB IMMUNOREACTIVITY; BRAIN C1 [Carreno, Flavia R.; Frazer, Alan] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Carreno, Flavia R.; Frazer, Alan] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [Frazer, Alan] Audie L Murphy Mem Vet Adm Med Ctr, South Texas Vet Hlth Care Syst, San Antonio, TX 78284 USA. RP Carreno, FR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr,Mail Code 7764, San Antonio, TX 78229 USA. EM Carrenof@uthscsa.edu NR 10 TC 0 Z9 0 U1 3 U2 14 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 FEB 15 PY 2016 VL 79 IS 4 BP 260 EP 261 DI 10.1016/j.biopsych.2015.11.016 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DA9BT UT WOS:000368102300002 PM 26796874 ER PT J AU Fang, JL Rong, PJ Hong, Y Fan, YY Liu, J Wang, HH Zhang, GL Chen, XY Shi, S Wang, LP Liu, RP Hwang, JW Li, ZJ Tao, J Wang, Y Zhu, B Kong, J AF Fang, Jiliang Rong, Peijing Hong, Yang Fan, Yangyang Liu, Jun Wang, Honghong Zhang, Guolei Chen, Xiaoyan Shi, Shan Wang, Liping Liu, Rupeng Hwang, Jiwon Li, Zhengjie Tao, Jing Wang, Yang Zhu, Bing Kong, Jian TI Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Default mode network; fMRI; Functional connectivity; Major depressive disorder; Transcutaneous vagus nerve stimulation; Vagus nerve stimulation ID TREATMENT-RESISTANT DEPRESSION; STATE FUNCTIONAL CONNECTIVITY; RESTING-STATE; AFFECTIVE NEUROSCIENCE; ORBITOFRONTAL CORTEX; CINGULATE CORTEX; THERAPY; MECHANISMS; DISEASE; TRIAL AB BACKGROUND: Depression is the most common form of mental disorder in community and health care settings and current treatments are far from satisfactory. Vagus nerve stimulation (VNS) is a Food and Drug Administration approved somatic treatment for treatment-resistant depression. However, the involvement of surgery has limited VNS only to patients who have failed to respond to multiple treatment options. Transcutaneous VNS (tVNS) is a relatively new, noninvasive VNS method based on the rationale that there is afferent/efferent vagus nerve distribution on the surface of the ear. The safe and low-cost characteristics of tVNS have the potential to significantly expand the clinical application of VNS. METHODS: In this study, we investigated how tVNS can modulate the default mode network (DMN) functional connectivity (FC) in mild or moderate major depressive disorder (MDD) patients. Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments. RESULTS: Thirty-four patients completed the study and were included in data analysis. After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale score reduced significantly in the tVNS group as compared with the stVNS group. The FC between the DMN and anterior insula and parahippocampus decreased; the FC between the DMN and precuneus and orbital prefrontal cortex increased compared with stVNS. All these FC increases are also associated with 24-item Hamilton Depression Rating Scale reduction. CONCLUSIONS: tVNS can significantly modulate the DMN FC of MDD patients; our results provide insights to elucidate the brain mechanism of tVNS treatment for MDD patients. C1 [Fang, Jiliang; Hong, Yang; Fan, Yangyang; Liu, Jun; Wang, Honghong; Zhang, Guolei; Shi, Shan] China Acad Chinese Med Sci, Guanganmen Hosp, Beijing 100700, Peoples R China. [Fang, Jiliang; Rong, Peijing; Liu, Rupeng; Zhu, Bing] China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Beijing 100700, Peoples R China. [Chen, Xiaoyan; Hwang, Jiwon; Li, Zhengjie; Tao, Jing; Kong, Jian] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wang, Liping] Beijing Univ Chinese Med, Huguosi Hosp, Beijing, Peoples R China. [Liu, Rupeng; Zhu, Bing] China Acad Chinese Med Sci, Hosp Acupuncture & Moxibust, Beijing 100700, Peoples R China. [Li, Zhengjie] Chengdu Univ Tradit Chinese Med, Acupuncture & Tuina Sch, Chengdu, Peoples R China. [Tao, Jing] Fujian Univ Tradit Chinese Med, Coll Rehabil Med, Fuzhou, Peoples R China. [Wang, Yang] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. RP Rong, PJ (reprint author), China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Physiol, 16 Dongzhimen Nan Xiao St, Beijing 100700, Peoples R China. EM rongpj@hotmail.com FU Chinese National Natural Science Foundation [30870668, 81273674]; Chinese National Natural Science Foundation Research [30973798, 81473780]; National Basic Research Program of China (973 Program) [2012CB518503]; National Twelfth Five-Year Plan of the National Science and Technology Support Program of China [2012BAF14B10]; Natural Science Foundation of Beijing China [7111007]; National Institutes of Health/National Center for Complementary and Integrative Health [R01AT006364, P01 AT006663]; Ministry of Science and Technology [2011EG152313] FX This scientific work was supported by Chinese National Natural Science Foundation (No. 30870668, 81273674) to Jiliang Fang, Chinese National Natural Science Foundation Research (No. 30973798, 81473780) to Peijing Rong, National Basic Research Program of China (973 Program, No. 2012CB518503) to Peijing Rong grant of technology development research from the Ministry of Science and Technology (2011EG152313), and the National Twelfth Five-Year Plan of the National Science and Technology Support Program of China (2012BAF14B10) the Natural Science Foundation of Beijing China (No. 7111007) to Peijing Rong. Jian Kong is supported by R01AT006364 (National Institutes of Health/National Center for Complementary and Integrative Health) and P01 AT006663 (National Institutes of Health/National Center for Complementary and Integrative Health). NR 76 TC 11 Z9 11 U1 10 U2 24 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 FEB 15 PY 2016 VL 79 IS 4 BP 266 EP 273 DI 10.1016/j.biopsych.2015.03.025 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DA9BT UT WOS:000368102300005 PM 25963932 ER PT J AU Widge, AS Deckersbach, T Eskandar, EN Dougherty, DD AF Widge, Alik S. Deckersbach, Thilo Eskandar, Emad N. Dougherty, Darin D. TI Deep Brain Stimulation for Treatment-Resistant Psychiatric Illnesses: What Has Gone Wrong and What Should We Do Next? SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID VENTRAL CAPSULE/VENTRAL STRIATUM; MAJOR DEPRESSION; TRIAL C1 [Widge, Alik S.; Deckersbach, Thilo; Dougherty, Darin D.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. [Widge, Alik S.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurol Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Widge, AS (reprint author), 149 13th St,Room 2625, Charlestown, MA 02129 USA. EM awidge@partners.org NR 10 TC 4 Z9 4 U1 0 U2 12 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 FEB 15 PY 2016 VL 79 IS 4 BP E9 EP E10 DI 10.1016/j.biopsych.2015.06.005 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DA9BT UT WOS:000368102300001 PM 26212895 ER PT J AU Chatterjee, NA Singh, JP Szymonifka, J Deano, RC Thai, WE Wai, BY Min, JK Januzzi, JL Truong, QA AF Chatterjee, Neal A. Singh, Jagmeet P. Szymonifka, Jackie Deano, Roderick C. Thai, Wai-ee Wai, Bryan Min, James K. Januzzi, James L. Truong, Quynh A. TI Incremental value of cystatin C over conventional renal metrics for predicting clinical response and outcomes in cardiac resynchronization therapy: The BIOCRT study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Cardiac resynchronization; Heart failure; Biomarkers; Cystatin C ID GLOMERULAR-FILTRATION-RATE; CHRONIC HEART-FAILURE; KIDNEY-DISEASE; MORTALITY; CREATININE; EVENTS; CARE AB Background: Despite the benefit of CRT in select patients with heart failure (HF), there remains significant need for predicting those at risk for adverse outcomes for this effective but costly therapy. CysC, an emerging marker of renal function, is predictive of worsening symptoms and mortality in patients with HF. This study assessed the utility of baseline and serial measures of cystatin C (CysC), compared to conventional creatinine-based measures of renal function (estimated glomerular filtration rate, eGFR), in predicting clinical outcomes following cardiac resynchronization therapy (CRT). Methods: In 133 patients, we measured peripheral venous (PV) and coronary sinus (CS) CysC concentrations and peripheral creatinine levels at the time of CRT implant. Study endpoints included clinical response to CRT at 6 months and major adverse cardiac events (MACE) at 2 years. Results: While all 3 renal metrics were predictive of MACE (all adjusted p <= 0.02), only CysC was associated with CRT non-response at 6 months (adjusted odds ratio 3.6, p = 0.02). CysC improved prediction of CRT non-response (p <= 0.003) in net reclassification index analysis compared to models utilizing standard renal metrics. Serial CysC >1 mg/L was associated with 6-month CRT non-response and reduced 6-minute walk distance as well as 2-year MACE (all p <= 0.04). Conclusion: In patients undergoing CRT, CysC demonstrated incremental benefit in the prediction of CRT non-response when compared to standard metrics of renal function. Baseline and serial measures of elevated CysC were predictive of CRT non-response and functional status at 6 months as well as long-term clinical outcomes. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Chatterjee, Neal A.; Singh, Jagmeet P.; Januzzi, James L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA. [Szymonifka, Jackie; Deano, Roderick C.; Min, James K.; Truong, Quynh A.] New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, New York, NY 10021 USA. [Szymonifka, Jackie; Deano, Roderick C.; Min, James K.; Truong, Quynh A.] Weill Cornell Med Coll, New York, NY 10021 USA. [Thai, Wai-ee; Wai, Bryan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program, Boston, MA USA. RP Truong, QA (reprint author), New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, 413 E 69th St,Suite 108, New York, NY 10021 USA. EM qat9001@med.cornell.edu FU NIH/NHLBI [K23HL098370]; NIH [L30HL093896]; St. Jude Medical; Medtronic Inc.; Boston Scientific Corp.; Sorin Group; Biotronik; BG Medicine; Siemens; GE Healthcare; Vital Images; Phillips Healthcare; Roman W. Desanctis Distinguished Clinical Scholar Endowment; Singulex; Thermo Fisher; American College of Radiology Imaging Network; Duke Clinical Research Institute FX The study was supported by NIH/NHLBI K23HL098370. Dr. Truong also received support from the NIH L30HL093896. The reagents/assays were provided and performed by Siemens Healthcare Diagnostics Inc. There was no role of the funding sources or disclosures in the design, analysis, and preparation of this manuscript. DisclosuresDrs. Chatterjee, Deano, Thai, and Wai as well as Ms. Szymonifka report no disclosures. Dr. Singh receives grant support from St. Jude Medical, Medtronic Inc., Boston Scientific Corp., Sorin Group, Biotronik, BG Medicine and Siemens. Dr. Min has served on the medical advisory boards of GE Healthcare, Arineta, Astra Zeneca, and Bristol-Myers Squibb; Speakers' Bureau of GE Healthcare; and received research support from GE Healthcare, Vital Images, and Phillips Healthcare. Dr. Januzzi is supported in part by the Roman W. Desanctis Distinguished Clinical Scholar Endowment, receives grant support from Siemens, Singulex, and Thermo Fisher and has served as a consultant to Roche Diagnostics, Critical Diagnostics, Sphingotec, Amgen, and Novartis. Dr. Truong received grant support from St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute. NR 22 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 15 PY 2016 VL 205 BP 43 EP 49 DI 10.1016/j.ijcard.2015.12.002 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DA9FL UT WOS:000368114100019 PM 26710332 ER PT J AU Pei, X Nadkarni, S Li, ZY AF Pei, Xuan Nadkarni, Seemantini Li, Zhi-Yong TI A parametric study of inflammatory effects on plaque mechanical stress SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Inflammation; Atherosclerosis; Vulnerable plaque; Parametric finite element analysis ID MRI C1 [Pei, Xuan; Li, Zhi-Yong] Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. [Nadkarni, Seemantini] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nadkarni, Seemantini] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Li, Zhi-Yong] Queensland Univ Technol, Sch Chem Phys & Mech Engn, Brisbane Qut, Qld 4001, Australia. RP Li, ZY (reprint author), Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. EM zylicam@gmail.com NR 5 TC 0 Z9 0 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 15 PY 2016 VL 205 BP 157 EP 159 DI 10.1016/j.ijcard.2015.12.019 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DA9FL UT WOS:000368114100010 PM 26736091 ER PT J AU Barone, FC Gustafson, D Crystal, HA Moreno, H Adamski, MG Arai, K Baird, AE Balucani, C Brickman, AM Cechetto, D Gorelick, P Biessels, GJ Kiliaan, A Launer, L Schneider, J Sorond, FA Whitmer, R Wright, C Zhang, ZG AF Barone, Frank C. Gustafson, Deborah Crystal, Howard A. Moreno, Herman Adamski, Mateusz G. Arai, Ken Baird, Alison E. Balucani, Clotilde Brickman, Adam M. Cechetto, David Gorelick, Philip Biessels, Geert Jan Kiliaan, Amanda Launer, Lenore Schneider, Julie Sorond, Farzaneh A. Whitmer, Rachel Wright, Clinton Zhang, Zheng Gang TI First translational 'Think Tank' on cerebrovascular disease, cognitive impairment and dementia SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID LATE-ONSET DEMENTIA; ALZHEIMERS-DISEASE; ISCHEMIC-STROKE; MEDITERRANEAN DIET; VASCULAR DEMENTIA; GENE-EXPRESSION; DIAGNOSTIC-CRITERIA; METABOLIC SYNDROME; BRAIN-INJURY; T-CELLS AB As the human population continues to age, an increasing number of people will exhibit significant deficits in cognitive function and dementia. It is now recognized that cerebrovascular, metabolic and neurodegenerative diseases all play major roles in the evolution of cognitive impairment and dementia. Thus with our more recent recognition of these relationships and our need to understand and more positively impact on this world health problem, "The Leo and Anne Albert Charitable Trust" (Gene Pranzo, Trustee with significant support from Susan Brogan, Meeting Planner) provided generous support for this inaugural international workshop that was held from April 13-16, 2015 at the beautiful Ritz Carlton Golf Resort in North Naples, Florida. Researchers from SUNY Downstate Medical Center, Brooklyn, NY organized the event by selecting the present group of translationally inclined preclinical, clinical and population scientists focused on cerebrovascular disease (CVD) risk and its progression to vascular cognitive impairment (VCI) and dementia. Participants at the workshop addressed important issues related to aging, cognition and dementia by: (1) sharing new data, information and perspectives that intersect vascular, metabolic and neurodegenerative diseases, (2) discussing gaps in translating population risk, clinical and preclinical information to the progression of cognitive loss, and (3) debating new approaches and methods to fill these gaps that can translate into future therapeutic interventions. Participants agreed on topics for group discussion prior to the meeting and focused on specific translational goals that included promoting better understanding of dementia mechanisms, the identification of potential therapeutic targets for intervention, and discussed/ debated the potential utility of diagnostic/ prognostic markers. Below summarizes the new data-presentations, concepts, novel directions and specific discussion topics addressed by this international translational team at our " First Leo and Anne Albert Charitable Trust 'Think Tank' VCI workshop". C1 [Barone, Frank C.; Gustafson, Deborah; Crystal, Howard A.; Moreno, Herman; Baird, Alison E.; Balucani, Clotilde] Suny Downstate Med Ctr, Neurol, Brooklyn, NY 11203 USA. [Barone, Frank C.; Moreno, Herman; Baird, Alison E.] Suny Downstate Med Ctr, Physiol & Pharmacol, Brooklyn, NY 11203 USA. [Gustafson, Deborah] Suny Downstate Med Ctr, Sect Neuroepidemiol, Brooklyn, NY 11203 USA. [Crystal, Howard A.] Suny Downstate Med Ctr, Pathol, Brooklyn, NY 11203 USA. [Adamski, Mateusz G.] Jagiellonian Univ, Jagiellonian Ctr Expt Therapeut, Krakow, Poland. [Arai, Ken] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Neuroprotect Res Lab, Boston, MA 02115 USA. [Arai, Ken] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Neuroprotect Res Lab, Boston, MA 02115 USA. [Brickman, Adam M.] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Cechetto, David] Univ Western Ontario, Dept Anat & Cell Biol, Schulich Sch Med & Dent, London, ON, Canada. [Gorelick, Philip] Michigan State Univ, Mercy Hlth Hauenstein Neurosci, Translat Sci & Mol Med, Coll Human Med, Grand Rapids, MI USA. [Biessels, Geert Jan] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands. [Kiliaan, Amanda] Radboud Univ Nijmegen, Dept Anat, Preclin Imaging Ctr, Donders Inst Brain Cognit & Behav,Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Launer, Lenore] NIA, Neuroepidemiol Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Schneider, Julie] Rush Univ, Med Ctr, Pathol Neuropathol & Neurol Sci, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Sorond, Farzaneh A.] Brigham & Womens Hosp, Dept Neurol, Stroke Div, 75 Francis St, Boston, MA 02115 USA. [Whitmer, Rachel] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Wright, Clinton] Univ Miami, McKnight Brain Inst, Div Cognit Disorders Neurol Publ Hlth Sci & Neuro, Miami, FL USA. [Zhang, Zheng Gang] Henry Ford Hosp, Neurol, Detroit, MI 48202 USA. RP Barone, FC (reprint author), Suny Downstate Med Ctr, Neurol, Brooklyn, NY 11203 USA. EM frank.barone@downstate.edu RI Adamski, Mateusz/K-7634-2016; Kiliaan, Amanda/D-8778-2012; Adamski, Mateusz G/F-6274-2015; OI Adamski, Mateusz G/0000-0002-8340-2181; barone, Frank C/0000-0001-8509-3936 FU Leo and Anne Albert Charitable Trust; American Heart Association [13GRNT14770012] FX "The Leo and Anne Albert Charitable Trust" fully supported this inaugural international workshop and also fully supported the publication of this summary of the meeting. The American Heart Association provided "Grant in Aid" (13GRNT14770012; Founders Affiliate) support to the primary organizer (FCB). NR 74 TC 0 Z9 0 U1 6 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 13 PY 2016 VL 14 AR 50 DI 10.1186/s12967-016-0806-z PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5BV UT WOS:000369938300001 PM 26873444 ER PT J AU Ritchie, C Andersen, R Eng, J Garrigues, SK Intinarelli, G Kao, H Kawahara, S Patel, K Sapiro, L Thibault, A Tunick, E Barnes, DE AF Ritchie, Christine Andersen, Robin Eng, Jessica Garrigues, Sarah K. Intinarelli, Gina Kao, Helen Kawahara, Suzanne Patel, Kanan Sapiro, Lisa Thibault, Anne Tunick, Erika Barnes, Deborah E. TI Implementation of an Interdisciplinary, Team-Based Complex Care Support Health Care Model at an Academic Medical Center: Impact on Health Care Utilization and Quality of Life SO PLOS ONE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; OUTPATIENT GERIATRIC EVALUATION; DWELLING OLDER-ADULTS; LOW-INCOME SENIORS; MANAGEMENT; RESOURCES; MORTALITY; PEOPLE AB Introduction The Geriatric Resources for the Assessment and Care of Elders (GRACE) program has been shown to decrease acute care utilization and increase patient self-rated health in lowincome seniors at community-based health centers. Aims To describe adaptation of the GRACE model to include adults of all ages (named Care Support) and to evaluate the process and impact of Care Support implementation at an urban academic medical center. Setting 152 high-risk patients (>= 5 ED visits or >= 2 hospitalizations in the past 12 months) enrolled from four medical clinics from 4/29/2013 to 5/31/2014. Program Description Patients received a comprehensive in-home assessment by a nurse practitioner/social worker (NP/SW) team, who then met with a larger interdisciplinary team to develop an individualized care plan. In consultation with the primary care team, standardized care protocols were activated to address relevant key issues as needed. Program Evaluation A process evaluation based on the Consolidated Framework for Implementation Research identified key adaptations of the original model, which included streamlining of standardized protocols, augmenting mental health interventions and performing some assessments in the clinic. A summative evaluation found a significant decline in the median number of ED visits (5.5 to 0, p = 0.015) and hospitalizations (5.5 to 0, p<0.001) 6 months before enrollment in Care Support compared to 6 months after enrollment. In addition, the percent of patients reporting better self-rated health increased from 31% at enrollment to 64% at 9 months (p = 0.002). Semi-structured interviews with Care Support team members identified patients with multiple, complex conditions; little community support; and mild anxiety as those who appeared to benefit the most from the program. Discussion It was feasible to implement GRACE/Care Support at an academic medical center by making adaptations based on local needs. Care Support patients experienced significant reductions in acute care utilization and significant improvements in self-rated health. C1 [Ritchie, Christine; Eng, Jessica; Garrigues, Sarah K.; Kawahara, Suzanne; Patel, Kanan; Barnes, Deborah E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Ritchie, Christine; Garrigues, Sarah K.; Kawahara, Suzanne; Patel, Kanan; Barnes, Deborah E.] Univ Calif San Francisco, Div Geriatr, Tideswell UCSF, San Francisco, CA 94143 USA. [Andersen, Robin; Intinarelli, Gina; Kao, Helen; Sapiro, Lisa; Thibault, Anne; Tunick, Erika] Univ Calif San Francisco, UCSF Hlth, San Francisco, CA 94143 USA. [Eng, Jessica] San Francisco VA Med Ctr, Geriatr Palliat & Extended Care Serv, San Francisco, CA USA. [Barnes, Deborah E.] San Francisco VA Med Ctr, Res Serv, San Francisco, CA USA. RP Ritchie, C; Barnes, DE (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA USA.; Ritchie, C; Barnes, DE (reprint author), Univ Calif San Francisco, Div Geriatr, Tideswell UCSF, San Francisco, CA 94143 USA.; Barnes, DE (reprint author), San Francisco VA Med Ctr, Res Serv, San Francisco, CA USA. EM Christine.ritchie@ucsf.edu; Deborah.barnes@ucsf.edu FU S.D. Bechtel, Jr. Foundation; SCAN Foundation FX Evaluation of Care Support was supported by a grant to TideswellTM at UCSF from the S.D. Bechtel, Jr. Foundation. The SCAN Foundation provided support for the training and implementation assistance provided by the Indiana University Geriatrics GRACE Training and Resource Center to the UCSF Care Support program. The SCAN Foundation - advancing a coordinated and easily navigated system of high-quality services for older adults that preserve dignity and independence. For more information, please visit www.TheSCANFoundation.org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 1 Z9 1 U1 9 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 12 PY 2016 VL 11 IS 2 AR e0148096 DI 10.1371/journal.pone.0148096 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6SI UT WOS:000370054100017 PM 26871704 ER PT J AU Singhal, G Fisher, FM Chee, MJ Tan, TG El Ouaamari, A Adams, AC Najarian, R Kulkarni, RN Benoist, C Flier, JS Maratos-Flier, E AF Singhal, Garima Fisher, Ffolliott Martin Chee, Melissa J. Tan, Tze Guan El Ouaamari, Abdelfattah Adams, Andrew C. Najarian, Robert Kulkarni, Rohit N. Benoist, Christophe Flier, Jeffrey S. Maratos-Flier, Eleftheria TI Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas SO PLOS ONE LA English DT Article ID IMPROVES INSULIN SENSITIVITY; ADIPOSE-TISSUE; PPAR-ALPHA; METABOLIC REGULATOR; RESISTANT STATES; MICE; RECEPTOR; LIVER; FIBROBLAST-GROWTH-FACTOR-21; ACTIVATION AB Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator expressed in multiple tissues including liver and adipose tissue. Although highest levels of expression are in pancreas, little is known about the function of FGF21 in this tissue. In order to understand the physiology of FGF21 in the pancreas, we analyzed its expression and regulation in both acinar and islet tissues. We found that acinar tissue express 20-fold higher levels than that observed in islets. We also observed that pancreatic FGF21 is nutritionally regulated; a marked reduction in FGF21 expression was noted with fasting while obesity is associated with 3-4 fold higher expression. Acinar and islet cells are targets of FGF21, which when systemically administered, leads to phosphorylation of the downstream target ERK 1/2 in about half of acinar cells and a small subset of islet cells. Chronic, systemic FGF21 infusion down-regulates its own expression in the pancreas. Mice lacking FGF21 develop significant islet hyperplasia and periductal lymphocytic inflammation when fed with a high fat obesogenic diet. Inflammatory infiltrates consist of TCRb+Thy1+T lymphocytes with increased levels of Foxp3+ regulatory T cells. Increased levels of inflammatory cells were coupled with elevated expression of cytokines such as TNF alpha, IFN gamma and IL1 beta. We conclude that FGF21 acts to limit islet hyperplasia and may also prevent pancreatic inflammation. C1 [Singhal, Garima; Fisher, Ffolliott Martin; Chee, Melissa J.; Flier, Jeffrey S.; Maratos-Flier, Eleftheria] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. [Tan, Tze Guan; Benoist, Christophe] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. [El Ouaamari, Abdelfattah; Kulkarni, Rohit N.] Joslin Diabet Ctr, Sect Islet Cell Biol & Regenerat Med, Boston, MA 02215 USA. [Adams, Andrew C.] Lilly Res Labs, Diabet Res, Indianapolis, IN 46225 USA. [Najarian, Robert] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Maratos-Flier, E (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. EM emaratos@bidmc.harvard.edu FU NIH [DK28082] FX The research work presented here is is funded by different sources as given below: NIH DK28082 (EMF) for study design, data collection, data analysis, writing manuscript. NIH RO1 DK67536 (RNK) and RO1 DK103215 (RNK) for data collection. Lilly research laboratories provided recombinant FGF21 and FGF21 Knock out mice on the basis of a Material transfer agreement. One of the co-authors, ACA, is employed and therefore paid by the company. Lilly research laboratories did not provide funding for the present manuscript. They do not have any role in study design, data collection, data analysis or writing manuscript. The authors have added the following statement to the amended funding statement. The funder provided support in the form of salaries for authors [ACA], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of ACA is articulated in the 'author contributions' section. NR 42 TC 6 Z9 7 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 FEB 12 PY 2016 VL 11 IS 2 AR e0148252 DI 10.1371/journal.pone.0148252 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6SI UT WOS:000370054100020 PM 26872145 ER PT J AU Held, KD Kawamura, H Kaminuma, T Paz, AES Yoshida, Y Liu, Q Willers, H Takahashi, A AF Held, Kathryn D. Kawamura, Hidemasa Kaminuma, Takuya Paz, Athena Evalour S. Yoshida, Yukari Liu, Qi Willers, Henning Takahashi, Akihisa TI Effects of Charged Particles on Human Tumor Cells SO FRONTIERS IN ONCOLOGY LA English DT Review DE charged particles; proton therapy; carbon-ion therapy; relative biological effectiveness; clustered DNA damage; cancer stem cells; hypoxic radioresistance; altered fractionation ID CANCER STEM-CELLS; CARBON-ION-BEAMS; RELATIVE BIOLOGICAL EFFECTIVENESS; LINEAR-ENERGY-TRANSFER; DOUBLE-STRAND BREAKS; HIGH-LET RADIATION; LOCAL EFFECT MODEL; HOMOLOGOUS RECOMBINATION REPAIR; HIGH-PRECISION RADIOTHERAPY; OXYGEN ENHANCEMENT RATIO AB The use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects, including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors, and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors, such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of relative biological effectiveness (RBE) for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions, and importance of fractionation, including use of hypofractionation, with charged particles. C1 [Held, Kathryn D.; Kaminuma, Takuya; Liu, Qi; Willers, Henning] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Kawamura, Hidemasa; Kaminuma, Takuya; Paz, Athena Evalour S.; Yoshida, Yukari; Takahashi, Akihisa] Gunma Univ, Heavy Ion Med Ctr, Gunma, Japan. [Kawamura, Hidemasa; Kaminuma, Takuya] Gunma Univ, Grad Sch Med, Dept Radiat Oncol, Gunma, Japan. RP Held, KD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. EM kheld@mgh.harvard.edu FU NCI NIH HHS [C06 CA059267, R21 CA182259] NR 179 TC 0 Z9 0 U1 5 U2 12 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD FEB 12 PY 2016 VL 6 AR 23 DI 10.3389/fonc.2016.00023 PG 19 WC Oncology SC Oncology GA DE4KX UT WOS:000370598700001 PM 26904502 ER PT J AU van de Donk, NWCJ Moreau, P Plesner, T Palumbo, A Gay, F Laubach, JP Malavasi, F Avet-Loiseau, H Mateos, MV Sonneveld, P Lokhorst, HM Richardson, PG AF van de Donk, Niels W. C. J. Moreau, Philippe Plesner, Torben Palumbo, Antonio Gay, Francesca Laubach, Jacob P. Malavasi, Fabio Avet-Loiseau, Herve Mateos, Maria-Victoria Sonneveld, Pieter Lokhorst, Henk M. Richardson, Paul G. TI Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma SO BLOOD LA English DT Review ID MINIMAL RESIDUAL DISEASE; DEPENDENT CELLULAR CYTOTOXICITY; CHRONIC LYMPHOCYTIC-LEUKEMIA; NATURAL-KILLER-CELL; PHASE-I TRIAL; FLOW-CYTOMETRY; HEMATOLOGIC MALIGNANCIES; ANTITUMOR-ACTIVITY; DOSE-ESCALATION; SERUM-PROTEIN AB Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pre-treated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies. C1 [van de Donk, Niels W. C. J.; Lokhorst, Henk M.] Vrije Univ Amsterdam Med Ctr, Dept Hematol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Moreau, Philippe] Univ Hosp Hotel Dieu, Dept Hematol, Nantes, France. [Plesner, Torben] Vejle Hosp, Vejle, Denmark. [Plesner, Torben] Univ Southern Denmark, Vejle, Denmark. [Palumbo, Antonio; Gay, Francesca] Univ Turin, Myeloma Unit, Div Hematol, Turin, Italy. [Laubach, Jacob P.; Richardson, Paul G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr,Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Malavasi, Fabio] Univ Turin, Immunogenet Lab, Dept Med Sci, Turin, Italy. [Avet-Loiseau, Herve] Inst Univ Canc Toulouse Oncopole, Insitut Claudius Regaud, Toulouse, France. [Mateos, Maria-Victoria] Univ Salamanca, Hosp Univ Salamanca, Inst Invest Biomed Salamanca, Inst Biol Mol & Celular Canc,CSIC, E-37008 Salamanca, Spain. [Sonneveld, Pieter] Erasmus MC Canc Insitute, Dept Hematol, Rotterdam, Netherlands. RP van de Donk, NWCJ (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Hematol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM n.vandedonk@vumc.nl RI richard, chrystelle/K-8595-2015; OI MALAVASI, Fabio/0000-0002-1844-174X FU Janssen Pharmaceuticals; AMGEN; Celgene; Onyx; Novartis; Millennium; Genmab; Johnson Johnson FX N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, and Celgene and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Novartis, and Celgene. P.M. serves on the advisory board and receives honoraria from Janssen Pharmaceuticals. T.P. serves on advisory boards for Genmab and Janssen Pharmaceuticals and has received research support from Janssen Pharmaceuticals. A. P. has consulted for Amgen, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc, Onyx Pharmaceuticals and has received honoraria from Amgen, Novartis, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc, Onyx Pharmaceuticals, and Sanofi Aventis. F.G. has received honoraria from Celgene and Janssen Pharmaceuticals and serves on advisory boards for Mundipharma, Janssen Pharmaceuticals, and Sanofi. J.P.L. has received grant support from Onyx, Celgene, Novartis, and Millennium. F.M. has received research support and honoraria as speaking fees from Janssen Pharmaceuticals. H.A.-L. declares no competing financial interests. P.S. has received research support and honoraria to the institution from Janssen Pharmaceuticals and honoraria to the institution from BMS and Sanofi. M.-V.M. has received honoraria for the participation on advisory boards of Janssen Pharmaceuticals. H.M.L. has received research support from Celgene, AMGEN, Genmab, and Johnson & Johnson. P.G.R. has served on advisory boards for Millennium Pharmaceuticals, Celgene Corporation, Novartis, Johnson & Johnson, and Bristol Myers Squibb. NR 100 TC 17 Z9 17 U1 5 U2 11 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 FEB 11 PY 2016 VL 127 IS 6 BP 681 EP 695 DI 10.1182/blood-2015-10-646810 PG 15 WC Hematology SC Hematology GA DI3JJ UT WOS:000373394600009 PM 26631114 ER PT J AU Richardson, PG Hungria, VTM Yoon, SS Beksac, M Dimopoulos, MA Elghandour, A Jedrzejczak, WW Guenther, A Nakorn, TN Siritanaratkul, N Schlossman, RL Hou, J Moreau, P Lonial, S Lee, JH Einsele, H Sopala, M Bengoudifa, BR Corrado, C Binlich, F San-Miguel, JF AF Richardson, Paul G. Hungria, Vania T. M. Yoon, Sung-Soo Beksac, Meral Dimopoulos, Meletios Athanasios Elghandour, Ashraf Jedrzejczak, Wieslaw W. Guenther, Andreas Nakorn, Thanyaphong Na Siritanaratkul, Noppadol Schlossman, Robert L. Hou, Jian Moreau, Philippe Lonial, Sagar Lee, Jae Hoon Einsele, Hermann Sopala, Monika Bengoudifa, Bourras-Rezki Corrado, Claudia Binlich, Florence San-Miguel, Jesus F. TI Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment SO BLOOD LA English DT Article ID REFRACTORY MYELOMA; QUALITY; LENALIDOMIDE; COMBINATION; MULTICENTER; CARFILZOMIB; SURVIVAL; PHASE-2; IMPACT; RISK AB Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3PANORAMA1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and >= 2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and >= 2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received >= 2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. C1 [Richardson, Paul G.; Schlossman, Robert L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hungria, Vania T. M.] Irmandade Santa Casa Misericordia Sao Paulo, Sao Paulo, Brazil. [Yoon, Sung-Soo] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. [Beksac, Meral] Ankara Univ, Sch Med, TR-06100 Ankara, Turkey. [Dimopoulos, Meletios Athanasios] Univ Athens, Athens 11528, Greece. [Elghandour, Ashraf] Univ Alexandria, Alexandria, Egypt. [Jedrzejczak, Wieslaw W.] Med Univ Warsaw, Warsaw, Poland. [Guenther, Andreas] Univ Hosp Schleswig Holstein, Div Stem Cell Transplantat & Immunotherapy, Dept Med 2, Kiel, Germany. [Guenther, Andreas] Univ Kiel, Kiel, Germany. [Nakorn, Thanyaphong Na] King Chulalongkorn Mem Hosp, Bangkok, Thailand. [Nakorn, Thanyaphong Na] Chulalongkorn Univ, Bangkok, Thailand. [Siritanaratkul, Noppadol] Siriraj Hosp, Bangkok, Thailand. [Hou, Jian] Chang Zheng Hosp, Shanghai, Peoples R China. [Moreau, Philippe] Univ Hosp Nantes, Nantes, France. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Lee, Jae Hoon] Gachon Univ, Gil Hosp, Dept Internal Med, Inchon, South Korea. [Einsele, Hermann] Univ Wurzburg, Med Klin & Poliklin 2, D-97070 Wurzburg, Germany. [Sopala, Monika; Bengoudifa, Bourras-Rezki; Corrado, Claudia] Novartis Pharma AG, Basel, Switzerland. [Binlich, Florence] Novartis Pharma SAS, Rueil Malmaison, France. [San-Miguel, Jesus F.] Univ Navarra Clin, Ctr Invest Med Aplicada, Inst Invest Sanit Navarra, Pamplona, Spain. RP Richardson, PG (reprint author), Harvard Univ, Dana Farber Canc Inst, 450 Brookline Ave,Mailstop Dana 1B02, Boston, MA 02215 USA. EM paul_richardson@dfci.harvard.edu RI richard, chrystelle/K-8595-2015; OI Sopala, Monika/0000-0001-9587-7953; Elghandour, ASHRAF/0000-0002-8841-048X FU Novartis Pharmaceuticals Corporation FX The authors thank Ashok Panneerselvam, Novartis Pharmaceuticals Corporation, for statistical support. The authors also thank William Fazzone, PhD, Articulate Science, for editorial writing support, funded by Novartis Pharmaceuticals Corporation.; The PANORAMA 1 study was funded by Novartis Pharmaceuticals Corporation. NR 20 TC 23 Z9 23 U1 4 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 11 PY 2016 VL 127 IS 6 BP 713 EP 721 DI 10.1182/blood-2015-09-665018 PG 9 WC Hematology SC Hematology GA DI3JJ UT WOS:000373394600012 PM 26631116 ER PT J AU Connolly, KR Thase, ME AF Connolly, K. Ryan Thase, Michael E. TI Vortioxetine: a New Treatment for Major Depressive Disorder SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); Vortioxetine; antidepressants; major depressive disorder (MDD); multimodal serotonin modulator ID PLACEBO-CONTROLLED TRIAL; 5 MG VORTIOXETINE; DOUBLE-BLIND; LU AA21004; MULTIMODAL ANTIDEPRESSANT; 5-HT DEPLETION; OPEN-LABEL; EFFICACY; ADULTS; SAFETY AB Introduction: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD). This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors, which may differentiate the drug's effects from those of current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration (FDA), discuss relevant post-marketing studies of this drug, and offer expert commentary on the significance of this new agent in clinical practice. Pre-approval studies were identified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search in August 2015 using the key search terms, vortioxetine and Lu AA21004, combined with additional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverse effects, side effects, safety, major depression, and major depressive disorder. We identified relevant systematic reviews, meta-analyses, randomized trials and preclinical studies of importance. Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. The most common side effects are nausea, vomiting and constipation. Results of several studies indicate that vortioxetine may have therapeutic effects on cognition (e.g., memory and executive functioning) that exceed that of standard antidepressants. Disadvantages include cost and the current paucity of long-term efficacy data from large clinical trials. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option. C1 [Connolly, K. Ryan; Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Connolly, K. Ryan; Thase, Michael E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Thase, ME (reprint author), Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA.; Thase, ME (reprint author), Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. EM thase@mail.med.upenn.edu FU Agency for Healthcare Research and Quality; Alkermes; AssureRx; Avanir; Forest Pharmaceuticals; Janssen; National Institute of Mental Health; Otsuka Pharmaceuticals FX M E Thase has been an advisory/consultant for Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor, Inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex, Inc., Neuronetics, Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle) Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals, Inc., Trius Therapeutical, Inc. and Takeda. He has received grant support from Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health and Otsuka Pharmaceuticals. M E Thase has equity holdings in MedAvante, Inc. and receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House and W.W. Norton & Company, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 50 TC 3 Z9 3 U1 7 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD FEB 11 PY 2016 VL 17 IS 3 BP 421 EP 431 DI 10.1517/14656566.2016.1133588 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DE0DD UT WOS:000370294100001 PM 26679430 ER PT J AU Wei, PC Chang, AN Kao, J Du, Z Meyers, RM Alt, FW Schwer, B AF Wei, Pei-Chi Chang, Amelia N. Kao, Jennifer Du, Zhou Meyers, Robin M. Alt, Frederick W. Schwer, Bjoern TI Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells SO CELL LA English DT Article ID COMMON FRAGILE SITES; DOUBLE-STRAND BREAKS; GENOME INSTABILITY; SEQUENCING REVEALS; MECHANISMS; REPAIR; TRANSLOCATIONS; AMPLIFICATION; TRANSCRIPTION; DOMAINS AB Repair of DNA double-strand breaks (DSBs) by non-homologous end joining is critical for neural development, and brain cells frequently contain somatic genomic variations that might involve DSB intermediates. We now use an unbiased, high-throughput approach to identify genomic regions harboring recurrent DSBs in primary neural stem/progenitor cells (NSPCs). We identify 27 recurrent DSB clusters (RDCs), and remarkably, all occur within gene bodies. Most of these NSPC RDCs were detected only upon mild, aphidicolin-induced replication stress, providing a nucleotide-resolution view of replication-associated genomic fragile sites. The vast majority of RDCs occur in long, transcribed, and late-replicating genes. Moreover, almost 90% of identified RDC-containing genes are involved in synapse function and/or neural cell adhesion, with a substantial fraction also implicated in tumor suppression and/or mental disorders. Our characterization of NSPC RDCs reveals a basis of gene fragility and suggests potential impacts of DNA breaks on neurodevelopment and neural functions. C1 [Wei, Pei-Chi; Chang, Amelia N.; Kao, Jennifer; Du, Zhou; Meyers, Robin M.; Alt, Frederick W.; Schwer, Bjoern] Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wei, Pei-Chi; Chang, Amelia N.; Kao, Jennifer; Du, Zhou; Meyers, Robin M.; Alt, Frederick W.; Schwer, Bjoern] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wei, Pei-Chi; Chang, Amelia N.; Kao, Jennifer; Du, Zhou; Meyers, Robin M.; Alt, Frederick W.; Schwer, Bjoern] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Schwer, B (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; bjoern.schwer@childrens.harvard.edu FU Porter Anderson Fund from Boston Children's Hospital; Howard Hughes Medical Institute; National Institute on Aging (NIA)/NIH grant [K01AG043630]; National Cancer Center postdoctoral fellowship FX We thank Drs. R. Axel, C. Boboila, and members of the F.W.A. laboratory for helpful comments and stimulating discussions; Drs. C. Guo, M. Gostissa, and J. Hu for experimental advice; and Drs. Y. Zhang, L. Shen, and F.-L. Meng for DNA sequencing assistance. This work in the F.W.A. lab was supported by the Porter Anderson Fund from Boston Children's Hospital and the Howard Hughes Medical Institute. B.S. is a Martin D. Abeloff Scholar of The V Foundation for Cancer Research and is supported by National Institute on Aging (NIA)/NIH grant K01AG043630. P.W. is supported by a National Cancer Center postdoctoral fellowship. NR 51 TC 23 Z9 23 U1 5 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 11 PY 2016 VL 164 IS 4 BP 644 EP 655 DI 10.1016/j.cell.2015.12.039 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DD5XN UT WOS:000369998300011 PM 26871630 ER PT J AU Yang, XP Coulombe-Huntington, J Kang, SL Sheynkman, GM Hao, T Richardson, A Sun, S Yang, F Shen, YA Murray, RR Spirohn, K Begg, BE Duran-Frigola, M MacWilliams, A Pevzner, SJ Zhong, Q Trigg, SA Tam, S Ghamsari, L Sahni, N Yi, S Rodriguez, MD Balcha, D Tan, GH Costanzo, M Andrews, B Boone, C Zhou, XHJ Salehi-Ashtiani, K Charloteaux, B Chen, AA Calderwood, MA Aloy, P Roth, FP Hill, DE Iakoucheva, LM Xia, Y Vidal, M AF Yang, Xinping Coulombe-Huntington, Jasmin Kang, Shuli Sheynkman, Gloria M. Hao, Tong Richardson, Aaron Sun, Song Yang, Fan Shen, Yun A. Murray, Ryan R. Spirohn, Kerstin Begg, Bridget E. Duran-Frigola, Miquel MacWilliams, Andrew Pevzner, Samuel J. Zhong, Quan Trigg, Shelly A. Tam, Stanley Ghamsari, Lila Sahni, Nidhi Yi, Song Rodriguez, Maria D. Balcha, Dawit Tan, Guihong Costanzo, Michael Andrews, Brenda Boone, Charles Zhou, Xianghong J. Salehi-Ashtiani, Kourosh Charloteaux, Benoit Chen, Alyce A. Calderwood, Michael A. Aloy, Patrick Roth, Frederick P. Hill, David E. Iakoucheva, Lilia M. Xia, Yu Vidal, Marc TI Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing SO CELL LA English DT Article ID OPEN READING FRAMES; OSTEOGENESIS IMPERFECTA; INTERACTION NETWORKS; HUMAN TRANSCRIPTOME; LINEAR MOTIFS; SCALE MAP; DOMAIN; DISCOVERY; GENE; COMPLEXITY AB While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms'' are functionally divergent (i.e., "functional alloforms''). C1 [Yang, Xinping; Sheynkman, Gloria M.; Hao, Tong; Richardson, Aaron; Shen, Yun A.; Spirohn, Kerstin; Begg, Bridget E.; Sahni, Nidhi; Yi, Song; Balcha, Dawit; Charloteaux, Benoit; Chen, Alyce A.; Calderwood, Michael A.; Roth, Frederick P.; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA. [Yang, Xinping; Sheynkman, Gloria M.; Hao, Tong; Richardson, Aaron; Shen, Yun A.; Murray, Ryan R.; Spirohn, Kerstin; Begg, Bridget E.; MacWilliams, Andrew; Pevzner, Samuel J.; Zhong, Quan; Trigg, Shelly A.; Tam, Stanley; Ghamsari, Lila; Sahni, Nidhi; Yi, Song; Rodriguez, Maria D.; Balcha, Dawit; Salehi-Ashtiani, Kourosh; Charloteaux, Benoit; Chen, Alyce A.; Calderwood, Michael A.; Roth, Frederick P.; Hill, David E.; Xia, Yu; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. [Yang, Xinping; Sheynkman, Gloria M.; Hao, Tong; Richardson, Aaron; Shen, Yun A.; Murray, Ryan R.; Spirohn, Kerstin; Begg, Bridget E.; MacWilliams, Andrew; Pevzner, Samuel J.; Zhong, Quan; Trigg, Shelly A.; Tam, Stanley; Ghamsari, Lila; Sahni, Nidhi; Yi, Song; Rodriguez, Maria D.; Balcha, Dawit; Salehi-Ashtiani, Kourosh; Charloteaux, Benoit; Chen, Alyce A.; Calderwood, Michael A.; Roth, Frederick P.; Hill, David E.; Xia, Yu; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Yang, Xinping; Sheynkman, Gloria M.; Hao, Tong; Richardson, Aaron; Shen, Yun A.; Murray, Ryan R.; Spirohn, Kerstin; Begg, Bridget E.; MacWilliams, Andrew; Pevzner, Samuel J.; Zhong, Quan; Trigg, Shelly A.; Tam, Stanley; Ghamsari, Lila; Sahni, Nidhi; Yi, Song; Rodriguez, Maria D.; Balcha, Dawit; Salehi-Ashtiani, Kourosh; Charloteaux, Benoit; Chen, Alyce A.; Calderwood, Michael A.; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Yang, Xinping] Southern Med Univ, Nanfang Hosp, Dept Obstet & Gynecol, Guangzhou 510515, Guangdong, Peoples R China. [Coulombe-Huntington, Jasmin; Xia, Yu] McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada. [Kang, Shuli; Iakoucheva, Lilia M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Sun, Song; Yang, Fan; Costanzo, Michael; Andrews, Brenda; Boone, Charles; Roth, Frederick P.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Sun, Song; Yang, Fan; Andrews, Brenda; Boone, Charles; Roth, Frederick P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Sun, Song; Yang, Fan; 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. [Duran-Frigola, Miquel; Aloy, Patrick] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain. [Pevzner, Samuel J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Pevzner, Samuel J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kang, Shuli; Zhou, Xianghong J.] Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA. [Aloy, Patrick] ICREA, Barcelona 08010, Catalonia, Spain. [Roth, Frederick P.] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada. [Coulombe-Huntington, Jasmin] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Murray, Ryan R.] Univ Helsinki, Biomedicum Helsinki 1, FIN-00290 Helsinki, Finland. [Begg, Bridget E.] MIT, Dept Biol, Cambridge, MA 02139 USA. [MacWilliams, Andrew] Tecan US Inc, Morrisville, NC 27560 USA. [Zhong, Quan] Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA. [Trigg, Shelly A.] Univ Calif San Diego, Dept Biol Sci, La Jolla, CA 92093 USA. [Tam, Stanley] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ghamsari, Lila] Genocea Biosci Inc, Cambridge, MA 02140 USA. [Rodriguez, Maria D.] Cedars Sinai Med Ctr, Biomed Sci & Translat Med, Los Angeles, CA 90048 USA. [Salehi-Ashtiani, Kourosh] New York Univ Abu Dhabi, Div Sci & Math, Abu Dhabi, U Arab Emirates. [Salehi-Ashtiani, Kourosh] New York Univ Abu Dhabi, Ctr Genom & Syst Biol CGSB, Abu Dhabi, U Arab Emirates. [Charloteaux, Benoit] Univ Liege, Unit Anim Genom, GIGA R, B-4000 Liege, Belgium. [Charloteaux, Benoit] Univ Liege, Fac Vet Med, B-4000 Liege, Belgium. RP Vidal, M (reprint author), Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. EM lilyak@ucsd.edu; brandon.xia@mcgill.ca; marc_vidal@dfci.harvard.edu OI Iakoucheva, Lilia/0000-0002-4542-5219; Xia, Yu/0000-0002-5596-5518; Salehi-Ashtiani, Kourosh/0000-0002-6521-5243 FU NHGRI CEGS grant [P50HG004233]; NHGRI grant [U01HG001715]; Ellison Foundation; NCI grant [R33CA132073]; Krembil Foundation (Canada); Canada Excellence Research Chair Award; Ontario Research Fund-Research Excellence Award; E.K. Shriver NICHD grant [R01HD065288]; NIMH grants [R01MH091350, R01MH105524, R21MH104766]; NSF [CCF-1219007]; NSERC grant (Canada) [RGPIN-2014-03892]; Canada Foundation for Innovation grant [JELF-33732]; Canada Research Chairs Program; NIH training grant [T32CA009361]; NSERC fellowship (Canada); NIGMS grant [R01GM105431]; Swedish Research Council International Postdoc Grant FX We thank B. Blencowe for valuable discussions and critical reading of the manuscript. This work was supported by NHGRI CEGS grant P50HG004233 (M.V. and F.P.R.); NHGRI grant U01HG001715 (M.V., D.E.H., and F.P.R.); the Ellison Foundation (M.V.), NCI grant R33CA132073 (M.V.); the Krembil Foundation (Canada) (F.P.R.); a Canada Excellence Research Chair Award (F.P.R.); an Ontario Research Fund-Research Excellence Award (F.P.R.); E.K. Shriver NICHD grant R01HD065288 (L.M.I. and K.S.-A.); NIMH grants R01MH091350 (L.M.I. and T.H.), R01MH105524 (L.M.I.), and R21MH104766 (L.M.I.); NSF grant CCF-1219007, NSERC grant RGPIN-2014-03892 (Canada), Canada Foundation for Innovation grant JELF-33732 and Canada Research Chairs Program (Y.X.); NIH training grant T32CA009361 (G.M.S.); a NSERC fellowship (Canada) (J.C.-H.); NIGMS grant R01GM105431 (X.J.Z.); and a Swedish Research Council International Postdoc Grant (S.S.). M.V. is a FRS-FNRS Chercheur Qualifie Honoraire (Belgium). NR 43 TC 19 Z9 20 U1 6 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 11 PY 2016 VL 164 IS 4 BP 805 EP 817 DI 10.1016/j.cell.2016.01.029 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DD5XN UT WOS:000369998300024 PM 26871637 ER PT J AU Erchegyi, J Wang, LX Gulyas, J Samant, M Perrin, MH Lewis, K Miller, C Vaughan, J Donaldson, C Fischer, W Low, W Yakabi, S Karasawa, H Tache, Y Rivier, C Rivier, J AF Erchegyi, Judit Wang, Lixin Gulyas, Jozsef Samant, Manoj Perrin, Marilyn H. Lewis, Kathy Miller, Charleen Vaughan, Joan Donaldson, Cynthia Fischer, Wolfgang Low, William Yakabi, Seiichi Karasawa, Hiroshi Tache, Yvette Rivier, Catherine Rivier, Jean TI Characterization of Multisubstituted Corticotropin Releasing Factor (CRF) Peptide Antagonists (Astressins) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HORMONE-RECEPTOR ANTAGONIST; STRESS-RELATED ALTERATIONS; COLONIC MOTOR FUNCTION; COMPETITIVE ANTAGONISTS; SEQUENCE-ANALYSIS; RHESUS-MONKEY; RATS; SECRETION; INJECTION; SAUVAGINE AB CRF mediates numerous stress-related endocrine, autonomic, metabolic, and behavioral responses. We present the synthesis and chemical and biological properties of astressin B analogues {cydo(30-33)[D-Phe(12),Nle(21,38),C(alpha)MeLeu(27,40),Glu(30),Lys(33)]-acetyl-h/r-CRF(9-41)}. Out of 37 novel peptides, 17 (2, 4, 6-8, 10, 11, 16, 17, 27, 29, 30, 32-36) and 16 (3, 5, 9, 12-15, 18, 19, 22-26, 28, 31) had k(i) to CRF receptors in the high picomolar and low nanomole ranges, respectively. Peptides 1, 2, and 11 inhibited h/rCRF and urocortin 1-induced cAMP release from AtT20 and A7r5 cells. When Astressin C 2 was administered to adrenalectomized rats at 1.0 mg subcutaneously, it inhibited ACTH release for >7 d. Additional rat data based on the inhibitory effect of (2) on h/rCRF-induced stimulation of colonic secretory motor activity and urocortin 2-induced delayed gastric emptying also indicate a safe and long-lasting antagonistic effect. The overall properties of selected analogues may fulfill the criteria expected from clinical candidates. C1 [Erchegyi, Judit; Gulyas, Jozsef; Samant, Manoj; Perrin, Marilyn H.; Lewis, Kathy; Miller, Charleen; Vaughan, Joan; Donaldson, Cynthia; Fischer, Wolfgang; Low, William; Rivier, Catherine; Rivier, Jean] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Wang, Lixin; Yakabi, Seiichi; Karasawa, Hiroshi; Tache, Yvette] Univ Calif Los Angeles, Dept Med, CURE Digest Dis Ctr, Div Digest Dis, Los Angeles, CA 90073 USA. [Wang, Lixin; Yakabi, Seiichi; Karasawa, Hiroshi; Tache, Yvette] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Rivier, J (reprint author), Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM jrivier@salk.edu FU NIH [P01 DK026741-34, R01 DK057238]; VA Career Scientist Award; NIH (Animal Core) [DK041301] FX We thank D. Kirby for the synthesis of 11, Y. Haas for technical assistance, and D. Doan for manuscript preparation. J.R. is the Dr. Frederik Paulsen Chair in Neurosciences. This work was supported by NIH Grants P01 DK026741-34 (J.R, J.E., M.H.P., J.G., M.S., K.L., C.M., J.V., W.F., W.L.), DK041301 (Animal Core, Y.T., L.W.), R01 DK057238 (Y.T.), and VA Career Scientist Award (Y.T.). NR 38 TC 0 Z9 0 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 11 PY 2016 VL 59 IS 3 BP 854 EP 866 DI 10.1021/acs.jmedchem.5b00926 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DD8YL UT WOS:000370212700005 PM 26789203 ER PT J AU Sekar, A Bialas, AR de Rivera, H Davis, A Hammond, TR Kamitaki, N Tooley, K Presumey, J Baum, M Van Doren, V Genovese, G Rose, SA Handsaker, RE Daly, MJ Carroll, MC Stevens, B McCarroll, SA AF Sekar, Aswin Bialas, Allison R. de Rivera, Heather Davis, Avery Hammond, Timothy R. Kamitaki, Nolan Tooley, Katherine Presumey, Jessy Baum, Matthew Van Doren, Vanessa Genovese, Giulio Rose, Samuel A. Handsaker, Robert E. Daly, Mark J. Carroll, Michael C. Stevens, Beth McCarroll, Steven A. CA Schizophrenia Working Grp TI Schizophrenia risk from complex variation of complement component 4 SO NATURE LA English DT Article ID CLASSICAL PATHWAY COMPLEMENT; CORTICAL PYRAMIDAL NEURONS; DENDRITIC SPINE DENSITY; ENDOGENOUS RETROVIRUSES; PRENATAL DEVELOPMENT; SYNAPSE ELIMINATION; COMMON VARIANTS; MHC HAPLOTYPES; C4; PROTEIN AB Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia. C1 [Sekar, Aswin; de Rivera, Heather; Davis, Avery; Kamitaki, Nolan; Tooley, Katherine; Baum, Matthew; Van Doren, Vanessa; Genovese, Giulio; Handsaker, Robert E.; McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Sekar, Aswin; de Rivera, Heather; Davis, Avery; Kamitaki, Nolan; Tooley, Katherine; Baum, Matthew; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert E.; Daly, Mark J.; Stevens, Beth; McCarroll, Steven A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Sekar, Aswin; Baum, Matthew] Harvard Univ, Sch Med, MD PhD Program, Boston, MA 02115 USA. [Bialas, Allison R.; Hammond, Timothy R.; Baum, Matthew; Stevens, Beth] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Neurol,FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Bialas, Allison R.; Presumey, Jessy; Carroll, Michael C.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. RP McCarroll, SA (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM mccarroll@genetics.med.harvard.edu RI Hansen, Thomas Folkmann/O-5965-2014; Hammer, Christian/C-5827-2014; Slominsky, Petr/B-4640-2016; Pantelis, Christos/H-7722-2014; Melle, Ingrid /B-4858-2011; Ruderfer, Douglas/M-5795-2016; McDonald, Colm/C-1430-2009; Domenici, Enrico/K-8194-2016; McQuillin, Andrew/C-1623-2008; OI Walters, James/0000-0002-6980-4053; Holmans, Peter/0000-0003-0870-9412; Suvisaari, Jaana/0000-0001-7167-0990; Bruggeman, Richard/0000-0002-3238-8471; /0000-0002-8114-7615; Adolfsson, Rolf/0000-0001-9785-8473; Jonsson, Erik/0000-0001-8368-6332; Nothen, Markus/0000-0002-8770-2464; Knight, Joanne/0000-0002-7148-1660; Hansen, Thomas Folkmann/0000-0001-6703-7762; Hammer, Christian/0000-0003-4548-7548; Slominsky, Petr/0000-0003-3530-0655; Pantelis, Christos/0000-0002-9565-0238; Melle, Ingrid /0000-0002-9783-548X; Ruderfer, Douglas/0000-0002-2365-386X; Domenici, Enrico/0000-0001-7436-6919; McQuillin, Andrew/0000-0003-1567-2240; Van Doren, Vanessa/0000-0003-4165-6025; Moran, Jennifer/0000-0002-5664-4716; Davis, Avery/0000-0002-1837-302X FU Stanley Center for Psychiatric Research; [R01 HG 006855]; [U01 MH105641]; [R01 MH077139]; [T32 GM007753] FX The authors would like to remember the late T. Stanley with appreciation and express their gratitude for his support. We thank S. Hyman, E. Lander, C. Bargmann, and C. Patil for conversations about the project and comments on drafts of the manuscript; M. Webster for expert advice on immunohistochemistry; B. Browning for expert advice on imputation; the Stanley Medical Research Institute Brain Collection and the NHGRI Gene and Tissue Expression (GTEx) Project for access to RNA and tissue samples; C. Emba for assistance with experiments; and C. Usher for contributions to manuscript figures. This work was supported by R01 HG 006855 (to S.A.M.), by the Stanley Center for Psychiatric Research (to S. A. M. and B. S.), by U01 MH105641 (to S. A. M.), by R01 MH077139 (to the PGC), and by T32 GM007753 (to A.S. and M.B.). NR 56 TC 139 Z9 141 U1 44 U2 112 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 FEB 11 PY 2016 VL 530 IS 7589 BP 177 EP + DI 10.1038/nature16549 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD4TX UT WOS:000369916700030 PM 26814963 ER PT J AU Drain, PK Gounder, L Sahid, F Moosa, MYS AF Drain, Paul K. Gounder, Lilishia Sahid, Faieza Moosa, Mahomed-Yunus S. TI Rapid Urine LAM Testing Improves Diagnosis of Expectorated Smear-Negative Pulmonary Tuberculosis in an HIV-endemic Region SO SCIENTIFIC REPORTS LA English DT Article ID ANTIRETROVIRAL THERAPY; HOSPITALIZED-PATIENTS; SPUTUM SAMPLES; SOUTH-AFRICA; LIPOARABINOMANNAN; ACCURACY; ASSAY; SETTINGS; ANTIGEN; UTILITY AB We sought to determine if urine lipoarabinomannan (LAM) would improve diagnosis of pulmonary TB. We enrolled consecutive adults presenting with >= 2 TB-related symptoms, obtained one induced sputum sample for smear microscopy (AFB) and mycobacterial culture, and performed urine LAM testing (Determine (TM) TB LAM, Alere). We used culture-confirmed pulmonary TB as the gold standard, and compared accuracy with area under receiver operating characteristic curves (AUROC). Among 90 participants, 82 of 88 tested (93%) were HIV-infected with a median CD4 168/mm(3) (IQR 89-256/mm(3)). Diagnostic sensitivities of urine LAM and sputum AFB were 42.1% (95% CI 29.1-55.9%) and 21.1% (95% CI 11.4-33.9%), and increased to 52.6% (95% CI 39.0-66.0%) when combined. Sensitivity of LAM increased significantly among participants with a lower Karnofsky Performance score, anemia, hypoalbuminemia, and higher C-reactive protein. Combining LAM with AFB had an AUROC = 0.68 (95% CI 0.59-0.77), significantly better than AFB alone (AUROC = 0.58; 95% CI 0.51-0.64). The combination of LAM and AFB was significantly better than AFB alone among patients with Karnofsky Performance score <= 90, hemoglobin <= 10 g/dL, albumin <= 25 g/L, C-reactive protein >= 25 mg/L, or CD4 < 200/mm(3). Urine LAM testing may be most beneficial among patients with functional impairment, elevated inflammatory markers, or greater immunosuppression. C1 [Drain, Paul K.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Drain, Paul K.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Drain, Paul K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Drain, Paul K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. [Gounder, Lilishia] Inkosi Albert Luthuli Cent Hosp, Natl Hlth Lab Serv, Dept Virol, Durban, South Africa. [Sahid, Faieza] Univ Witwatersrand, Chris Hani Baragwanath Acad Hosp, Dept Internal Med, Div Infect Dis, Johannesburg, South Africa. [Moosa, Mahomed-Yunus S.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Dept Infect Dis, Durban, South Africa. RP Drain, PK (reprint author), Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA.; Drain, PK (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA.; Drain, PK (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Drain, PK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. EM pkdrain@uw.edu FU Medical Research Council of South Africa; Howard Hughes Medical Institute; KwaZulu-Natal Research Institute for TB; HIV (K-RITH); United Kingdom's Department for International Development; Harvard Global Health Institute; Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988]; Infectious Disease Society of America Education & Research Foundation; National Foundation for Infectious Diseases; Program in AIDS Clinical Research Training Grant [T32 AI007433]; National Institute of Allergy and Infectious Disease [K23 AI108293]; Harvard University Center for AIDS Research [P30 AI060354]; Massachusetts General Hospital Executive Committee on Research FX We would like to acknowledge the excellent work and valuable contributions of our research staff and nurses, and Thirumalai Govender for assistance in the chemical pathology laboratory. We graciously thank all of the men and women who participated in this study. This research was funded by the Medical Research Council of South Africa, the Howard Hughes Medical Institute, the KwaZulu-Natal Research Institute for TB and HIV (K-RITH), and the United Kingdom's Department for International Development. Dr. Drain was supported by the Harvard Global Health Institute, the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988), the Infectious Disease Society of America Education & Research Foundation and National Foundation for Infectious Diseases, The Program in AIDS Clinical Research Training Grant (T32 AI007433), the National Institute of Allergy and Infectious Disease (K23 AI108293), the Harvard University Center for AIDS Research (P30 AI060354), and Massachusetts General Hospital Executive Committee on Research. NR 33 TC 0 Z9 0 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 FEB 11 PY 2016 VL 6 AR 19992 DI 10.1038/srep19992 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD4LK UT WOS:000369894200001 PM 26865526 ER PT J AU Handley, RR Reid, SJ Patassini, S Rudiger, SR Obolonkin, V McLaughlan, CJ Jacobsen, JC Gusella, JF MacDonald, ME Waldvogel, HJ Bawden, CS Faull, RLM Snell, RG AF Handley, Renee. R. Reid, Suzanne J. Patassini, Stefano Rudiger, Skye R. Obolonkin, Vladimir McLaughlan, Clive. J. Jacobsen, Jessie C. Gusella, James F. MacDonald, Marcy E. Waldvogel, Henry J. Bawden, C. Simon Faull, Richard L. M. Snell, Russell G. TI Metabolic disruption identified in the Huntington's disease transgenic sheep model SO SCIENTIFIC REPORTS LA English DT Article ID HEPATIC MITOCHONDRIAL DYSFUNCTION; WEIGHT-LOSS; REPEAT; GENE; DEFICIENCY; MECHANISMS; RUMINANTS; PROFILE; BRAIN; MOUSE AB Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissuespecificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease. C1 [Handley, Renee. R.; Reid, Suzanne J.; Patassini, Stefano; Jacobsen, Jessie C.; Waldvogel, Henry J.; Faull, Richard L. M.; Snell, Russell G.] Univ Auckland, Ctr Brain Res, Auckland 1010, New Zealand. [Rudiger, Skye R.; McLaughlan, Clive. J.; Bawden, C. Simon] South Australian Res & Dev, Mol Biol & Reprod Technol Labs, Adelaide, SA 5350, Australia. [Obolonkin, Vladimir] Livestock Improvement Corp, Res & Dev, Hamilton 3240, New Zealand. [Gusella, James F.; MacDonald, Marcy E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Snell, RG (reprint author), Univ Auckland, Ctr Brain Res, Auckland 1010, New Zealand. EM r.snell@auckland.ac.nz OI Reid, Suzanne/0000-0002-8068-6529 FU CHDI Foundation; Neurological Foundation of New Zealand; Health Research Council of New Zealand; Auckland Medical Research Foundation Senior Scholarship; Freemasons New Zealand FX We thank the incredible on-farm SARDI team for all animal management, in particular Ian Gollan, Kylie Chenoweth and Nick Brown. We also thank Tim Kuchel and the team at SAMHRI for their assistance in sample collection. We wish to acknowledge Dang-Dung Nguyen and Yuri Zubenko of the Mass Spectrometry Centre, Auckland Science Analytical Service, The University of Auckland, Auckland, New Zealand, for performing Gas Chromatography Mass Spectrometry and assisting in the quantification of the data. We thank Jenny Morton, Alex Osmand, Neil Aronin, Marian DiFiglia, Andreas Weiss and David Howland (members of the Huntington's Disease Sheep Collaborative Research Group) for contributions to the manuscript. This work was supported by the CHDI Foundation, Freemasons New Zealand, the Neurological Foundation of New Zealand and the Health Research Council of New Zealand. RRH was supported by an Auckland Medical Research Foundation Senior Scholarship. NR 37 TC 3 Z9 3 U1 1 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 FEB 11 PY 2016 VL 6 AR 20681 DI 10.1038/srep20681 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD4MO UT WOS:000369897300001 PM 26864449 ER PT J AU Baggett, MV Gonzalez, RG Bhattacharyya, RP Mahowald, MA AF Baggett, Meridale V. Gonzalez, R. Gilberto Bhattacharyya, Roby P. Mahowald, Michael A. TI Case 4-2016: A 58-Year-Old Woman with a Skin Ulcer, Fever, and Lymphadenopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OROPHARYNGEAL TULAREMIA; FRANCISELLA-TULARENSIS; UNITED-STATES; ANTHRAX C1 [Baggett, Meridale V.; Bhattacharyya, Roby P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Mahowald, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Baggett, Meridale V.; Bhattacharyya, Roby P.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mahowald, Michael A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Baggett, MV (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA USA.; Baggett, MV (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. NR 23 TC 0 Z9 0 U1 0 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 FEB 11 PY 2016 VL 374 IS 6 BP 573 EP 581 DI 10.1056/NEJMcpc1508550 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DD2ME UT WOS:000369755800012 PM 26863359 ER PT J AU Hong, TS Wo, JY Yeap, BY Ben-Josef, E McDonnell, EI Blaszkowsky, LS Kwak, EL Allen, JN Clark, JW Goyal, L Murphy, JE Javle, MM Wolfgang, JA Drapek, LC Arellano, RS Mamon, HJ Mullen, JT Yoon, SS Tanabe, KK Ferrone, CR Ryan, DP DeLaney, TF Crane, CH Zhu, AX AF Hong, Theodore S. Wo, Jennifer Y. Yeap, Beow Y. Ben-Josef, Edgar McDonnell, Erin I. Blaszkowsky, Lawrence S. Kwak, Eunice L. Allen, Jill N. Clark, Jeffrey W. Goyal, Lipika Murphy, Janet E. Javle, Milind M. Wolfgang, John A. Drapek, Lorraine C. Arellano, Ronald S. Mamon, Harvey J. Mullen, John T. Yoon, Sam S. Tanabe, Kenneth K. Ferrone, Cristina R. Ryan, David P. DeLaney, Thomas F. Crane, Christopher H. Zhu, Andrew X. TI Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEREOTACTIC BODY RADIOTHERAPY; RADIATION-THERAPY; LIVER; CANCER; MALIGNANCIES AB Purpose To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Materials and Methods In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate >80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. Results Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. Conclusion High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC. (C) 2015 by American Society of Clinical Oncology C1 [Hong, Theodore S.; Wo, Jennifer Y.; Yeap, Beow Y.; McDonnell, Erin I.; Blaszkowsky, Lawrence S.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Goyal, Lipika; Murphy, Janet E.; Wolfgang, John A.; Drapek, Lorraine C.; Arellano, Ronald S.; Mullen, John T.; Yoon, Sam S.; Tanabe, Kenneth K.; Ferrone, Cristina R.; Ryan, David P.; DeLaney, Thomas F.; Zhu, Andrew X.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Mamon, Harvey J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, 44 Binney St, Boston, MA 02115 USA. [Ben-Josef, Edgar] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Javle, Milind M.; Crane, Christopher H.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,COX-3, Boston, MA 02114 USA. EM tshong1@partners.org FU National Institutes of Health [2P01CA021239-29A1]; Cancer Clinical Investigator Team Leadership Award - National Cancer Institute [P30CA006516] FX Supported by National Institutes of Health Grant No. 2P01CA021239-29A1 Revised and in part by the Cancer Clinical Investigator Team Leadership Award, awarded by the National Cancer Institute through a supplement to Grant No. P30CA006516. NR 23 TC 14 Z9 16 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2016 VL 34 IS 5 BP 460 EP + DI 10.1200/JCO.2015.64.2710 PG 11 WC Oncology SC Oncology GA DJ6OK UT WOS:000374332600015 PM 26668346 ER PT J AU Ho, JE Larson, MG Ghorbani, A Cheng, S Chen, MH Keyes, M Rhee, EP Clish, CB Vasan, RS Gerszten, RE Wang, TJ AF Ho, Jennifer E. Larson, Martin G. Ghorbani, Anahita Cheng, Susan Chen, Ming-Huei Keyes, Michelle Rhee, Eugene P. Clish, Clary B. Vasan, Ramachandran S. Gerszten, Robert E. Wang, Thomas J. TI Metabolomic Profiles of Body Mass Index in the Framingham Heart Study Reveal Distinct Cardiometabolic Phenotypes SO PLOS ONE LA English DT Article ID TYPE-2 DIABETES-MELLITUS; INSULIN-RESISTANCE; AMINO-ACIDS; GLUCOSE-TOLERANCE; BRANCHED-CHAIN; YOUNG-ADULTS; RISK-FACTORS; FINNISH MEN; DISEASE; HUMANS AB Background Although obesity and cardiometabolic traits commonly overlap, underlying pathways remain incompletely defined. The association of metabolite profiles across multiple cardiometabolic traits may lend insights into the interaction of obesity and metabolic health. We sought to investigate metabolic signatures of obesity and related cardiometabolic traits in the community using broad-based metabolomic profiling. Methods and Results We evaluated the association of 217 assayed metabolites and cross-sectional as well as longitudinal changes in cardiometabolic traits among 2,383 Framingham Offspring cohort participants. Body mass index (BMI) was associated with 69 of 217 metabolites (P<0.00023 for all), including aromatic (tyrosine, phenylalanine) and branched chain amino acids (valine, isoleucine, leucine). Additional metabolic pathways associated with BMI included the citric acid cycle (isocitrate, alpha-ketoglutarate, aconitate), the tryptophan pathway (kynurenine, kynurenic acid), and the urea cycle. There was considerable overlap in metabolite profiles between BMI, abdominal adiposity, insulin resistance [IR] and dyslipidemia, modest overlap of metabolite profiles between BMI and hyperglycemia, and little overlap with fasting glucose or elevated blood pressure. Metabolite profiles were associated with longitudinal changes in fasting glucose, but the involved metabolites (ornithine, 5-HIAA, aminoadipic acid, isoleucine, cotinine) were distinct from those associated with baseline glucose or other traits. Obesity status appeared to "modify" the association of 9 metabolites with IR. For example, bile acid metabolites were strongly associated with IR among obese but not lean individuals, whereas isoleucine had a stronger association with IR in lean individuals. Conclusions In this large-scale metabolite profiling study, body mass index was associated with a broad range of metabolic alterations. Metabolite profiling highlighted considerable overlap with abdominal adiposity, insulin resistance, and dyslipidemia, but not with fasting glucose or blood pressure traits. C1 [Ho, Jennifer E.; Larson, Martin G.; Cheng, Susan; Chen, Ming-Huei; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ho, Jennifer E.; Larson, Martin G.; Cheng, Susan; Chen, Ming-Huei; Vasan, Ramachandran S.] Boston Univ, Sch Med, Framingham, MA USA. [Ho, Jennifer E.; Keyes, Michelle; Rhee, Eugene P.; Gerszten, Robert E.] Harvard Univ, Sch Med, Dept Med, Cardiovasc Res Ctr,Massachusetts Gen Hosp, Boston, MA USA. [Ho, Jennifer E.; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ghorbani, Anahita] Mt Auburn Hosp, Cambridge, MA USA. [Cheng, Susan] Harvard Univ, Brigham & Womens Hosp, Div Cardiol, Sch Med, Boston, MA 02115 USA. [Rhee, Eugene P.] Harvard Univ, Sch Med, Dept Med, Renal Div,Massachusetts Gen Hosp, Boston, MA USA. [Rhee, Eugene P.; Clish, Clary B.; Gerszten, Robert E.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Vasan, Ramachandran S.] Boston Univ, Div Cardiol & Prevent Med, Dept Med, Boston, MA 02215 USA. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. RP Ho, JE (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA.; Ho, JE (reprint author), Boston Univ, Sch Med, Framingham, MA USA.; Ho, JE (reprint author), Harvard Univ, Sch Med, Dept Med, Cardiovasc Res Ctr,Massachusetts Gen Hosp, Boston, MA USA.; Ho, JE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. EM jho1@mgh.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; National Institutes of Health [K23-HL116780, 2R01-DK081572]; Boston University School of Medicine Department of Medicine Career Investment Award; Ellison Foundation FX This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I), National Institutes of Health grants K23-HL116780 (JEH), 2R01-DK081572 (MGL, REG, TJW), a Boston University School of Medicine Department of Medicine Career Investment Award (JEH), and the Ellison Foundation (SC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 7 Z9 7 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 10 PY 2016 VL 11 IS 2 AR e0148361 DI 10.1371/journal.pone.0148361 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6PR UT WOS:000370046600059 PM 26863521 ER PT J AU Yueh, AE Payne, SN Leystra, AA Van De Hey, DR Foley, TM Pasch, CA Clipson, L Matkowskyj, KA Deming, DA AF Yueh, Alexander E. Payne, Susan N. Leystra, Alyssa A. Van De Hey, Dana R. Foley, Tyler M. Pasch, Cheri A. Clipson, Linda Matkowskyj, Kristina A. Deming, Dustin A. TI Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K SO PLOS ONE LA English DT Article ID COLORECTAL-CANCER; GENETIC ALTERATIONS; PIK3CA MUTATION; PATHWAY; INHIBITION AB The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3-ca(H1047R) mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (beta-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling. C1 [Yueh, Alexander E.; Van De Hey, Dana R.; Foley, Tyler M.; Deming, Dustin A.] Univ Wisconsin, Dept Med, Div Hematol & Oncol, Sch Med & Publ Hlth, Madison, WI USA. [Payne, Susan N.; Pasch, Cheri A.; Matkowskyj, Kristina A.; Deming, Dustin A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Leystra, Alyssa A.; Clipson, Linda] Univ Wisconsin, Dept Oncol, Madison, WI USA. [Matkowskyj, Kristina A.] Univ Wisconsin, Dept Pathol & Lab Med, Sch Med & Publ Hlth Madison, Madison, WI USA. [Matkowskyj, Kristina A.; Deming, Dustin A.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Deming, DA (reprint author), Univ Wisconsin, Dept Med, Div Hematol & Oncol, Sch Med & Publ Hlth, Madison, WI USA.; Deming, DA (reprint author), Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA.; Deming, DA (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. EM ddeming@medicine.wisc.edu FU National Institutes of Health [P30 CA014520]; UW Carbone Cancer Center; UW Department of Medicine; UW School of Medicine and Public Health; UW Graduate School through the Wisconsin Alumni Research Foundation; Funk Out Cancer; UW Carbone Cancer Center Gastrointestinal Disease Oriented Working Group FX This project was supported by the National Institutes of Health (http://www.nih.gov/) P30 CA014520 (Core Grant, University of Wisconsin Carbone Cancer Center); start-up funds (D.A.D) from the UW Carbone Cancer Center, UW Department of Medicine, UW School of Medicine and Public Health, and the UW Graduate School through the Wisconsin Alumni Research Foundation; Funk Out Cancer (http://www.funkoutcancer.com/) and UW Carbone Cancer Center Gastrointestinal Disease Oriented Working Group. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 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 FEB 10 PY 2016 VL 11 IS 2 AR e0148730 DI 10.1371/journal.pone.0148730 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6PR UT WOS:000370046600102 PM 26863299 ER PT J AU Nasr, S Polimeni, JR Tootell, RBH AF Nasr, Shahin Polimeni, Jonathan R. Tootell, Roger B. H. TI Interdigitated Color- and Disparity-Selective Columns within Human Visual Cortical Areas V2 and V3 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE high-resolution fMRI; stereoscopic depth; streams; stripes; visual features ID OCULAR DOMINANCE COLUMNS; MACAQUE STRIATE CORTEX; SURFACE-BASED ANALYSIS; FUNCTIONAL-ORGANIZATION; CYTOCHROME-OXIDASE; CEREBRAL-CORTEX; BINOCULAR DISPARITY; PRIMATE AREA-18; HUMAN V1; 7 TESLA AB In nonhuman primates (NHPs), secondary visual cortex (V2) is composed of repeating columnar stripes, which are evident in histological variations of cytochrome oxidase (CO) levels. Distinctive "thin" and "thick" stripes of dark CO staining reportedly respond selectively to stimulus variations in color and binocular disparity, respectively. Here, we first tested whether similar color-selective or disparity-selective stripes exist in human V2. If so, available evidence predicts that such stripes should (1) radiate "outward" from the V1-V2 border, (2) interdigitate, (3) differ from each other in both thickness and length, (4) be spaced similar to 3.5-4 mm apart (center-to-center), and, perhaps, (5) have segregated functional connections. Second, we tested whether analogous segregated columns exist in a "next-higher" tier area, V3. To answer these questions, we used high-resolution fMRI (1 x 1 x 1 mm(3)) at high field (7T), presenting color-selective or disparity-selective stimuli, plus extensive signal averaging across multiple scan sessions and cortical surface-based analysis. All hypotheses were confirmed. V2 stripes and V3 columns were reliably localized in all subjects. The two stripe/column types were largely interdigitated (e.g., nonoverlapping) in both V2 and V3. Color-selective stripes differed from disparity-selective stripes in both width (thickness) and length. Analysis of resting-state functional connections (eyes closed) showed a stronger correlation between functionally alike (compared with functionally unlike) stripes/columns in V2 and V3. These results revealed a fine-scale segregation of color-selective or disparity-selective streams within human areas V2 and V3. Together with prior evidence from NHPs, this suggests that two parallel processing streams extend from visual subcortical regions through V1, V2, and V3. C1 [Nasr, Shahin; Polimeni, Jonathan R.; Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Nasr, Shahin; Polimeni, Jonathan R.; Tootell, Roger B. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Nasr, S (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM shahin@nmr.mgh.harvard.edu RI Polimeni, Jonathan/P-1395-2014 OI Polimeni, Jonathan/0000-0002-1348-1179 FU Massachusetts General Hospital Executive Committee on Research (ECOR) fund [2015A051305]; National Institutes of Health [5P41-EB-015896-17] FX This study was supported by Massachusetts General Hospital Executive Committee on Research (ECOR) fund Grant 2015A051305 to S.N. and R.B.H.T. Crucial support was also provided by the Martinos Center for Biomedical Imaging and National Institutes of Health (Grant 5P41-EB-015896-17), and by the help and cooperation of all of our subjects. We thank Dr. Douglas Greve for help in data analysis, Dr. Boris Keil for technical support, and Cesar Echavarria for help in making stimuli. NR 72 TC 3 Z9 3 U1 4 U2 8 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 FEB 10 PY 2016 VL 36 IS 6 BP 1841 EP 1857 DI 10.1523/JNEUROSCI.3518-15.2016 PG 17 WC Neurosciences SC Neurosciences & Neurology GA DD5LF UT WOS:000369964500006 PM 26865609 ER PT J AU Hu, Z Xia, JX Fan, W Wargo, J Yang, YG AF Hu, Zheng Xia, Jinxing Fan, Wei Wargo, Jennifer Yang, Yong-Guang TI Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice SO ONCOTARGET LA English DT Article DE animal model; immunotherapy; melanoma; TCR; T cells; Immunology and Microbiology Section; Immune response; Immunity ID HEMATOPOIETIC STEM-CELLS; IN-VIVO; ANTITUMOR-ACTIVITY; CANCER REGRESSION; GENE-TRANSFER; TCR; LYMPHOCYTES; EXPRESSION; RESPONSES; THERAPY AB A major factor hindering the exploration of adoptive immunotherapy in preclinical settings is the limited availability of tumor-reactive human T cells. Here we developed a humanized mouse model that permits large-scale production of human T cells expressing the engineered melanoma antigen MART-1-specific TCR. Humanized mice, made by transplantation of human fetal thymic tissue and CD34(+) cells virally-transduced with HLA class I-restricted melanoma antigen (MART-1)-specific TCR gene, showed efficient development of MART-1-TCR+ human T cells with predominantly CD8(+) cells. Importantly, MART-1-TCR(+)CD8(+) T cells developing in these mice were capable of mounting antigen-specific responses in vivo, as evidenced by their proliferation, phenotypic conversion and IFN-gamma production following MART-1 peptide immunization. Moreover, these MART-1-TCR(+)CD8(+) T cells mediated efficient killing of melanoma cells in an HLA/antigen-dependent manner. Adoptive transfer of in vitro expanded MART-1-TCR(+)CD8(+) T cells induced potent antitumor responses that were further enhanced by IL-15 treatment in melanoma-bearing recipients. Finally, a short incubation of MART-1-specific T cells with rapamycin acted synergistically with IL-15, leading to significantly improved tumor-free survival in recipients with metastatic melanoma. These data demonstrate the practicality of using humanized mice to produce potentially unlimited source of tumor-specific human T cells for experimental and preclinical exploration of cancer immunotherapy. This study also suggests that pretreatment of tumor-reactive T cells with rapamycin in combination with IL-15 administration may be a novel strategy to improve the efficacy of adoptive T cell therapy. C1 [Hu, Zheng; Fan, Wei; Yang, Yong-Guang] Jilin Univ, Bethune Hosp 1, Changchun 130023, Peoples R China. [Hu, Zheng; Fan, Wei; Yang, Yong-Guang] Jilin Univ, Inst Immunol, Changchun 130023, Peoples R China. [Hu, Zheng; Xia, Jinxing; Yang, Yong-Guang] Columbia Univ Coll Phys & Surg, Dept Med, Columbia Ctr Translat Immunol, New York, NY USA. [Wargo, Jennifer] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Yang, YG (reprint author), Jilin Univ, Bethune Hosp 1, Changchun 130023, Peoples R China.; Yang, YG (reprint author), Jilin Univ, Inst Immunol, Changchun 130023, Peoples R China.; Yang, YG (reprint author), Columbia Univ Coll Phys & Surg, Dept Med, Columbia Ctr Translat Immunol, New York, NY USA. EM yy2324@columbia.edu FU Chinese MOST [2015CB964400, 2013CB966900, 2014AA021601]; NSFC [81273334, 81200397, 81570145]; Project of Science and Technology of Jilin Province [20140520013JH]; NIH [P01AI045897, R01AI064569] FX The authors thank Dr. Kang Liu (Columbia University) for critical review of this manuscript, Dr. Steven A. Rosenberg for providing the MART-1-specific lentiviral vector and human melanoma cell lines, and Dr. Jianzhu Chen at MIT for providing huIL-15 plasmid. This study was supported by grants from Chinese MOST (2015CB964400, 2013CB966900, and 2014AA021601), NSFC (81273334, 81200397 and 81570145), the Project of Science and Technology of Jilin Province (20140520013JH), and NIH (P01AI045897 and R01AI064569). NR 35 TC 6 Z9 6 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 9 PY 2016 VL 7 IS 6 BP 6448 EP 6459 DI 10.18632/oncotarget.7044 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DM1RE UT WOS:000376123100008 PM 26824989 ER PT J AU Sexton, BS Druliner, BR Vera, DL Avey, D Zhu, FX Dennis, JH AF Sexton, Brittany S. Druliner, Brooke R. Vera, Daniel L. Avey, Denis Zhu, Fanxiu Dennis, Jonathan H. TI Hierarchical regulation of the genome: global changes in nucleosome organization potentiate genome response SO ONCOTARGET LA English DT Article DE nucleosome; chromatin; iSLK.219; KSHV; next generation sequencing; Chromosome Section ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; TRANSCRIPTION FACTORS; ENDOTHELIAL ORIGIN; GENE-EXPRESSION; CELL-LINE; RESOLUTION; PROMOTER; PARTICLE AB Nucleosome occupancy is critically important in regulating access to the eukaryotic genome. Few studies in human cells have measured genome-wide nucleosome distributions at high temporal resolution during a response to a common stimulus. We measured nucleosome distributions at high temporal resolution following Kaposi's-sarcoma-associated herpesvirus (KSHV) reactivation using our newly developed mTSS-seq technology, which maps nucleosome distribution at the transcription start sites (TSS) of all human genes. Nucleosomes underwent widespread changes in organization 24 hours after KSHV reactivation and returned to their basal nucleosomal architecture 48 hours after KSHV reactivation. The widespread changes consisted of an indiscriminate remodeling event resulting in the loss of nucleosome rotational phasing signals. Additionally, one in six TSSs in the human genome possessed nucleosomes that are translationally remodeled. 72% of the loci with translationally remodeled nucleosomes have nucleosomes that moved to positions encoded by the underlying DNA sequence. Finally we demonstrated that these widespread alterations in nucleosomal architecture potentiated regulatory factor binding. These descriptions of nucleosomal architecture changes provide a new framework for understanding the role of chromatin in the genomic response, and have allowed us to propose a hierarchical model for chromatin-based regulation of genome response. C1 [Sexton, Brittany S.; Druliner, Brooke R.; Vera, Daniel L.; Avey, Denis; Zhu, Fanxiu; Dennis, Jonathan H.] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. [Sexton, Brittany S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Sexton, Brittany S.] Harvard Univ, Sch Med, Dept Med, Charlestown, MA USA. [Druliner, Brooke R.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Vera, Daniel L.; Dennis, Jonathan H.] Florida State Univ, Ctr Genom & Personalized Med, Tallahassee, FL 32306 USA. [Dennis, Jonathan H.] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. RP Dennis, JH (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA.; Dennis, JH (reprint author), Florida State Univ, Ctr Genom & Personalized Med, Tallahassee, FL 32306 USA.; Dennis, JH (reprint author), Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. EM dennis@bio.fsu.edu FU National Institutes of Health [R01 DA033775, F31CA183250, R01 DE016680] FX We would like to thank Drs. Jinjong Myoung and Don Ganem for providing the iSLK.rKSHV219 cells. B.S.S., B.R.D., D.L.V., and J.H.D. were supported by National Institutes of Health Award R01 DA033775. D.A. was supported by National Institutes of Health Award F31CA183250. F.Z. was supported by National Institutes of Health Award R01 DE016680. NR 44 TC 1 Z9 1 U1 1 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 FEB 9 PY 2016 VL 7 IS 6 BP 6460 EP 6475 DI 10.18632/oncotarget.6841 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DM1RE UT WOS:000376123100009 PM 26771136 ER PT J AU Chouchani, ET Pell, VR James, AM Work, LM Saeb-Parsy, K Frezza, C Krieg, T Murphy, MP AF Chouchani, Edward T. Pell, Victoria R. James, Andrew M. Work, Lorraine M. Saeb-Parsy, Kourosh Frezza, Christian Krieg, Thomas Murphy, Michael P. TI A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury SO CELL METABOLISM LA English DT Review ID PERFUSED RAT HEARTS; ELECTRON TRANSFER REACTIONS; OXYGEN SPECIES GENERATION; RESPIRATORY COMPLEX-I; S-NITROSATION; FREE-RADICALS; ISCHEMIA/REPERFUSION INJURY; PERMEABILITY TRANSITION; CEREBRAL-ISCHEMIA; CARDIAC ISCHEMIA AB Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted-ischemia-and then restored-reperfusion-leading to a burst of reactive oxygen species (ROS) from mitochondria. It has been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies. C1 [Chouchani, Edward T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chouchani, Edward T.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Pell, Victoria R.; Krieg, Thomas] Univ Cambridge, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 0QQ, England. [James, Andrew M.; Murphy, Michael P.] MRC Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. [Work, Lorraine M.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Saeb-Parsy, Kourosh] Univ Dept Surg, Cambridge CB2 0QQ, England. [Saeb-Parsy, Kourosh] Addenbrookes Hosp, Cambridge NIHR Biomed Res Ctr, Cambridge CB2 0QQ, England. [Frezza, Christian] Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England. RP Murphy, MP (reprint author), MRC Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. EM mpm@mrc-mbu.cam.ac.uk OI Saeb-Parsy, Kourosh/0000-0002-0633-3696; Work, Lorraine/0000-0002-6462-4109 FU Medical Research Council (UK); British Heart Foundation; Human Frontiers Science Program fellowship FX We apologize to our many colleagues whose work we were unable to cite due to space constraints. Work in our laboratories is supported by the Medical Research Council (UK) and the British Heart Foundation. E.T.C. is supported by a Human Frontiers Science Program fellowship. NR 100 TC 18 Z9 18 U1 11 U2 24 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 FEB 9 PY 2016 VL 23 IS 2 BP 254 EP 263 DI 10.1016/j.cmet.2015.12.009 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MR UT WOS:000373613800005 PM 26777689 ER PT J AU Kir, S Komaba, H Garcia, AP Economopoulos, KP Liu, W Lanske, B Hodin, RA Spiegelman, BM AF Kir, Serkan Komaba, Hirotaka Garcia, Ana P. Economopoulos, Konstantinos P. Liu, Wei Lanske, Beate Hodin, Richard A. Spiegelman, Bruce M. TI PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer SO CELL METABOLISM LA English DT Article ID BROWN-ADIPOSE-TISSUE; RESTING ENERGY-EXPENDITURE; VITAMIN-D; PARATHYROID-HORMONE; MUSCLE STRENGTH; GENE-EXPRESSION; FAT; DISEASE; PROTEIN; PTH AB Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia. C1 [Kir, Serkan; Garcia, Ana P.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. [Komaba, Hirotaka; Lanske, Beate] Harvard Univ, Dept Oral Med Infect & Immun, Sch Dent Med, Boston, MA 02115 USA. [Economopoulos, Konstantinos P.; Liu, Wei; Hodin, Richard A.] Harvard Univ, Dept Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu FU NIH [DK31405, DK097105]; JPB Foundation FX S.K. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation (DRG-2153-13). H.K. is a JSPS Postdoctoral Fellow for Research Abroad. This work was supported by grants from the NIH (DK31405) and the JPB Foundation (to B.M.S.) and NIH grant (DK097105 to B.L.). NR 35 TC 9 Z9 9 U1 2 U2 10 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 FEB 9 PY 2016 VL 23 IS 2 BP 315 EP 323 DI 10.1016/j.cmet.2015.11.003 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MR UT WOS:000373613800010 PM 26669699 ER PT J AU Logan, A Pell, VR Shaffer, KJ Evans, C Stanley, NJ Robb, EL Prime, TA Chouchani, ET Cocheme, HM Fearnley, IM Vidoni, S James, AM Porteous, CM Partridge, L Krieg, T Smith, RAJ Murphy, MP AF Logan, Angela Pell, Victoria R. Shaffer, Karl J. Evans, Cameron Stanley, Nathan J. Robb, Ellen L. Prime, Tracy A. Chouchani, Edward T. Cocheme, Helena M. Fearnley, Ian M. Vidoni, Sara James, Andrew M. Porteous, Carolyn M. Partridge, Linda Krieg, Thomas Smith, Robin A. J. Murphy, Michael P. TI Assessing the Mitochondrial Membrane Potential in Cells and In Vivo using Targeted Click Chemistry and Mass Spectrometry SO CELL METABOLISM LA English DT Article ID TRIPHENYLPHOSPHONIUM CATIONS; COMPLEX I; DEFICIENCY; PROBES; HEART AB The mitochondrial membrane potential (Delta Psi(m)) is a major determinant and indicator of cell fate, but it is not possible to assess small changes in Delta Psi(m) within cells or in vivo. To overcome this, we developed an approach that utilizes two mitochondria-targeted probes each containing a triphenylphosphonium (TPP) lipophilic cation that drives their accumulation in response to Delta Psi(m) and the plasma membrane potential (Delta Psi(p)). One probe contains an azido moiety and the other a cyclooctyne, which react together in a concentration-dependent manner by "click'' chemistry to form MitoClick. As the mitochondrial accumulation of both probes depends exponentially on Delta Psi(m) and Delta Psi(p), the rate of MitoClick formation is exquisitely sensitive to small changes in these potentials. MitoClick accumulation can then be quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach enables assessment of subtle changes in membrane potentials within cells and in the mouse heart in vivo. C1 [Logan, Angela; Robb, Ellen L.; Prime, Tracy A.; Chouchani, Edward T.; Fearnley, Ian M.; Vidoni, Sara; James, Andrew M.; Murphy, Michael P.] MRC, Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. [Pell, Victoria R.; Chouchani, Edward T.; Krieg, Thomas] Univ Cambridge, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 2QQ, England. [Shaffer, Karl J.; Evans, Cameron; Stanley, Nathan J.; Porteous, Carolyn M.; Smith, Robin A. J.] Univ Otago, Dept Chem, POB 56, Dunedin 9054, New Zealand. [Chouchani, Edward T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chouchani, Edward T.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Cocheme, Helena M.; Partridge, Linda] UCL, Inst Healthy Ageing, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Cocheme, Helena M.] Univ London Imperial Coll Sci Technol & Med, Ctr Clin Sci, MRC, Du Cane Rd, London W12 0NN, England. [Porteous, Carolyn M.] Univ Otago, Dept Dept Biochem, POB 56, Dunedin 9054, New Zealand. RP Murphy, MP (reprint author), MRC, Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. EM mpm@mrc-mbu.cam.ac.uk OI Stanley, Nathan/0000-0002-2625-9876 FU MRC (UK) [MC-A070-5PS30]; Biotechnology and BSRC (UK) [BB/D020786/1]; Foundation for Research Science and Technology (NZ); British Heart Foundation [BHF-PG12/42/29655]; Human Frontiers Science Program FX This work was supported by the MRC (UK) (MC-A070-5PS30), the Biotechnology and BSRC (UK) (BB/D020786/1), the Foundation for Research Science and Technology (NZ), the British Heart Foundation (BHF-PG12/42/29655), and the Human Frontiers Science Program (long-term fellowship to E.T.C.). NR 25 TC 7 Z9 7 U1 6 U2 22 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 FEB 9 PY 2016 VL 23 IS 2 BP 379 EP 385 DI 10.1016/j.cmet.2015.11.014 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MR UT WOS:000373613800017 PM 26712463 ER PT J AU Silvestri, V Barrowdale, D Mulligan, AM Neuhausen, SL Fox, S Karlan, BY Mitchell, G James, P Thull, DL Zorn, KK Carter, NJ Nathanson, KL Dornchek, SM Rebbeck, TR Ramus, SJ Nussbaum, RL Olopade, OI Rantala, J Yoon, SY Caligo, MA Spugnesi, L Bojesen, A Pedersen, IS Thomassen, M Jensen, UB Toland, AE Senter, L Andrulis, IL Glendon, G Hulick, PJ Irnyanitov, EN Greene, MH Mai, PL Singer, CF Rappaport-Fuerhauser, C Kramer, G Vijai, J Offit, K Robson, M Lincoln, A Jacobs, L Machackova, E Foretova, L Navratilova, M Vasickova, P Couch, FJ Hallberg, E Ruddy, KJ Sharma, P Kim, SW Teixeira, MR Pinte, P Montagna, M Matricardi, L Arason, A Johannsson, OT Barkardottir, RB Jakubowska, A Lubinski, J Izquierdo, A Pujana, MA Balmana, J Diez, O Ivady, G Papp, J Olah, E Kwong, A Nevanlinna, H Aittomaki, K Segura, PP Caldes, T Van Maerken, T Poppe, B Claes, KBM Isaacs, C Elan, C Lasset, C Stoppa-Lyonnet, D Barjhoux, L Belotti, M Meindl, A Gehrig, A Sutter, C Enger, C Niederacher, D Steinemann, D Hahnen, E Kast, K Arnold, N Varon-Mateeva, R Wand, D Godwin, AK Evans, DG Frost, D Perkins, J Adlard, J Izatt, L Platte, R Eeles, R Ellis, S Hamann, U Garber, J Fostira, F Fountzilas, G Pasini, B Giannini, G Rizzolo, P Russo, A Cortesi, L Papi, L Varesco, L Palli, D Zanna, I Savarese, A Radice, P Manoukian, S Peissel, B Barile, M Bonanni, B Viel, A Pensotti, V Tommasi, S Peterlongo, P Weitzel, JN Osorio, A Benitez, J McGuffog, L Healey, S Gerdes, AM Ejlertsen, B Hansen, TVO Steele, L Ding, YC Tung, N Janavicius, R Goldgar, DE Buys, SS Daly, MB Bane, A Terry, MB John, EM Southey, M Easton, DF Chenevix-Trench, G Antoniou, AC Ottini, L AF Silvestri, Valentina Barrowdale, Daniel Mulligan, Anna Marie Neuhausen, Susan L. Fox, Stephen Karlan, Beth Y. Mitchell, Gillian James, Paul Thull, Darcy L. Zorn, Kristin K. Carter, Natalie J. Nathanson, Katherine L. Dornchek, Susan M. Rebbeck, Timothy R. Ramus, Susan J. Nussbaum, Robert L. Olopade, Olufunrnilayo I. Rantala, Johanna Yoon, Sook-Yee Caligo, Maria A. Spugnesi, Laura Bojesen, Anders Pedersen, Inge Sokilde Thomassen, Muds Jensen, Uffe Birk Toland, Amanda Ewart Senter, Leigha Andrulis, Irene L. Glendon, Gord Hulick, Peter J. Irnyanitov, Evgeny N. Greene, Mark H. Mai, Phuong L. Singer, Christian F. Rappaport-Fuerhauser, Christine Kramer, Gero Vijai, Joseph Offit, Kenneth Robson, Mark Lincoln, Anne Jacobs, Lauren Machackova, Eva Foretova, Lenka Navratilova, Marie Vasickova, Petra Couch, Fergus J. Hallberg, Emily Ruddy, Kathryn J. Sharma, Priyanka Kim, Sung-Won Teixeira, Manuel R. Pinte, Pedro Montagna, Marco Matricardi, Laura Arason, Adalgeir Johannsson, Oskar Th Barkardottir, Rosa B. Jakubowska, Anna Lubinski, Jan Izquierdo, Angel Angel Pujana, Miguel Balmana, Judith Diez, Orland Ivady, Gabriella Papp, Janos Olah, Edith Kwong, Ava Nevanlinna, Heli Aittomaki, Kristiina Perez Segura, Pedro Caldes, Trinidad Van Maerken, Tom Poppe, Bruce Claes, Kathleen B. M. Isaacs, Claudine Elan, Camille Lasset, Christine Stoppa-Lyonnet, Dominique Barjhoux, Laure Belotti, Muriel Meindl, Alfons Gehrig, Andrea Sutter, Christian Enger, Christoph Niederacher, Dieter Steinemann, Doris Hahnen, Eric Kast, Karin Arnold, Norbert Varon-Mateeva, Raymonda Wand, Dorothea Godwin, Andrew K. Evans, D. Gareth Frost, Debra Perkins, Jo Adlard, Julian Izatt, Louise Platte, Radka Eeles, Ros Ellis, Steve Hamann, Ute Garber, Judy Fostira, Florentia Fountzilas, George Pasini, Barbara Giannini, Giuseppe Rizzolo, Piera Russo, Antonio Cortesi, Laura Papi, Laura Varesco, Liliana Palli, Domenico Zanna, Ines Savarese, Antonella Radice, Paolo Manoukian, Siranoush Peissel, Bernard Barile, Monica Bonanni, Bernardo Viel, Alessandra Pensotti, Valeria Tommasi, Stefania Peterlongo, Paolo Weitzel, Jeffrey N. Osorio, Ana Benitez, Javier McGuffog, Lesley Healey, Sue Gerdes, Anne-Marie Ejlertsen, Bent Hansen, Thomas V. O. Steele, Linda Ding, Yuan Chun Tung, Nadine Janavicius, Ramunas Goldgar, David E. Buys, Saundra S. Daly, Mary B. Bane, Anita Terry, Mary Beth John, Esther M. Southey, Melissa Easton, Douglas F. Chenevix-Trench, Georgia Antoniou, Antonis C. Ottini, Laura CA kConFab Investigators Hereditary Breast Ovarian Canc Res EMBRACE TI Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2 SO BREAST CANCER RESEARCH LA English DT Article DE Male breast cancer; BRCA1/2; Pathology; Histologic grade; Genotype-phenotype correlations ID POPULATION; RISK; CARCINOMA; FEATURES; GRADE AB Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 x 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 x 10(-12)). Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management. C1 [Silvestri, Valentina; Giannini, Giuseppe; Rizzolo, Piera; Ottini, Laura] Univ Roma La Sapienza, Dept Mol Med, Viale Regina Elena 324, I-00161 Rome, Italy. [Barrowdale, Daniel; Frost, Debra; Perkins, Jo; Ellis, Steve; McGuffog, Lesley; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie; Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Neuhausen, Susan L.; Steele, Linda; Ding, Yuan Chun] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Fox, Stephen] Peter MacCallum Canc Inst, East Melbourne, Australia. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Mitchell, Gillian; James, Paul] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia. [Mitchell, Gillian; James, Paul] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia. [Thull, Darcy L.; Zorn, Kristin K.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Carter, Natalie J.] UPMC Canc Ctr, Pittsburgh, PA USA. [Nathanson, Katherine L.; Dornchek, Susan M.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. 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EM laura.ottini@uniroma1.it RI montagna, marco/E-2225-2012; Teixeira, Manuel/E-4885-2011; Osorio, Ana/I-4324-2014; Andrulis, Irene/E-7267-2013; Arnold, Norbert/E-3012-2010; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; OI Fox, Stephen/0000-0002-7648-8896; Evans, Gareth/0000-0002-8482-5784; montagna, marco/0000-0002-4929-2150; Barrowdale, Daniel/0000-0003-1661-3939; Teixeira, Manuel/0000-0002-4896-5982; Osorio, Ana/0000-0001-8124-3984; Arnold, Norbert/0000-0003-4523-8808; Eeles, Rosalind/0000-0002-3698-6241; Ramus, Susan/0000-0003-0005-7798; PALLI, Domenico/0000-0002-5558-2437; Joseph, Vijai/0000-0002-7933-151X; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Robson, Mark/0000-0002-3109-1692; Tommasi, Stefania/0000-0002-2157-2978 FU National Cancer Institute [UM1 CA164920, RC4CA153828]; Research Council of Lithuania [LIG-07/2012]; Breast Cancer Research Foundation; Morris and Horowitz Families Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08]; Mutua Madrilena Foundation (FMMA); RTICC [06/0020/1060]; Office of the Director, National Institutes of Health; Fondazione IRCCS Istituto Nazionale Tumori; FiorGen Foundation for Pharmacogenomics; AIRC [IG12780]; FIRC; Cancer Research UK [C1287/A10118, C1287/A11990, C5047/A8385, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; NHMRC; European Union [European Social Fund (ESF)]; Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA; European Social Fund; DKFZ. EMBRACE; NIHR grant to the Biomedical Research Centre, Manchester, UK; Royal Marsden NHS Foundation Trust; NIHR; Biomedical Research Centre; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Cancer Aid [110837]; Center for Molecular Medicine Cologne (CMMC); Ligue Nationale Contre le Cancer; Association "Le cancer du sein, parlors-enl" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer; National Institute of Cancer (INCa); Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI) [P30-CA051008]; Fisher Center for Familial Cancer Research; GOA [BOF10/GOA/019]; ISCIII (Spain) [RD12/00369/0006, 12/00539]; European Regional Development FEDER funds; Helsinki University Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society and the Sigrid Juselius Foundation; Dutch Cancel Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005, 2014-187.WO76]; BBMRI [NWO 184.021.007/CP46]; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Transcan [JTC 2012]; Cancer [12-054]; Hong Kong Hereditary Breast Cancer Family Registry; Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian research [KTA-OTKA CK-80745, OTPA K-112228]; Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/OP-9]; Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; ISCIIRETIC [RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; IHCC [PBZ_KBN_122/P05/2004]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation, and previously; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; National Breast Cancer Foundation, Cancer Australia; National Institutes of Health (USA); National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; NIH, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116167, CA128978, CA176785, CA116201]; U.S. Department of Defense Ovarian Cancer Idea award [W81XWH-10-1-0341]; David F. and Margaret rein Family Foundation; Ting Tsung and We Fong Chao Foundation; MH CZ - DRO [MMCI, 00209805]; European Regional Development Fund; State Budget of the Czech Republic [RECAMO,CZ.1.05./21.00/03.0101]; Charles University in Prague [UNCE204024]; Robert. and Kate Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Reserch Fund; Intramural Research Program of the National Cancer Institute, [711]; Russian Federation for Basic Research [13-04-92613, 14-04-93959, 15-04-01744]; Ohio State University Comprehensive Cancer Center; ITT (Istituto Toscano Tumori); SEABASS: Ministry of Science, Technology and Innovation Ministry of Higher Education and Cancer Research Initiatives Foundation [UMC/HIR/MOHE/06]; Malaysia Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HIR/MOHE/06]; Cancer Research Initiatives Foundation; Swedish, Cancer Society; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA125183, R01 CA142996, 1U01CA161032]; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Womens Can Research Alliance and the Breast Cancer research Foundation; CRUK; University Pennsylvania National Instiutes of Health (NIH) [R01-CA102776, R01-CA083855]; Susan G. Komen Foundation forte Cure, Basser Research Center; UPITT/MWH: Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation Geoffrey Lindeman, Marion Harris, Martin Delatyki of the Victorian Familial Cancer Trials Group; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA146112]; U.S. Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); CIHR Team in Familial Risks of Breast Cancer, Komen Foundation; Ovarian Cancer Research Fund; [SAF2010-20493]; [FISPI08/1120]; [5U01CA113916]; [R01CA140323]; [NO2-CP-11019-50]; [N02-CP-65504] FX BCFR: This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government or the BCFR. BCFR-AU: Acknowledge Maggie Angelakos, Judi Maskiell, Gillian Dite and Helen Tsimiklis. BCFR-NY: We thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON: We thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT is partly supported by Research Council of Lithuania grant LIG-07/2012. We acknowledge Vilius Rudaitis and Laimonas Griskevicius. BIDMC is supported by the Breast Cancer Research Foundation. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CBCS: This work was supported by the NEYE Foundation. CNIO: This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493. We thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. COH-CCGCRN: City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by award number RC4CA153828 (JNW, principal investigator) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT TEAM: Funds from Italian citizens who allocated the 5 x 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT institutional strategic projects '5 x 1000') to SM and from FiorGen Foundation for Pharmacogenomics to LP. LO is supported by AIRC (IG12780). VS is supported by FIRC (triennial fellowship "Mario e Valeria Rindi"). We acknowledge Maria Grazia Tibiletti of the Ospedale di Circolo-Universita dell'Insubria, Varese, Italy. CORE: The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. SH is supported by an NHMRC program grant (to GCT). ACA is a Cancer Research UK senior cancer research fellow. GCT is an NHMRC senior principal research fellow. DEMOKRITOS: This research has been co-financed by the European Union [European Social Fund (ESF)] and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF)-Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. Investing in knowledge society through the European Social Fund. DKFZ: The DKFZ study was supported by the DKFZ. EMBRACE is supported by Cancer Research UK grants C1287/A10118 and C1287/A11990. DGE and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester, UK. The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. RE and Elizabeth Bancroft are supported by Cancer Research UK grant C5047/A8385.; RE is also supported by NIHR support of the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. RE is supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. We thank Ms. Jo Ellen Weaver and Dr. Betsy Bove for their technical support. GC-HBOC: The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant 110837 to Rita K. Schmutgler) and by the Center for Molecular Medicine Cologne (CMMC). GEMo: The study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlors-enl" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer program and the trench National Institute of Cancer (INCa). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: National Cancer Genetics Network "UNICANCER Genetic Group", France. We thank all the GEMO collaborating groups for their contribution to this study. DEMO Collaborating Centers are Coordinating Centres: Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Gyms de Lyon - Centre Leon Berard, & Equipe Genetique du cancer du sein", Centre de Recherche en Cancerologie de Lyon: Olga Sinilnikova dagger, Sylvie Nlazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Melanie Leone, Nadia Boutry-Kryza, Alain Calender, Sophie Grand; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnes Collet Virginie Moncoutier, Cedrick Lefol, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme Anne-Marie Birot. Institut Gustave Roussy,Villejuif Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Batasille Centre Jean Perrin, Clerrnont-Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona, Sandrine Handallou. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi Audrey Remenieras, Francois Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joelle Fournier, Francoise Revillion PhilippeVennint dagger, Claude Adenis. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Emmanuelle Barouk-Simonet, Francoisc Bonn I, Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulousee: Christine Tor la Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux Helene Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay CHU Limoges: Laurence Venat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonncau, Tours: Isabelle Mortemonsque.; Groupe Hospitalier Pitie-Salpetriere, Pals: Florence Coulet, Chrystelle Cobs, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy Johanna Sokolowska, Myriam Bronner CHU Besancon: Marie-Agnes Collonge-Rame, Alexandre Damette. Creighton University, On NE, USA Henry T. Lynch, Carrie L. Snyder. Georgetown University: CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing for the Cure. G-FAST: Kim De Leeneer is supported by GOA glaint BOF10/GOA/019 (Ghent University) and spearhead financing of Ghent University Hospital. We thank the technical support of IIse Coene en Brecht Crombez. was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. We acknowledge Alicia Tosar for her technical assistance. HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBCS thanks Taru A. Mu amen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkila and Virpi Palola for their help with the HEBCS data and samples. HERON is supported by the Dutch Cancel Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HERON) consists of the following collaborating centres: coordinating centre: Netherlands Cancer Institute, Amsterdam, the Netherlands: M. A. Rookus, F. B. L. Hogervorst F. E. van Leeuwen, S. Verhoef, M. K Schmidt, N. S. Russell, J. L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, the Netherlands:1 M. Collee A. M. W. van den Ouweland, M. J. Floc ning, C. Seynaeve, C. H. M. van Deurzen, I. M. Obdeijn; Leiden University Medical Center, the Netherlands: C. J. van Asperen, J. T. Wijnen, R. A. E. M. Tollenaar, P. Devilee, T. C T. E. F. van Cronenburg; Radboud University Nijmegen Medical Center, the Netherlands: C. M. Kets, A. R. Mensenkamp; University Medical Center Utrecht, the Netherlands: M. G. E. M. Ausems, R. B. van der Luijt, C. C. van der Pol; Amsterdam Medical Center, Amsterdam, the Netherlands: C. M. Aalfs, T. A. M. van Os; VU University Medical Center, Amsterdam, Amsterdam, the Netherlands: j. J. P. Gille, Q. Waisfisz, H University Hospital Maastricht, the Netherlands: E. B. Gomez-Garcia M. J Blok; University Medical Center (Groningen, the Netherlands: J.C Oosterwijk, A. H. van der Hout, M. J. Mourits, G. H. de Bock; -File Netherlands Foundation for the detection of hereditary tumours, Leiden, the Netherlands: H. F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology Registy (PALGA): L. I. H. Overbeek. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of IKNL. and PALGA for part of the data collection.; HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. We, the thank Hong Kong Sanatorium and Hospital for their continual support HUNBOCS: Hungarian Breast and Ovarian Cancer Study was supported by Hungarian research grants KTA-OTKA CK-80745, OTPA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9. We thank the ilungarian Breast and Ovarian Cancer Study Group members Gangs Papp, Tibor Vaszko Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest Hungary) and the clinicians and patients for their contributions to this study. HVH: We, thank the Oncogcnetics Group (VHIO), and the High Risk and Cancer Prevention Unit of the University Hospital Vall d'Hebron. ICO: Contract grant sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. contract grant numbers: ISCIIRETIC RD06/0020/1051, RD12/0036/008 PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364. We thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. IOVHBOCS is supported by Minister() della Salute and "5x1000" Istituto Oncologico Veneto grant. IPOBCS: This study was part supported by Liga Portuguesa Contra o Cancro. We thank Drs. Ana Peixoto, Catarina Santos, Patricia Rocha and Pedro Pinto for their skilful contribution to the study. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia; We, thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and. staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study [which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institutes of Health (USA)] for their contributions to this resource, and the many familles who contribute to kConFab. KOIIBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret rein Family Foundation and the Ting Tsung and We Fong Chao Foundation. MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO,CZ.1.05./21.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (to MZ).; MODSQUAD acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA) and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert. and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Reserch Fund. NCI: The research of MHG and PLM was supported by the Intramural Research Program of the National Cancer Institute, 711, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD, USA. NNPIO: This work has been supported by the Russian Federation for Basic Research (grants 13-04-92613, 14-04-93959 and 15-04-01744). OCGN: We thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSUCCG is supported by The Ohio State University Comprehensive Cancer Center. Leigha Senter, Kevin Sweet, Caroline Craven and Michelle O'Conor were in in accrual of study participants, ascertainment of medical records and database management. Samples were processed by the OSU Human Genetics Sample Bank. PBCS: This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013. SEABASS: Ministry of Science, Technology and Innovation Ministry of Higher Education (UMC/HIR/MOHE/06) and Cancer Research Initiatives Foundation. We thank Yip Cheng Har, Nur Aishah Mohd Talb, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collet on and sample preparation. In addition, we thank Philip lau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively. The Malaysian Breast Cancer Genetic Study is funded by resarch grants from the Malaysia Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from Cancer Research Initiatives Foundation. SWE-BRCA collaborators are supported by the Swedish, Cancer Society. Swedish, scientists participating as SWE-BRCA collaborators are as follows: from Lund University and University Hospital: angstrom ke Borg, Hakan Olsson, Helena Jemstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelle Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umea University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. The University of Chicago is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Womens Can Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society clinical research professor.; We thank Cecilla Zvocec, Qun Niu, physicians, genetic counsellors, research nurses anti staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to Our program. UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. We thank the following genetic counsellors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart Robin Lee, Amie Blanco and Peggy Conrad. Thanks are also extended to Ms. Salina Chan for her data management. UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Simon Gayther Susan Ramus, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions to the UKFOCR. University Pennsylvania National Instiutes of Health (NIH) (grants R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation forte Cure, Basser Research Center for BRCA. UPITT/MWH: Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation Geoffrey Lindeman, Marion Harris, Martin Delatyki of the Victorian Familial Cancer Trials Group.;Ale thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification. WCP: BYK is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and National Center for Advancing Translational Sciences (NCATS) grant UL1TR000124. Funding for the ICOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA146112 - the GAME-ON Initiative), the U.S. Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. NR 30 TC 1 Z9 1 U1 11 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD FEB 9 PY 2016 VL 18 AR 15 DI 10.1186/s13058-016-0671-y PG 13 WC Oncology SC Oncology GA DD0DQ UT WOS:000369590900001 PM 26857456 ER PT J AU Liu, XF Li, HP Rajurkar, M Li, Q Cotton, JL Ou, JH Zhu, LHJ Goel, HL Mercurio, AM Park, JS Davis, RJ Mao, JH AF Liu, Xiangfan Li, Huapeng Rajurkar, Mihir Li, Qi Cotton, Jennifer L. Ou, Jianhong Zhu, Lihua J. Goel, Hira L. Mercurio, Arthur M. Park, Joo-Seop Davis, Roger J. Mao, Junhao TI Tead and AP1 Coordinate Transcription and Motility SO CELL REPORTS LA English DT Article ID HIPPO PATHWAY; CELL-PROLIFERATION; GENE-EXPRESSION; EMERGING ROLES; SIZE-CONTROL; PROTEIN YAP; CANCER; FAMILY; GROWTH; TAZ AB The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells. C1 [Liu, Xiangfan; Li, Huapeng; Rajurkar, Mihir; Cotton, Jennifer L.; Ou, Jianhong; Zhu, Lihua J.; Goel, Hira L.; Mercurio, Arthur M.; Mao, Junhao] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. [Li, Qi; Davis, Roger J.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Park, Joo-Seop] Cincinnati Childrens Hosp Med Ctr, Div Pediat Urol, Cincinnati, OH 45229 USA. [Park, Joo-Seop] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Davis, Roger J.] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA. [Rajurkar, Mihir] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. RP Mao, JH (reprint author), Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. EM junhao.mao@umassmed.edu FU National Institutes of Health [R01DK099510]; American Cancer Society [RSG-11-040-01-DDC]; National Nature Science Foundation of China [81201913] FX National Institutes of Health grant R01DK099510 (to J.M.) and American Cancer Society grant RSG-11-040-01-DDC (to J.M.) were the major support for this work. X.L. was also supported in part by a grant from the National Nature Science Foundation of China (81201913). R.J.D. is an investigator of the Howard Hughes Medical Institute. We thank members of the J.M. lab for helpful discussion. NR 45 TC 14 Z9 15 U1 5 U2 10 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 FEB 9 PY 2016 VL 14 IS 5 BP 1169 EP 1180 DI 10.1016/j.celrep.2015.12.104 PG 12 WC Cell Biology SC Cell Biology GA DD0NG UT WOS:000369616100018 PM 26832411 ER PT J AU Malleshaiah, M Padi, M Rue, P Quackenbush, J Martinez-Arias, A Gunawardena, J AF Malleshaiah, Mohan Padi, Megha Rue, Pau Quackenbush, John Martinez-Arias, Alfonso Gunawardena, Jeremy TI Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation SO CELL REPORTS LA English DT Article ID SELF-RENEWAL; TRANSCRIPTIONAL NETWORK; NAIVE PLURIPOTENCY; MOUSE EMBRYOS; CIRCUITRY; PROTEIN; NANOG; TCF3; REPRESSION; RESISTANCE AB Pluripotent cells give rise to distinct cell types during development and are regulated by often self-reinforcing molecular networks. How such networks allow cells to differentiate is less well understood. Here, we use integrative methods to show that external signals induce reorganization of the mouse embryonic stem cell pluripotency network and that a sub-network of four factors, Nac1, Oct4, Tcf3, and Sox2, regulates their differentiation into the alternative mesendodermal and neuroectodermal fates. In the mesendodermal fate, Nac1 and Oct4 were constrained within quantitative windows, whereas Sox2 and Tcf3 were repressed. In contrast, in the neuroectodermal fate, Sox2 and Tcf3 were constrained while Nac1 and Oct4 were repressed. In addition, we show that Nac1 coordinates differentiation by activating Oct4 and inhibiting both Sox2 and Tcf3. Reorganization of progenitor cell networks around shared factors might be a common differentiation strategy and our integrative approach provides a general methodology for delineating such networks. C1 [Malleshaiah, Mohan; Gunawardena, Jeremy] Harvard Univ, Sch Med, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. [Padi, Megha; Quackenbush, John] Dana Farber Canc Inst, Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Rue, Pau; Martinez-Arias, Alfonso] Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England. RP Malleshaiah, M; Gunawardena, J (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. EM mohan_malleshaiah@hms.harvard.edu; jeremy_gunawardena@hms.harvard.edu RI Martinez Arias, Alfonso/F-1966-2010 FU Human Frontier Science Program grant [RGP0029/2010]; Canadian Institutes of Health Research award [201411MFE-339075-254265]; NIH award [R01GM105375]; European Research Council Advanced Investigator award; National Human Genome Research Institute grant [K25HG006031]; NIH grant [1R01 HL111759] FX We thank Anna-Katerina Hadjantonakis and Gordon Keller for the ESC lines used in this study; Rebecca Ward, Marc Kirschner, Stephen Michnick, Tathagata Dasgupta, Satabhisa Mukhopadhyay, Victor Li, and members of the J.G. and A.M.-A. labs for comments and discussions; Panos Xenopoulos and Silvia Munoz-Descalzo for help with ESC culture and immunofluorescence; Tathagata Dasgupta for help with the Bayesian analysis; the Nikon Imaging Center at Harvard Medical School for help with microscopy; and the Flow Cytometry facility at the Department of Systems Biology. This work was supported by the following funding sources: the Human Frontier Science Program grant RGP0029/2010 (M.M., A.M.-A., and J.G.); the Canadian Institutes of Health Research award 201411MFE-339075-254265 (M.M.); the NIH award R01GM105375 (M.M. and J.G.); the European Research Council Advanced Investigator award (P.R. and A.M.-A.); the National Human Genome Research Institute grant K25HG006031 (M.P.); and the NIH grant 1R01 HL111759 (J.Q.). NR 49 TC 3 Z9 3 U1 1 U2 2 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 FEB 9 PY 2016 VL 14 IS 5 BP 1181 EP 1194 DI 10.1016/j.celrep.2015.12.101 PG 14 WC Cell Biology SC Cell Biology GA DD0NG UT WOS:000369616100019 PM 26832399 ER PT J AU Lee, JS Giesler, DL Gellad, WF Fine, MJ AF Lee, Jonathan S. Giesler, Daniel L. Gellad, Walid F. Fine, Michael J. TI Antibiotic Therapy for Adults Hospitalized With Community-Acquired Pneumonia A Systematic Review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID BETA-LACTAM MONOTHERAPY; QUALITY-OF-CARE; ELDERLY-PATIENTS; OUTCOMES; MORTALITY; METAANALYSIS; PATIENT; LACTAM/MACROLIDE; AZITHROMYCIN; ASSOCIATION AB IMPORTANCE Antibiotic therapy is the cornerstone of medical management for community-acquired pneumonia. OBJECTIVE To assess the associations between 3 key aspects of antibiotic therapy (optimal time to antibiotic initiation, initial antibiotic selection, and criteria for the transition from intravenous to oral therapy) and short-term mortality in adults hospitalized with community-acquired pneumonia. EVIDENCE REVIEW Bibliographic databases of MEDLINE, EMBASE, and the Cochrane Collaboration were searched for studies of adults hospitalized with radiographically confirmed community-acquired pneumonia published from January 1, 1995, until November 5, 2015. FINDINGS Twenty studies (17 observational and 3 randomized trials) met eligibility criteria. Among 8 observational studies identified, the 4 largest (study populations of 2878 to 1 170 022) found that antibiotic initiation within 4 to 8 hours of hospital arrival was associated with relative reductions of 5% to 43% in mortality; the 4 smallest studies (study populations of 451 to 2076) found no associations between the timing of antibiotic initiation and mortality. One cluster randomized trial (n = 1737) demonstrated noninferiority of beta-lactam monotherapy (n = 506) vs beta-lactam plus macrolide combination therapy (n = 566), with an absolute adjusted difference of 2.5%(90% CI, -0.6% to 5.2%) in 90-day mortality favoring beta-lactam monotherapy. A second randomized trial (n = 580) failed to demonstrate noninferiority of beta-lactam monotherapy vs beta-lactam plus macrolide combination therapy, with an absolute difference of 7.6%(1-sided 90% CI upper limit, 13.0%) in attainment of clinical stability on hospital day 7 favoring beta-lactam plus macrolide combination therapy. Six of 8 observational studies (study populations of 1188 to 24 780) found that beta-lactam plus macrolide combination therapy was associated with relative reductions of 26% to 68% in short-term mortality and all 3 observational studies (study populations of 2068 to 24 780) reported that fluoroquinolone monotherapy was associated with relative reductions of 30% to 43% in mortality compared with beta-lactam monotherapy. One randomized trial (n = 302) reported significantly reduced hospital length of stay (absolute difference, 1.9 days; 95% CI, 0.6 to 3.2 days), but no differences in treatment failure when objective clinical criteria were used to decide when to transition patients from intravenous to oral therapy. CONCLUSIONS AND RELEVANCE In adults hospitalized with community-acquired pneumonia, antibiotic therapy consisting of beta-lactam plus macrolide combination therapy or fluoroquinolone monotherapy initiated within 4 to 8 hours of hospital arrival was associated with lower adjusted short-term mortality, supported predominantly by low-quality observational studies. One randomized trial supports the use of objective clinical criteria to guide the transition from intravenous to oral antibiotic therapy. C1 [Lee, Jonathan S.; Giesler, Daniel L.; Gellad, Walid F.; Fine, Michael J.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Lee, Jonathan S.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Gellad, Walid F.; Fine, Michael J.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Fine, MJ (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 151C Univ Dr,Bldg 30, Pittsburgh, PA 15240 USA. EM michael.fine@va.gov NR 44 TC 11 Z9 12 U1 2 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 FEB 9 PY 2016 VL 315 IS 6 BP 593 EP 602 DI 10.1001/jama.2016.0115 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DD0UJ UT WOS:000369635200018 PM 26864413 ER PT J AU Biffi, A Rosand, J AF Biffi, Alessandro Rosand, Jonathan TI Blood Pressure Control and Recurrence of Intracerebral Hemorrhage Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CEREBRAL AMYLOID ANGIOPATHY; GUIDELINES; MANAGEMENT C1 [Biffi, Alessandro; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Rosand, J (reprint author), Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. EM jrosand@partners.org NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 9 PY 2016 VL 315 IS 6 BP 611 EP 612 DI 10.1001/jama.2015.16017 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DD0UJ UT WOS:000369635200023 PM 26864418 ER PT J AU Wong, SY Tan, MGK Banks, WA Wong, WSF Wong, PTH Lai, MKP AF Wong, Siew Ying Tan, Michelle G. K. Banks, William A. Wong, W. S. Fred Wong, Peter T. -H. Lai, Mitchell K. P. TI Andrographolide attenuates LPS-stimulated up-regulation of C-C and C-X-C motif chemokines in rodent cortex and primary astrocytes SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Andrographolide; Cytokines; Chemokines; Astrocyte; Neuroinflammation ID NF-KAPPA-B; CENTRAL-NERVOUS-SYSTEM; RECEPTOR MODULATORS DECREASE; CEREBRAL-ISCHEMIA; BACTERIAL-MENINGITIS; CEREBROSPINAL-FLUID; SPINAL-CORD; TNF-ALPHA; IN-VITRO; MULTIPLE-SCLEROSIS AB Background: Andrographolide is the major bioactive compound isolated from Andrographis paniculata, a native South Asian herb used medicinally for its anti-inflammatory properties. In this study, we aimed to assess andrographolide's potential utility as an anti-neuroinflammatory therapeutic. Methods: The effects of andrographolide on lipopolysaccharide (LPS)-induced chemokine up-regulation both in mouse cortex and in cultured primary astrocytes were measured, including cytokine profiling, gene expression, and, in cultured astrocytes, activation of putative signaling regulators. Results: Orally administered andrographolide significantly attenuated mouse cortical chemokine levels from the C-C and C-X-C subfamilies. Similarly, andrographolide abrogated a range of LPS-induced chemokines as well as tumor necrosis factor (TNF)-alpha in astrocytes. In astrocytes, the inhibitory actions of andrographolide on chemokine and TNF-alpha up-regulation appeared to be mediated by nuclear factor-kappa B (NF-kappa B) or c-Jun N-terminal kinase (JNK) activation. Conclusions: These results suggest that andrographolide may be useful as a therapeutic for neuroinflammatory diseases, especially those characterized by chemokine dysregulation. C1 [Wong, Siew Ying; Tan, Michelle G. K.; Wong, W. S. Fred; Wong, Peter T. -H.; Lai, Mitchell K. P.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, 16 Med Dr, Singapore 117600, Singapore. [Tan, Michelle G. K.] Singapore Gen Hosp, Dept Clin Res, Singapore, Singapore. [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Banks, William A.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Wong, W. S. Fred] Natl Univ Singapore, Immunol Program, Inst Life Sci, Singapore 117548, Singapore. RP Lai, MKP (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, 16 Med Dr, Singapore 117600, Singapore. EM mitchell.lai@dementia-research.org OI Lai, Mitchell K.P./0000-0001-7685-1424; Wong, Siew Ying/0000-0002-3152-9930 FU Yong Loo Lin School of Medicine, National University of Singapore [W184-000-223-133]; Singapore National Medical Research Council [NMRC/CBRG/0027/2012] FX This study was supported by the Yong Loo Lin School of Medicine, National University of Singapore (grant W184-000-223-133) to MKPL and the Singapore National Medical Research Council (NMRC/CBRG/0027/2012) to WSFW. We thank Y Zhu for the technical assistance. NR 72 TC 3 Z9 3 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD FEB 9 PY 2016 VL 13 AR 34 DI 10.1186/s12974-016-0498-6 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DD5HN UT WOS:000369954000002 PM 26860080 ER PT J AU Clauss, S Wakili, R Hildebrand, B Kaab, S Hoster, E Klier, I Martens, E Hanley, A Hanssen, H Halle, M Nickel, T AF Clauss, Sebastian Wakili, Reza Hildebrand, Bianca Kaeaeb, Stefan Hoster, Eva Klier, Ina Martens, Eimo Hanley, Alan Hanssen, Henner Halle, Martin Nickel, Thomas TI MicroRNAs as Biomarkers for Acute Atrial Remodeling in Marathon Runners (The miRathon Study - A Sub-Study of the Munich Marathon Study) SO PLOS ONE LA English DT Article ID MUSCLE-SPECIFIC MICRORNA; CIRCULATING MICRORNAS; DIASTOLIC DYSFUNCTION; MYOCARDIAL-INFARCTION; POTENTIAL BIOMARKER; ENDURANCE EXERCISE; AEROBIC EXERCISE; TISSUE DOPPLER; HEART-FAILURE; FOLLOW-UP AB Introduction Physical activity is beneficial for individual health, but endurance sport is associated with the development of arrhythmias like atrial fibrillation. The underlying mechanisms leading to this increased risk are still not fully understood. MicroRNAs are important mediators of proarrhyth-mogenic remodeling and have potential value as biomarkers in cardiovascular diseases. Therefore, the objective of our study was to determine the value of circulating microRNAs as potential biomarkers for atrial remodeling in marathon runners (miRathon study). Methods 30 marathon runners were recruited into our study and were divided into two age-matched groups depending on the training status: elite (ER, >= 55 km/week, n = 15) and non-elite runners (NER, <= 40 km/week, n = 15). All runners participated in a 10 week training program before the marathon. MiRNA plasma levels were measured at 4 time points: at baseline (V1), after a 10 week training period (V2), immediately after the marathon (V3) and 24h later (V4). Additionally, we obtained clinical data including serum chemistry and echocardiography at each time point. Results MiRNA plasma levels were similar in both groups over time with more pronounced changes in ER. After the marathon miR-30a plasma levels increased significantly in both groups. MiR-1 and miR-133a plasma levels also increased but showed significant changes in ER only. 24h after the marathon plasma levels returned to baseline. MiR-26a decreased significantly after the marathon in elite runners only and miR-29b showed a non-significant decrease over time in both groups. In ER miRNA plasma levels showed a significant correlation with LA diameter, in NER miRNA plasma levels did not correlate with echocardiographic parameters. Conclusion MiRNAs were differentially expressed in the plasma of marathon runners with more pronounced changes in ER. Plasma levels in ER correlate with left atrial diameter suggesting that circulating miRNAs could potentially serve as biomarkers of atrial remodeling in athletes. C1 [Clauss, Sebastian; Wakili, Reza; Hildebrand, Bianca; Kaeaeb, Stefan; Klier, Ina; Martens, Eimo; Nickel, Thomas] Univ Munich, Med Klin & Poliklin 1, Campus Grosshadern, Munich, Germany. [Clauss, Sebastian; Wakili, Reza; Kaeaeb, Stefan; Halle, Martin] DZHK German Ctr Cardiovasc Res, Partner Site Munich, Munich Heart Alliance, Munich, Germany. [Clauss, Sebastian; Hanley, Alan] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Hoster, Eva] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Hanssen, Henner; Halle, Martin] Tech Univ Munich, Klinikum Rechts Isar MRI, Dept Prevent & Sports Med, D-80290 Munich, Germany. [Hanssen, Henner] Univ Basel, Inst Exercise & Hlth Sci, Sports Med, Basel, Switzerland. RP Clauss, S (reprint author), Univ Munich, Med Klin & Poliklin 1, Campus Grosshadern, Munich, Germany.; Clauss, S (reprint author), DZHK German Ctr Cardiovasc Res, Partner Site Munich, Munich Heart Alliance, Munich, Germany.; Clauss, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. EM sebastian.clauss@med.uni-muenchen.de FU Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [PIOF-GA-2012-328352]; German Centre for Cardiovascular Research (DZHK); Heinrich and Lotte Muehlfenzl Foundation FX This study was supported by Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (PIOF-GA-2012-328352), SC; German Centre for Cardiovascular Research (DZHK), SC, RW, SK, MH; and Heinrich and Lotte Muehlfenzl Foundation, TN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Dr. Clauss was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (PIOF-GA-2012-328352). Dres. Clauss, Kaab, Wakili, Halle were supported by the German Centre for Cardiovascular Research (DZHK). Dr. Nickel was supported by the Heinrich and Lotte Muehlfenzl Foundation, which provides educational grants for young scientists. NR 66 TC 5 Z9 5 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 9 PY 2016 VL 11 IS 2 AR e0148599 DI 10.1371/journal.pone.0148599 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6MN UT WOS:000370038400054 PM 26859843 ER PT J AU Solano-Aguilar, G Molokin, A Botelho, C Fiorino, AM Vinyard, B Li, R Chen, C Urban, J Dawson, H Andreyeva, I Haverkamp, M Hibberd, PL AF Solano-Aguilar, Gloria Molokin, Aleksey Botelho, Christine Fiorino, Anne-Maria Vinyard, Bryan Li, Robert Chen, Celine Urban, Joseph, Jr. Dawson, Harry Andreyeva, Irina Haverkamp, Miriam Hibberd, Patricia L. TI Transcriptomic Profile of Whole Blood Cells from Elderly Subjects Fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study SO PLOS ONE LA English DT Article ID NF-KAPPA-B; DIFFERENTIAL EXPRESSION ANALYSIS; PLACEBO-CONTROLLED TRIAL; RNA-SEQ DATA; SYNCYTIAL VIRUS-INFECTION; LACTIC-ACID BACTERIA; GENE-EXPRESSION; STATISTICAL-METHODS; CYTOKINE PRODUCTION; IMMUNE-RESPONSES AB We examined gene expression of whole blood cells (WBC) from 11 healthy elderly volunteers participating on a Phase I open label study before and after oral treatment with Lactobacillus rhamnosus GG-ATCC 53103 (LGG)) using RNA-sequencing (RNA-Seq). Elderly patients (65-80 yrs) completed a clinical assessment for health status and had blood drawn for cellular RNA extraction at study admission (Baseline), after 28 days of daily LGG treatment (Day 28) and at the end of the study (Day 56) after LGG treatment had been suspended for 28 days. Treatment compliance was verified by measuring LGG-DNA copy levels detected in host fecal samples. Normalized gene expression levels in WBC RNA were analyzed using a paired design built within three analysis platforms (edgeR, DESeq2 and TSPM) commonly used for gene count data analysis. From the 25,990 transcripts detected, 95 differentially expressed genes (DEGs) were detected in common by all analysis platforms with a nominal significant difference in gene expression at Day 28 following LGG treatment (FDR<0.1; 77 decreased and 18 increased). With a more stringent significance threshold (FDR< 0.05), only two genes (FCER2 and LY86), were down-regulated more than 1.5 fold and met the criteria for differential expression across two analysis platforms. The remaining 93 genes were only detected at this threshold level with DESeq2 platform. Data analysis for biological interpretation of DEGs with an absolute fold change of 1.5 revealed down-regulation of overlapping genes involved with Cellular movement, Cell to cell signaling interactions, Immune cell trafficking and Inflammatory response. These data provide evidence for LGG-induced transcriptional modulation in healthy elderly volunteers because pre-treatment transcription levels were restored at 28 days after LGG treatment was stopped. To gain insight into the signaling pathways affected in response to LGG treatment, DEG were mapped using biological pathways and genomic data mining packages to indicate significant biological relevance. C1 [Solano-Aguilar, Gloria; Molokin, Aleksey; Chen, Celine; Urban, Joseph, Jr.; Dawson, Harry] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. [Botelho, Christine; Fiorino, Anne-Maria; Andreyeva, Irina; Haverkamp, Miriam; Hibberd, Patricia L.] Massachusetts Gen Hosp, Div Global Hlth, Boston, MA 02114 USA. [Vinyard, Bryan] ARS, Stat Grp, Northeast Area, USDA, Beltsville, MD USA. [Li, Robert] ARS, Anim Genom & Improvement Lab, USDA, Beltsville, MD USA. RP Solano-Aguilar, G (reprint author), ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. EM Gloria.SolanoAguilar@ars.usda.gov FU National Institutes of Health, National Center for Complementary and Alternative Medicine (NIH/NCCAM) [3U01AT002952, 3K24AT003683]; National Institute of Health, National Center for Advancing Translational Sciences (NIH/NCATS) [1UL1 TR001102]; United States Department of Agriculture, Agricultural Research Service (USDA-ARS) [8040-51000-058-03]; Harvard Catalyst FX Funding support was provided by National Institutes of Health, National Center for Complementary and Alternative Medicine (NIH/NCCAM); http://nccam.nih.gov; 3U01AT002952 (PLH) and 3K24AT003683 (PLH), the Harvard Catalyst and National Institute of Health, National Center for Advancing Translational Sciences (NIH/NCATS); http://www.ncats.nih.gov; 1UL1 TR001102 (PLH) and United States Department of Agriculture, Agricultural Research Service (USDA-ARS); http://www.ars.usda.gov; project no 8040-51000-058-03. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of NCCAM or USDA. NIH/NCCAM Program Officer Linda Duffy, PhD, MPH, contributed to the structuring of the U01 study design, inclusion of validation approaches and implementations of protocols under phased regulatory approved IND. Other than Dr. Duffy's contributions, the funders had no role in study design, data collection and analysis, decision to publish or preparation of manuscript. NR 102 TC 2 Z9 2 U1 5 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 9 PY 2016 VL 11 IS 2 AR e0147426 DI 10.1371/journal.pone.0147426 PG 34 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6MN UT WOS:000370038400008 PM 26859761 ER PT J AU Garot, A Marquet, M Saintamand, A Bender, S Le Noir, S Rouaud, P Carrion, C Oruc, Z Bebin, AG Moreau, J Lebrigandd, K Denizot, Y Alt, FW Cogne, M Pinauda, E AF Garot, Armand Marquet, Marie Saintamand, Alexis Bender, Sebastien Le Noir, Sandrine Rouaud, Pauline Carrion, Claire Oruc, Zeliha Bebin, Anne-Gaelle Moreau, Jeanne Lebrigandd, Kevin Denizot, Yves Alt, Frederick W. Cogne, Michel Pinauda, Eric TI Sequential activation and distinct functions for distal and proximal modules within the IgH 3 ' regulatory region SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunoglobulin gene regulation; enhancers; B-cell development ID CLASS-SWITCH RECOMBINATION; HEAVY-CHAIN-LOCUS; CENTER B-CELLS; V(D)J RECOMBINATION; INTRONIC ENHANCER; SOMATIC HYPERMUTATION; IN-VIVO; ANTISENSE TRANSCRIPTION; GERMLINE DELETION; CTCF SITES AB As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3' regulatory region (3'RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3'RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasipalindromic structure. By comparing relevant previous knockout (KO) mouse models (3'RR KO and hs3b-4 KO) to a novel mutant devoid of the 3'RR quasi-palindromic region (3' PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3'RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naive B-cell subsets. At mature stages, the 3'RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells. C1 [Garot, Armand; Marquet, Marie; Saintamand, Alexis; Bender, Sebastien; Le Noir, Sandrine; Rouaud, Pauline; Carrion, Claire; Oruc, Zeliha; Bebin, Anne-Gaelle; Moreau, Jeanne; Denizot, Yves; Cogne, Michel; Pinauda, Eric] Univ Limoges, CNRS, Controle Reponse Immune & Lymphoproliferat B, UMR 7276, F-87025 Limoges, France. [Marquet, Marie] Ctr Hosp Univ Dupuytren, Serv Nephrol, F-87042 Limoges, France. [Bender, Sebastien] Ctr Hosp Univ Dupuytren, Ctr Reference Amyloses, F-87042 Limoges, France. [Lebrigandd, Kevin] Univ Nice Sophia Antipolis, CNRS, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne Sophia Antipoli, France. [Alt, Frederick W.] Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston Childrens Hosp, Boston, MA 02115 USA. [Cogne, Michel] Univ Limoges, Inst Univ France, F-87000 Limoges, France. [Rouaud, Pauline] SILAB R&D, F-19240 St Viance, France. [Bebin, Anne-Gaelle] Univ Georgia, Ctr Vaccine & Immunol, Athens, GA 30602 USA. RP Pinauda, E (reprint author), Univ Limoges, CNRS, Controle Reponse Immune & Lymphoproliferat B, UMR 7276, F-87025 Limoges, France. EM eric.pinaud@unilim.fr RI Denizot, Yves Pierre/H-9769-2016; PINAUD, Eric/O-8443-2016; cogne, michel/D-7370-2015; Le Noir, Sandrine/P-5382-2016; OI PINAUD, Eric/0000-0001-7405-9273; cogne, michel/0000-0002-8519-4427; Le Noir, Sandrine/0000-0002-2297-4186; Moreau, Jeanne/0000-0003-3590-1602 FU Canceropole PACA; Commissariat aux Grands Investissements [PB: ANR-10-INBS-09-03, ANR-10-INBS-09-02]; Centre National de la Recherche Scientifique; Region Limousin; Ministere de l'Enseignement Superieur et de la Recherche; Fondation ARC [DOC20150602943]; ARC [SL220100601332]; Conseil Regional du Limousin; Ligue Contre le Cancer; Comites de la Region Limousin; Comite d'Orientation Recherche Cancer en Limousin; [ANR-11-BSV302701]; [ANR-11-BSV30270] FX We thank all members of the Service Commun d'Animalerie and Plateforme de Transgenose of Limoges University for mouse work; Catherine Ouk-Martin and the FACS sorting facility of Limoges University; Drs. Laurent Delpy, Christophe Sirac, and Brice Laffleur for discussions and helpful comments; and Virginie Magnone, Alexandra Popa, and Pascal Barbry for help and fruitful discussions. This work was developed in close collaboration with the functional genomics platform of Nice Sophia Antipolis, a partner of the National Infrastructure France Genomique, thanks to support by the Canceropole PACA and Commissariat aux Grands Investissements (PB: ANR-10-INBS-09-03 and ANR-10-INBS-09-02). This work was supported in part by a PhD joint scholarship from Centre National de la Recherche Scientifique and Region Limousin (to M.M.); a PhD scholarship from the Region Limousin (to A.G., P.R., and A.-G.B.); a PhD scholarship from the Ministere de l'Enseignement Superieur et de la Recherche (to A.S.); Grant DOC20150602943 from Fondation ARC (to A.S.); post doc Fellowship Grant ANR-11-BSV302701 (to S.L.N.); and grants from ARC (#SL220100601332), Conseil Regional du Limousin, Ligue Contre le Cancer, Comites de la Region Limousin, ANR-11-BSV30270, and Comite d'Orientation Recherche Cancer en Limousin. NR 49 TC 5 Z9 5 U1 1 U2 1 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 FEB 9 PY 2016 VL 113 IS 6 BP 1618 EP 1623 DI 10.1073/pnas.1514090113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9WG UT WOS:000369571700051 PM 26831080 ER PT J AU Welch, JLM Rossetti, BJ Rieken, CW Dewhirst, FE Borisy, GG AF Welch, Jessica L. Mark Rossetti, Blair J. Rieken, Christopher W. Dewhirst, Floyd E. Borisy, Gary G. TI Biogeography of a human oral microbiome at the micron scale SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biofilm; imaging; microscopy; microbial ecology ID TARGETED OLIGONUCLEOTIDE PROBES; IN-SITU DETECTION; DENTAL PLAQUE; FUSOBACTERIUM-NUCLEATUM; PERIODONTAL HEALTH; COMMUNITY; BIOFILMS; MEMBERS; MICROORGANISMS; IDENTIFICATION AB The spatial organization of complex natural microbiomes is critical to understanding the interactions of the individual taxa that comprise a community. Although the revolution in DNA sequencing has provided an abundance of genomic-level information, the biogeography of microbiomes is almost entirely uncharted at the micron scale. Using spectral imaging fluorescence in situ hybridization as guided by metagenomic sequence analysis, we have discovered a distinctive, multigenus consortium in the microbiome of supragingival dental plaque. The consortium consists of a radially arranged, nine-taxon structure organized around cells of filamentous corynebacteria. The consortium ranges in size from a few tens to a few hundreds of microns in radius and is spatially differentiated. Within the structure, individual taxa are localized at the micron scale in ways suggestive of their functional niche in the consortium. For example, anaerobic taxa tend to be in the interior, whereas facultative or obligate aerobes tend to be at the periphery of the consortium. Consumers and producers of certain metabolites, such as lactate, tend to be near each other. Based on our observations and the literature, we propose a model for plaque microbiome development and maintenance consistent with known metabolic, adherence, and environmental considerations. The consortium illustrates how complex structural organization can emerge from the micron-scale interactions of its constituent organisms. The understanding that plaque community organization is an emergent phenomenon offers a perspective that is general in nature and applicable to other microbiomes. C1 [Welch, Jessica L. Mark; Rossetti, Blair J.; Dewhirst, Floyd E.; Borisy, Gary G.] Forsyth Inst, Cambridge, MA 02142 USA. [Welch, Jessica L. Mark; Rossetti, Blair J.; Rieken, Christopher W.; Borisy, Gary G.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Dewhirst, Floyd E.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Welch, JLM; Borisy, GG (reprint author), Forsyth Inst, Cambridge, MA 02142 USA.; Welch, JLM; Borisy, GG (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. EM jmarkwelch@mbl.edu; gborisy@forsyth.org FU NIH National Institute of Dental and Craniofacial Research Grant [DE022586] FX We thank Alex Valm for probe design; Katherine Lemon and Matthew Ramsey for helpful discussions; and Jake Casper, Louie Kerr, Carissa McKinney, Janina Schuhmann, Braden Tierney, Steven Wilbert, Liping Xun, and the members of the MBL 2014 Physiology Summer Course. This research was supported by NIH National Institute of Dental and Craniofacial Research Grant DE022586 (to G.G.B.). NR 50 TC 21 Z9 21 U1 10 U2 33 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 FEB 9 PY 2016 VL 113 IS 6 BP E791 EP E800 DI 10.1073/pnas.1522149113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9WG UT WOS:000369571700016 ER PT J AU Tuohy, CV Montez-Rath, ME Turakhia, M Chang, TI Winkelman, JW Winkelmayer, WC AF Tuohy, C. Vaughan Montez-Rath, Maria E. Turakhia, Mintu Chang, Tara I. Winkelman, John W. Winkelmayer, Wolfgang C. TI Sleep disordered breathing and cardiovascular risk in older patients initiating dialysis in the United States: a retrospective observational study using medicare data SO BMC NEPHROLOGY LA English DT Article DE Obstructive sleep apnea; Autonomous neuropathy; End-stage renal disease; Risk assessment ID POSITIVE AIRWAY PRESSURE; STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; HEART HEALTH; NOCTURNAL ARRHYTHMIAS; HEMODIALYSIS-PATIENTS; ATRIAL-FIBRILLATION; BLOOD-PRESSURE; DAYTIME SLEEPINESS; APNEA-HYPOPNEA AB Background: Sleep disordered breathing (SDB) such as sleep apnea is associated with cardiovascular disease in the general population. However, little is known about the cardiovascular risks of SDB in patients with end-stage renal disease (ESRD). Methods: We identified Medicare fee-for-service beneficiaries aged >= 67 years initiating dialysis between 2004 and 2009. Outcomes of interest included all-cause mortality, incident myocardial infarction, ischemic stroke, and atrial fibrillation. We compared patients with and without diagnosed SDB using Cox proportional hazards regression. Results: Between 2004 and 2009, 184,217 older patients developed ESRD, of whom 15,121 (8.2 %) were previously diagnosed with SDB. Patients diagnosed with SDB were younger, more likely to be male and Caucasian, less Medicaid eligible, had more non-Nephrology clinic visits, higher body mass index, and more comorbidity. In analyses adjusting for demographics and BMI, diagnosed SDB was associated with higher risk of death and atrial fibrillation, but not associated with myocardial infarction or ischemic stroke risk. After further adjustment for all baseline characteristics, diagnosed SDB was associated with slightly lower risks of death (hazard ratio [HR]: 0.93, 95 % confidence interval [CI]: 0.91-0.96), myocardial infarction (HR: 0.92, CI: 0.87-0.98), and ischemic stroke (HR: 0.90, 95 % CI: 0.82-0.98), and not associated with atrial fibrillation (HR: 1.02, CI: 0.98-1.07). Conclusions: In older patients initiating dialysis in the U. S., diagnosed SDB was weakly associated with lower risks of death and important cardiovascular outcomes, thus adding to the list of established risk factors that are paradoxically associated with cardiovascular outcomes in the ESRD population. C1 [Tuohy, C. Vaughan; Montez-Rath, Maria E.; Chang, Tara I.; Winkelmayer, Wolfgang C.] Stanford Univ, Sch Med, Dept Med, Div Nephrol, Palo Alto, CA 94304 USA. [Turakhia, Mintu] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94304 USA. [Winkelmayer, Wolfgang C.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Turakhia, Mintu] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Winkelman, John W.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Tuohy, C. Vaughan] NYU, Sch Med, Dept Med, New York, NY USA. [Winkelmayer, Wolfgang C.] Baylor Coll Med, Selzman Inst Kidney Hlth, Nephrol Sect, One Baylor Plaza,Suite ABBR R705, Houston, TX 77030 USA. RP Winkelmayer, WC (reprint author), Stanford Univ, Sch Med, Dept Med, Div Nephrol, Palo Alto, CA 94304 USA.; Winkelmayer, WC (reprint author), Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA.; Winkelmayer, WC (reprint author), Baylor Coll Med, Selzman Inst Kidney Hlth, Nephrol Sect, One Baylor Plaza,Suite ABBR R705, Houston, TX 77030 USA. EM wcw1@stanford.edu FU National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) [R01DK095024]; Veterans Health Services Research and Development Career Development Award [CDA09027-1]; NIDDK [K23DK095914] FX This work has been supported by grant R01DK095024 from the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to Dr. Winkelmayer. The manuscript was reviewed and approved for publication by an officer of the NIDDK. Dr. Turakhia is supported by a Veterans Health Services Research and Development Career Development Award (CDA09027-1). Dr. Chang was supported by grant K23DK095914 from NIDDK. Data reported herein were supplied by the United States Renal Data System (USRDS). Interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government. The content and opinions expressed are solely the responsibility of the authors and do not necessarily represent the views or policies of the Department of Veterans Affairs. NR 40 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD FEB 9 PY 2016 VL 17 AR 16 DI 10.1186/s12882-016-0229-3 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DD0PA UT WOS:000369620700001 PM 26861778 ER PT J AU Peralta, CA McClure, LA Scherzer, R Odden, MC White, CL Shlipak, M Benavente, O Pergola, P AF Peralta, Carmen A. McClure, Leslie A. Scherzer, Rebecca Odden, Michelle C. White, Carole L. Shlipak, Michael Benavente, Oscar Pergola, Pablo TI Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial SO CIRCULATION LA English DT Article DE cerebrovascular disorders; hypertension; kidney; stroke ID GLOMERULAR-FILTRATION-RATE; CONVERTING ENZYME-INHIBITOR; TYPE-2 DIABETES-MELLITUS; STAGE RENAL-DISEASE; CLINICAL-TRIALS; GFR DECLINE; END-POINT; HYPERTENSION; PROGRESSION; OUTCOMES AB Background The effect of intensive blood pressure (BP) lowering on kidney function among individuals with established cerebrovascular disease and preserved estimated glomerular filtration rate (eGFR) is not established. Methods and Results- Among 2610 participants randomized to a lower (< 130 mm Hg) versus higher ( 130- 149 mm Hg) systolic BP target with repeated measures of serum creatinine, we evaluated differences by study arm in annualized eGFR decline and rapid decline ( eGFR decline > 30%) using linear mixed models and logistic regression, respectively. We assessed associations of both treatment and kidney function decline with stroke, major vascular events, and the composite of stroke, death, major vascular events, or myocardial infarction using multivariable Cox regression, separately and jointly including a test for interaction. Analyses were conducted by treatment arm. Mean age was 63 +/- 11 years; 949 participants ( 36%) were diabetic; and mean eGFR was 80 +/- 19 mL center dot min- 1 center dot 1.73 m- 2. At 9 months, achieved systolic BP was 137 +/- 15 versus 127 +/- 14 mm Hg in the higher versus lower BP group, and differences were maintained throughout follow- up ( mean, 3.2 years). Compared with the higher target, the lower BP target had a - 0.50- mL center dot min- 1 center dot 1.73 m- 2 per year ( 95% confidence interval [ CI], - 0.79 to - 0.21) faster eGFR decline. Differences were most pronounced during the first year (- 2.1 mL center dot min- 1 center dot 1.73 m- 2; 95% CI, - 0.97 to - 3.2), whereas rates of eGFR decline did not differ after year 1 (- 0.095; 95% CI, - 0.47 to 0.23). A total of 313 patients ( 24%) in the lower BP group had rapid kidney function decline compared with 247 ( 19%) in the higher BP group ( odds ratio, 1.4; 95% CI, 1.1- 1.6). Differences in rapid decline by treatment arm were apparent in the first year ( odds ratio, 1.4; 95% CI, 1.1- 1.8) but were not significant after year 1 ( odds ratio, 1.0; 95% CI, 0.73- 1.4). Rapid decline was associated with higher risk for stroke, major vascular events, and composite after full adjustment among individuals randomized to the higher BP target ( stroke hazard ratio, 1.93; 95% CI, 1.15- 3.21) but not the lower BP arm ( stroke hazard ratio, 0.93; 95% CI, 0.50- 1.75; all P for interaction < 0.06). Conclusions In patients with prior lacunar stroke and relatively preserved kidney function, intensive BP lowering was associated with a greater likelihood of rapid kidney function decline. Differences were observed primarily during the first year of antihypertensive treatment. Rapid kidney function decline was not associated with increased risk for clinical events among those undergoing intensive BP lowering. C1 [Peralta, Carmen A.; Scherzer, Rebecca; Shlipak, Michael] Univ Calif San Francisco, Kidney Hlth Res Collaborat, San Francisco, CA 94121 USA. [Peralta, Carmen A.; Scherzer, Rebecca; Shlipak, Michael] San Francisco VA Med Ctr, San Francisco, CA USA. [McClure, Leslie A.] Univ Alabama Birmingham, Birmingham, AL USA. [Odden, Michelle C.] Oregon State Univ, Corvallis, OR 97331 USA. [White, Carole L.; Pergola, Pablo] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Benavente, Oscar] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Peralta, CA (reprint author), Univ Calif San Francisco, 4150 Clement St,111A1, San Francisco, CA 94121 USA. EM carmenalicia.peralta@ucsf.edu FU Robert Wood Johnson Foundation Harold Amos Grant; [1R01AG046206-01A1]; [5R03DK095877-03] FX Dr Peralta was funded by grant 1R01AG046206-01A1, 5R03DK095877-03, and the Robert Wood Johnson Foundation Harold Amos Grant. NR 38 TC 9 Z9 9 U1 1 U2 3 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 FEB 9 PY 2016 VL 133 IS 6 BP 584 EP 591 DI 10.1161/CIRCULATIONAHA.115.019657 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC8XV UT WOS:000369504400007 PM 26762524 ER PT J AU Melman, YF Shah, R Danielson, K Xiao, JJ Simonson, B Barth, A Chakir, K Lewis, GD Lavender, Z Truong, QA Kleber, A Das, R Rosenzweig, A Wang, YY Kass, DA Singh, JP Das, S AF Melman, Yonathan F. Shah, Ravi Danielson, Kirsty Xiao, Junjie Simonson, Bridget Barth, Andreas Chakir, Khalid Lewis, Gregory D. Lavender, Zachary Truong, Quynh A. Kleber, Andre Das, Ranendra Rosenzweig, Anthony Wang, Yaoyu Kass, David A. Singh, Jagmeet P. Das, Saumya TI Response to Letter Regarding Article, "Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study" SO CIRCULATION LA English DT Letter C1 [Melman, Yonathan F.; Shah, Ravi; Danielson, Kirsty; Simonson, Bridget; Kleber, Andre; Das, Saumya] Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. [Shah, Ravi; Lewis, Gregory D.; Lavender, Zachary; Truong, Quynh A.; Rosenzweig, Anthony; Singh, Jagmeet P.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Xiao, Junjie] Shanghai Univ, Sch Life Sci, Expt Ctr Life Sci & Regenerat Lab, Shanghai, Peoples R China. [Barth, Andreas; Chakir, Khalid; Kass, David A.] Johns Hopkins Univ Med Inst, Baltimore, MD USA. [Das, Ranendra] Johns Hopkins Univ, Baltimore, MD USA. [Wang, Yaoyu] Dana Farber Canc Inst, Ctr Computat Biol, Boston, MA 02115 USA. RP Melman, YF (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. FU NCATS NIH HHS [UH3 TR000901]; NHLBI NIH HHS [R01 HL122547] NR 5 TC 0 Z9 0 U1 4 U2 8 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 FEB 9 PY 2016 VL 133 IS 6 BP E389 EP E390 DI 10.1161/CIRCULATIONAHA.115.019228 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC8XX UT WOS:000369504600004 PM 26858296 ER PT J AU Charidimou, A Boulouis, G Haley, K Auriel, E van Etten, ES Fotiadis, P Reijmer, Y Ayres, A Vashkevich, A Dipucchio, ZY Schwab, KM Martinez-Ramirez, S Rosand, J Viswanathan, A Greenberg, SM Gurol, ME AF Charidimou, Andreas Boulouis, Gregoire Haley, Kellen Auriel, Eitan van Etten, Ellis S. Fotiadis, Panagiotis Reijmer, Yael Ayres, Alison Vashkevich, Anastasia Dipucchio, Zora Y. Schwab, Kristin M. Martinez-Ramirez, Sergi Rosand, Jonathan Viswanathan, Anand Greenberg, Steven M. Gurol, M. Edip TI White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy SO NEUROLOGY LA English DT Article ID SMALL VESSEL DISEASE; ENLARGED PERIVASCULAR SPACES; LOBAR INTRACEREBRAL HEMORRHAGE; APOLIPOPROTEIN-E GENOTYPE; MRI MARKERS; MICROBLEEDS; COHORT AB Objective:To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA).Methods:Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri-basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression.Results:The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic regression, presence of multiple subcortical spots was associated with lobar CMBs (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.01-1.50, p = 0.039) and high degree of centrum semiovale EPVS (OR 2.43; 95% CI 1.56-3.80, p < 0.0001). By contrast, age (OR 1.05; 95% CI 1.02-1.09, p = 0.002), deep CMBs (OR 2.46; 95% CI 1.44-4.20, p = 0.001), total WMH volume (OR 1.02; 95% CI 1.01-1.04, p = 0.002), and high BG EPVS degree (OR 8.81; 95% CI 3.37-23.02, p < 0.0001) were predictors of peri-BG WMH pattern.Conclusion:Different patterns of subcortical leukoaraiosis visually identified on MRI might provide insights into the dominant underlying microangiopathy type as well as mechanisms of tissue injury in patients with ICH. C1 [Charidimou, Andreas; Boulouis, Gregoire; Haley, Kellen; Auriel, Eitan; van Etten, Ellis S.; Fotiadis, Panagiotis; Reijmer, Yael; Ayres, Alison; Vashkevich, Anastasia; Dipucchio, Zora Y.; Schwab, Kristin M.; Martinez-Ramirez, Sergi; Rosand, Jonathan; Viswanathan, Anand; Greenberg, Steven M.; Gurol, M. Edip] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Hemorrhag Stroke Res Program,Dept Neurol,Stroke R, Boston, MA 02115 USA. [Rosand, Jonathan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02115 USA. RP Gurol, ME (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Hemorrhag Stroke Res Program,Dept Neurol,Stroke R, Boston, MA 02115 USA. EM edip@mail.harvard.edu RI Gurol, Edip/J-2279-2014; OI Gurol, Edip/0000-0002-2169-4457; Boulouis, Gregoire/0000-0001-8422-9205 FU NIH [5K23NS083711, R01 NS070834, 2R01 AG26484] FX Supported by the following NIH grants: 5K23NS083711 (M.E.G.), R01 NS070834, and 2R01 AG26484 (S.M.G.). NR 32 TC 5 Z9 5 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 9 PY 2016 VL 86 IS 6 BP 505 EP 511 DI 10.1212/WNL.0000000000002362 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DC9KT UT WOS:000369541200004 PM 26747886 ER PT J AU Abbott, RD Ross, GW Petrovitch, H Masaki, KH Launer, LJ Nelson, JS White, LR Tanner, CM AF Abbott, Robert D. Ross, G. Webster Petrovitch, Helen Masaki, Kamal H. Launer, Lenore J. Nelson, James S. White, Lon R. Tanner, Caroline M. TI Midlife milk consumption and substantia nigra neuron density at death SO NEUROLOGY LA English DT Article ID IDIOPATHIC PARKINSONS-DISEASE; CORONARY-HEART-DISEASE; ORGANOCHLORINE PESTICIDES; DAIRY-PRODUCTS; FUTURE RISK; LIFE-STYLE; MEN; CALIFORNIA; STROKE; HAWAII AB Objective:To examine the relationship between midlife milk intake and Parkinson disease (PD) incidence through associations with substantia nigra (SN) neuron density and organochlorine pesticide exposure in decedent brains from the Honolulu-Asia Aging Study.Methods:Milk intake data were collected from 1965 to 1968 in 449 men aged 45-68 years with postmortem examinations from 1992 to 2004. Neuron density (count/mm(2)) was measured in quadrants from a transverse section of the SN. Additional measures included brain residues of heptachlor epoxide, an organochlorine pesticide found at excessively high levels in the milk supply in Hawaii in the early 1980s.Results:Neuron density was lowest in nonsmoking decedents who consumed high amounts of milk (>16 oz/d). After removing cases of PD and dementia with Lewy bodies, adjusted neuron density in all but the dorsomedial quadrant was 41.5% lower for milk intake >16 oz/d vs intake that was less (95% confidence interval 22.7%-55.7%, p < 0.001). Among those who drank the most milk, residues of heptachlor epoxide were found in 9 of 10 brains as compared to 63.4% (26/41) for those who consumed no milk (p = 0.017). For those who were ever smokers, an association between milk intake and neuron density was absent.Conclusions:Milk intake is associated with SN neuron loss in decedent brains unaffected by PD. Whether contamination of milk with organochlorine pesticides has a role in SN neurodegeneration warrants further study. C1 [Abbott, Robert D.] Shiga Univ Med Sci, Ctr Epidemiol Res Asia, Otsu, Shiga 52021, Japan. [Abbott, Robert D.; Ross, G. Webster; Petrovitch, Helen; Nelson, James S.; White, Lon R.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Ross, G. Webster] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Abbott, Robert D.; Ross, G. Webster; Petrovitch, Helen; Masaki, Kamal H.] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, John A Hartford Fdn Ctr Excellence Geriatr, Honolulu, HI 96822 USA. [Ross, G. Webster; Petrovitch, Helen; White, Lon R.] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Masaki, Kamal H.] Kuakini Med Ctr, Honolulu, HI USA. [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. [Tanner, Caroline M.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. RP Abbott, RD (reprint author), Shiga Univ Med Sci, Ctr Epidemiol Res Asia, Otsu, Shiga 52021, Japan.; Abbott, RD (reprint author), Pacific Hlth Res & Educ Inst, Honolulu, HI USA.; Abbott, RD (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, John A Hartford Fdn Ctr Excellence Geriatr, Honolulu, HI 96822 USA. EM rda3e@virginia.edu FU National Institute on Aging [N01-AG-4-2149, 1 UO1 AG19349, 5 R01 AG017155]; National Heart, Lung, and Blood Institute [N01-HC-05102]; National Institute of Neurological Disorders and Stroke [5 R01 NS041265]; United States Department of the Army [DAMD17-98-1-8621]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs; Kuakini Medical Center; National Institute on Aging FX Supported by a contract (N01-AG-4-2149) and grants (1 UO1 AG19349 and 5 R01 AG017155) from the National Institute on Aging, by a contract (N01-HC-05102) from the National Heart, Lung, and Blood Institute, by a grant (5 R01 NS041265) from the National Institute of Neurological Disorders and Stroke, by a grant from the United States Department of the Army (DAMD17-98-1-8621), by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, by the Kuakini Medical Center, and in part by the Intramural Research Program of the National Institute on Aging. The information contained in this article does not necessarily reflect the position or the policy of the US Government, and no official endorsement should be inferred. NR 39 TC 4 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 9 PY 2016 VL 86 IS 6 BP 512 EP 519 DI 10.1212/WNL.0000000000002254 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DC9KT UT WOS:000369541200005 PM 26658906 ER PT J AU Gao, X O'Reilly, EJ Schwarzschild, MA Ascherio, A AF Gao, Xiang O'Reilly, Eilis J. Schwarzschild, Michael A. Ascherio, Alberto TI Prospective study of plasma urate and risk of Parkinson disease in men and women SO NEUROLOGY LA English DT Article ID URIC-ACID CONCENTRATION; SERUM-CHOLESTEROL; IRON; COHORT; GOUT; HYPERTENSION; ASSOCIATION; ANTIOXIDANT; PROGRESSION; PREDICTOR AB Objective:To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate-PD relationship.Methods:We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk.Results:In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; p(trend) = 0.049) in men and 1.04 (95% CI 0.61, 1.78; p(trend) = 0.44) in women (p(heterogeneity) = 0.001). In the meta-analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women.Conclusion:We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease. C1 [Gao, Xiang] Penn State Univ, Dept Nutr Hlth, University Pk, PA 16802 USA. [O'Reilly, Eilis J.; Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [O'Reilly, Eilis J.; Schwarzschild, Michael A.; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gao, X (reprint author), Penn State Univ, Dept Nutr Hlth, University Pk, PA 16802 USA. EM xxg14@psu.edu FU NIH [P01 CA055075, UM1 CA186107, UM1 CA167552, R01 NS061858, R21 NS087235-01A1] FX Supported by grants (P01 CA055075, UM1 CA186107, UM1 CA167552, R01 NS061858, and R21 NS087235-01A1) from the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 40 TC 6 Z9 7 U1 1 U2 1 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 FEB 9 PY 2016 VL 86 IS 6 BP 520 EP 526 DI 10.1212/WNL.0000000000002351 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DC9KT UT WOS:000369541200006 PM 26764029 ER PT J AU Nakagawa, A Adams, CE Huang, YS Hamarneh, SR Liu, W Von Alt, KN Mino-Kenudson, M Hodin, RA Lillemoe, KD Fernandez-del Castillo, C Warshaw, AL Liss, AS AF Nakagawa, Akifumi Adams, Curtis E. Huang, Yinshi Hamarneh, Sulaiman R. Liu, Wei Von Alt, Kate N. Mino-Kenudson, Mari Hodin, Richard A. Lillemoe, Keith D. Fernandez-del Castillo, Carlos Warshaw, Andrew L. Liss, Andrew S. TI Selective and reversible suppression of intestinal stem cell differentiation by pharmacological inhibition of BET bromodomains SO SCIENTIFIC REPORTS LA English DT Article ID TUFT CELLS; INNATE IMMUNITY; EPITHELIUM; PROTEIN; GFI-1B; SPECIFICATION; GEMCITABINE; CHROMATIN; LINEAGE; CANCER AB Absorptive and secretory cells of the small intestine are derived from a single population of Lgr5-expressing stem cells. While key genetic pathways required for differentiation into specific lineages have been defined, epigenetic programs contributing to this process remain poorly characterized. Members of the BET family of chromatin adaptors contain tandem bromodomains that mediate binding to acetylated lysines on target proteins to regulate gene expression. In this study, we demonstrate that mice treated with a small molecule inhibitor of BET bromodomains, CPI203, exhibit greater than 90% decrease in tuft and enteroendocrine cells in both crypts and villi of the small intestine, with no changes observed in goblet or Paneth cells. BET bromodomain inhibition did not alter the abundance of Lgr5-expressing stem cells in crypts, but rather exerted its effects on intermediate progenitors, in part through regulation of Ngn3 expression. When BET bromodomain inhibition was combined with the chemotherapeutic gemcitabine, pervasive apoptosis was observed in intestinal crypts, revealing an important role for BET bromodomain activity in intestinal homeostasis. Pharmacological targeting of BET bromodomains defines a novel pathway required for tuft and enteroendocrine differentiation and provides an important tool to further dissect the progression from stem cell to terminally differentiated secretory cell. C1 [Nakagawa, Akifumi; Adams, Curtis E.; Huang, Yinshi; Hamarneh, Sulaiman R.; Liu, Wei; Von Alt, Kate N.; Hodin, Richard A.; Lillemoe, Keith D.; Fernandez-del Castillo, Carlos; Warshaw, Andrew L.; Liss, Andrew S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Liss, AS (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM aliss@mgh.harvard.edu NR 39 TC 1 Z9 1 U1 5 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 FEB 9 PY 2016 VL 6 AR 20390 DI 10.1038/srep20390 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9YA UT WOS:000369576300001 PM 26856877 ER PT J AU Liu, Z Tsai, TY Wang, SB Wu, MF Zhong, WY Li, JS Cha, T Wood, K Li, GA AF Liu, Zhan Tsai, Tsung-Yuan Wang, Shaobai Wu, Minfei Zhong, Weiye Li, Jing-Sheng Cha, Thomas Wood, Kirk Li, Guoan TI Sagittal plane rotation center of lower lumbar spine during a dynamic weight-lifting activity SO JOURNAL OF BIOMECHANICS LA English DT Article DE Lower lumbar spine; Intervertebral disc; Center of rotation; Kinematics; Fluoroscope ID TOTAL DISC REPLACEMENT; COMPRESSIVE FOLLOWER PRELOAD; FLEXION-EXTENSION RESPONSE; IN-VIVO; KNEE KINEMATICS; INSTANTANEOUS AXIS; ARTIFICIAL DISC; MOTION; LOAD; OUTCOMES AB This study investigated the center of rotation (COR) of the intervertebral segments of the lower lumbar spine (L4-L5 and L5-S1 segments) in sagittal plane during a weight-lifting (3.6 kg in each hand) extension activity performed with the pelvis constrained. Seven healthy subjects were studied using a dual fluoroscopic imaging technique. Using the non-weightbearing, supine position during MRI scan as a reference, the average intervertebral flexion angles of the L4-L5 and L5-S1 were 6.6 degrees and 5.3 degrees at flexion position of the body, respectively, and were -1.8 degrees and -3.5 degrees at extension position of the body, respectively. The CORs of the lower lumbar spine were found segment-dependent and changed with the body postures. The CORs of the L4-L5 segment were at the location about 75% posterior from the anterior edge of the disc at flexion positions of the body, and moved to about 92% of the posterior portion of the disc at extension positions of the body. The CORs of the L5-S1 segment were at 95% posterior portion of the disc at flexion positions of the body, and moved outside of the posterior edge of the disc by about 12% of the disc length at extension positions of the body. These results could help understand the physiological motion characters of the lower lumbar spine. The data could also provide important insights for future improvement of artificial disc designs and surgical implantation of the discs that are aimed to reproduce normal spinal functions. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Liu, Zhan; Tsai, Tsung-Yuan; Wang, Shaobai; Zhong, Weiye; Li, Jing-Sheng; Cha, Thomas; Wood, Kirk; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Liu, Zhan] Sichuan Univ, Prov Key Lab Biomech Engn, Chengdu 610065, Sichuan, Peoples R China. [Wu, Minfei] Jilin Univ, Hosp 2, Changchun 130041, Jilin, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, 55 Fruit St,GRJ-1215, Boston, MA 02114 USA. EM gli1@mgh.harvard.edu FU National Institute of Health [R21AR057989]; Synthes, Inc.; Department of Orthopaedic Surgery at Massachusetts General Hospital; National Natural Science Foundation of China [11202143]; Sichuan University Scholarship Fund FX The authors would like to gratefully acknowledge the financial support from the National Institute of Health (R21AR057989), Synthes, Inc., the Department of Orthopaedic Surgery at Massachusetts General Hospital, The National Natural Science Foundation of China (11202143) and Sichuan University Scholarship Fund. NR 43 TC 2 Z9 2 U1 4 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD FEB 8 PY 2016 VL 49 IS 3 BP 371 EP 375 DI 10.1016/j.jbiomech.2015.12.029 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DF7PA UT WOS:000371548700008 ER PT J AU Vistamehr, A Kautz, SA Bowden, MG Neptune, RR AF Vistamehr, Arian Kautz, Steven A. Bowden, Mark G. Neptune, Richard R. TI Correlations between measures of dynamic balance in individuals with post-stroke hemiparesis SO JOURNAL OF BIOMECHANICS LA English DT Article DE Berg balance scale; Dynamic gait index; Margin of stability; Angular momentum; Biomechanics ID PLANE ANGULAR-MOMENTUM; HUMAN WALKING; STROKE REHABILITATION; LATERAL BALANCE; SUPPORT LIMB; OLDER-ADULTS; GAIT INDEX; STABILITY; FALLS; MARGINS AB Mediolateral balance control during walking is a challenging task in post-stroke hemiparetic individuals. To detect and treat dynamic balance disorders, it is important to assess balance using reliable methods. The Berg Balance Scale (BBS), Dynamic Gait Index (DGI), margin-of-stability (MoS), and peak-to-peak range of angular-momentum (H) are some of the most commonly used measures to assess dynamic balance and fall risk in clinical and laboratory settings. However, it is not clear if these measures lead to similar conclusions. Thus, the purpose of this study was to assess dynamic balance in post-stroke hemiparetic individuals using BBS, DGI, MoS and the range of H and determine if these measure are correlated. BBS and DGI were collected from 19 individuals post-stroke. Additionally, kinematic and kinetic data were collected while the same individuals walked at their self-selected speed. MoS and the range of H were calculated in the mediolateral direction for each participant. Correlation analyses revealed moderate associations between all measures. Overall, a higher range of angular-momentum was associated with a higher MoS, wider step width and lower BBS and DGI scores, indicating poor balance control. Further, only the MoS from the paretic foot placement, but not the nonparetic foot, correlated with the other balance measures. Although moderate correlations existed between all the balance measures, these findings do not necessarily advocate the use of a single measure as each test may assess different constructs of dynamic balance. These findings have important implications for the use and interpretation of dynamic balance assessments. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Vistamehr, Arian] Brooks Rehabil Hosp, Motion Anal Ctr, Jacksonville, FL USA. [Kautz, Steven A.; Bowden, Mark G.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Kautz, Steven A.; Bowden, Mark G.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Kautz, Steven A.; Bowden, Mark G.] Med Univ S Carolina, Div Phys Therapy, Charleston, SC 29425 USA. [Neptune, Richard R.] Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. RP Neptune, RR (reprint author), Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. EM rneptune@mail.utexas.edu FU American Heart Association SouthWest Affiliate pre-doctoral fellowship [12PRE12030414]; Rehabilitation Research and Development Service of the Department of Veteran's Affairs [N0787-W]; Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20-GM109040] FX The authors would like to acknowledge Ms. Leah Carter for her valuable contributions to this study. This work was supported by an American Heart Association SouthWest Affiliate pre-doctoral fellowship (12PRE12030414), the Rehabilitation Research and Development Service of the Department of Veteran's Affairs (N0787-W) and an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant number P20-GM109040. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the AHA, the VA or the NIH. NR 37 TC 2 Z9 3 U1 8 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD FEB 8 PY 2016 VL 49 IS 3 BP 396 EP 400 DI 10.1016/j.jbiomech.2015.12.047 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DF7PA UT WOS:000371548700012 PM 26795124 ER PT J AU Best, MG Sol, N Tannous, BA Wesseling, P Wurdinger, T AF Best, Myron G. Sol, Nik Tannous, Bakhos A. Wesseling, Pieter Wurdinger, Thomas TI Re: a Word of Caution on New and Revolutionary Diagnostic Tests SO CANCER CELL LA English DT Letter ID EXPRESSION; DISEASE C1 [Best, Myron G.; Wesseling, Pieter] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Med Ctr, Dept Pathol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Best, Myron G.; Wurdinger, Thomas] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Med Ctr, Dept Neurosurg, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Sol, Nik] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Med Ctr, Dept Neurol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Tannous, Bakhos A.; Wurdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, 149 13th St, Charlestown, MA 02129 USA. [Tannous, Bakhos A.; Wurdinger, Thomas] Harvard Univ, Sch Med, Neurosci Program, 149 13th St, Charlestown, MA 02129 USA. [Wesseling, Pieter] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6500 HB Nijmegen, Netherlands. [Wurdinger, Thomas] thromboDx BV, NL-1098 EA Amsterdam, Netherlands. RP Wurdinger, T (reprint author), Vrije Univ Amsterdam, Canc Ctr Amsterdam, Med Ctr, Dept Neurosurg, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands.; Wurdinger, T (reprint author), Massachusetts Gen Hosp, Dept Neurol, 149 13th St, Charlestown, MA 02129 USA.; Wurdinger, T (reprint author), Harvard Univ, Sch Med, Neurosci Program, 149 13th St, Charlestown, MA 02129 USA.; Wurdinger, T (reprint author), thromboDx BV, NL-1098 EA Amsterdam, Netherlands. EM t.wurdinger@vumc.nl OI Wesseling, P./0000-0001-5453-5201 NR 5 TC 0 Z9 0 U1 0 U2 4 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 FEB 8 PY 2016 VL 29 IS 2 BP 143 EP 144 DI 10.1016/j.ccell.2016.01.004 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD2FX UT WOS:000369739100007 PM 26859454 ER PT J AU Ham, J Costa, C Sano, R Lochmann, TL Sennott, EM Patel, NU Dastur, A Gomez-Caraballo, M Krytska, K Hata, AN Floros, KV Hughes, MT Jakubik, CT Heisey, DAR Ferrell, JT Bristol, ML March, RJ Yates, C Hicks, MA Nakajima, W Gowda, M Windle, BE Dozmorov, MG Garnett, MJ McDermott, U Harada, H Taylor, SM Morgan, IM Benes, CH Engelman, JA Mosse, YP Faber, AC AF Ham, Jungoh Costa, Carlotta Sano, Renata Lochmann, Timothy L. Sennott, Erin M. Patel, Neha U. Dastur, Anahita Gomez-Caraballo, Maria Krytska, Kateryna Hata, Aaron N. Floros, Konstantinos V. Hughes, Mark T. Jakubik, Charles T. Heisey, Daniel A. R. Ferrell, Justin T. Bristol, Molly L. March, Ryan J. Yates, Craig Hicks, Mark A. Nakajima, Wataru Gowda, Madhu Windle, Brad E. Dozmorov, Mikhail G. Garnett, Mathew J. McDermott, Ultan Harada, Hisashi Taylor, Shirley M. Morgan, Iain M. Benes, Cyril H. Engelman, Jeffrey A. Mosse, Yael P. Faber, Anthony C. TI Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination SO CANCER CELL LA English DT Article ID DIRECT TRANSCRIPTIONAL TARGET; SMALL-MOLECULE INHIBITOR; CELL LUNG-CANCER; DRUG-SENSITIVITY; AURORA KINASE; N-MYC; TRANSLATIONAL CONTROL; BCL-2 INHIBITOR; MITOTIC ARREST; LIFE-SPAN AB Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression. C1 [Ham, Jungoh; Patel, Neha U.; Floros, Konstantinos V.; Hughes, Mark T.; Heisey, Daniel A. R.; Ferrell, Justin T.; Bristol, Molly L.; Yates, Craig; Hicks, Mark A.; Windle, Brad E.; Harada, Hisashi; Morgan, Iain M.; Faber, Anthony C.] Virginia Commonwealth Univ, Sch Dent, Philips Inst Oral Hlth Res, Perkinson Bldg, Richmond, VA 23298 USA. [Ham, Jungoh; Patel, Neha U.; Floros, Konstantinos V.; Hughes, Mark T.; Heisey, Daniel A. R.; Ferrell, Justin T.; Bristol, Molly L.; Yates, Craig; Hicks, Mark A.; Windle, Brad E.; Harada, Hisashi; Morgan, Iain M.; Faber, Anthony C.] Virginia Commonwealth Univ, Massey Canc Ctr, Perkinson Bldg, Richmond, VA 23298 USA. [Sano, Renata; Krytska, Kateryna; Mosse, Yael P.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Sano, Renata; Mosse, Yael P.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Mosse, Yael P.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Costa, Carlotta; Sennott, Erin M.; Dastur, Anahita; Gomez-Caraballo, Maria; Hata, Aaron N.; Jakubik, Charles T.; March, Ryan J.; Benes, Cyril H.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Costa, Carlotta; Sennott, Erin M.; Dastur, Anahita; Gomez-Caraballo, Maria; Hata, Aaron N.; Jakubik, Charles T.; March, Ryan J.; Benes, Cyril H.; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dozmorov, Mikhail G.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Garnett, Mathew J.; McDermott, Ultan] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. [Lochmann, Timothy L.; Taylor, Shirley M.] Massey Canc Ctr, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Nakajima, Wataru] Nippon Med Sch, Inst Adv Med Sci, Dept Mol Oncol, Kawasaki, Kanagawa 2118533, Japan. [Gowda, Madhu] Virginia Commonwealth Univ, Childrens Hosp Richmond, Dept Pediat, Med Coll Virginia Campus, Richmond, VA 23298 USA. RP Faber, AC (reprint author), Virginia Commonwealth Univ, Sch Dent, Philips Inst Oral Hlth Res, Perkinson Bldg, Richmond, VA 23298 USA.; Faber, AC (reprint author), Virginia Commonwealth Univ, Massey Canc Ctr, Perkinson Bldg, Richmond, VA 23298 USA. EM acfaber@vcu.edu OI McDermott, Ultan/0000-0001-9032-4700 FU Rally Foundation for Childhood Cancer Research; The Truth 365; Alex's Lemonade Stand Innovation grant; Wipe out Kids Cancer research grant; VCU Massey Cancer Center Pilot Project Application grant; Wellcome Trust [102696]; George and Lavina Blick Research Fund FX This study was supported by a grant from The Rally Foundation for Childhood Cancer Research and The Truth 365 (A.C.F.); an Alex's Lemonade Stand Innovation grant (A.C.F. and Y.P.M.); a Wipe out Kids Cancer research grant (A.C.F.); a VCU Massey Cancer Center Pilot Project Application grant (A.C.F. and B.E.W.); and a grant from the Wellcome Trust (102696; C.H.B., M.J.G., and U.M.). A.C.F. is supported by the George and Lavina Blick Research Fund. J.A.E. is a consultant for AstraZeneca and has research agreements with AstraZeneca. We thank Dr. Sarah Conine for critical reading of the manuscript. NR 64 TC 9 Z9 10 U1 2 U2 7 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 FEB 8 PY 2016 VL 29 IS 2 BP 159 EP 172 DI 10.1016/j.ccell.2016.01.002 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD2FX UT WOS:000369739100009 PM 26859456 ER PT J AU Lechman, ER Gentner, B Ng, SWK Schoof, EM van Galen, P Kennedy, JA Nucera, S Ciceri, F Kaufmann, KB Takayama, N Dobson, SM Trotman-Grant, A Krivdova, G Elzinga, J Mitchell, A Nilsson, B Hermans, KG Eppert, K Marke, R Isserlin, R Voisin, V Bader, GD Zandstra, PW Golub, TR Ebert, BL Lu, J Minden, M Wang, JCY Naldini, L Dick, JE AF Lechman, Eric R. Gentner, Bernhard Ng, Stanley W. K. Schoof, Erwin M. van Galen, Peter Kennedy, James A. Nucera, Silvia Ciceri, Fabio Kaufmann, Kerstin B. Takayama, Naoya Dobson, Stephanie M. Trotman-Grant, Aaron Krivdova, Gabriela Elzinga, Janneke Mitchell, Amanda Nilsson, Bjorn Hermans, Karin G. Eppert, Kolja Marke, Rene Isserlin, Ruth Voisin, Veronique Bader, Gary D. Zandstra, Peter W. Golub, Todd R. Ebert, Benjamin L. Lu, Jun Minden, Mark Wang, Jean C. Y. Naldini, Luigi Dick, John E. TI miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TUMOR-SUPPRESSOR; GENE-EXPRESSION; IN-VIVO; KINASE-ACTIVITY; CANCER CELLS; MICRORNA; INDUCTION; QUIESCENCE; PHOSPHORYLATION AB To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly couplingmiR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance. C1 [Lechman, Eric R.; Schoof, Erwin M.; van Galen, Peter; Kennedy, James A.; Kaufmann, Kerstin B.; Takayama, Naoya; Dobson, Stephanie M.; Trotman-Grant, Aaron; Krivdova, Gabriela; Elzinga, Janneke; Mitchell, Amanda; Hermans, Karin G.; Minden, Mark; Wang, Jean C. Y.; Dick, John E.] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada. [Lechman, Eric R.; Schoof, Erwin M.; van Galen, Peter; Kaufmann, Kerstin B.; Takayama, Naoya; Dobson, Stephanie M.; Trotman-Grant, Aaron; Krivdova, Gabriela; Elzinga, Janneke; Mitchell, Amanda; Hermans, Karin G.; Dick, John E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada. [Gentner, Bernhard; Nucera, Silvia; Naldini, Luigi] Hosp San Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy. [Gentner, Bernhard; Naldini, Luigi] Univ Vita Salute San Raffaele, Hosp San Raffaele, San Raffaele Sci Inst, I-20132 Milan, Italy. [Gentner, Bernhard; Ciceri, Fabio] Hosp San Raffaele, Hematol & Bone Marrow Transplantat Unit, I-20132 Milan, Italy. [Ng, Stanley W. K.; Zandstra, Peter W.] Univ Toronto, Inst Biomat & Biomed Engn, Dept Chem Engn & Appl Chem, Toronto, ON M5G 2M9, Canada. [Ng, Stanley W. K.; Isserlin, Ruth; Voisin, Veronique; Bader, Gary D.; Zandstra, Peter W.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Kennedy, James A.; Minden, Mark; Wang, Jean C. Y.] Univ Toronto, Dept Med, Toronto, ON M5G 2M9, Canada. [Nilsson, Bjorn] Univ Lund Hosp, Dept Hematol & Transfus Med, S-22184 Lund, Sweden. [Eppert, Kolja] McGill Univ, Ctr Hlth, Dept Pediat, Montreal, PQ H4A 3J1, Canada. [Eppert, Kolja] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H4A 3J1, Canada. [Marke, Rene] Radboud Univ Nijmegen, Med Ctr, Lab Pediat Oncol, NL-6500 HB Nijmegen, Netherlands. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. [Ebert, Benjamin L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol,Dept Med, Boston, MA 02115 USA. [Lu, Jun] Yale Univ, Sch Med, Yale Canc Ctr, Yale Stem Cell Ctr, New Haven, CT 06520 USA. [Dick, John E.] Princess Margaret Canc Res Tower, Room 8-301,101 Coll St, Toronto, ON M5G 1L7, Canada. RP Dick, JE (reprint author), Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada.; Dick, JE (reprint author), Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada.; Dick, JE (reprint author), Princess Margaret Canc Res Tower, Room 8-301,101 Coll St, Toronto, ON M5G 1L7, Canada. EM jdick@uhnresearch.ca OI Kaufmann, Kerstin B./0000-0001-5013-6123 FU Telethon (TIGET grant); EU [FP7 GA 222878 PERSIST]; EU (ERC) [249845 TARGETING GENE THERAPY]; Italian Ministry of Health; Canadian Institutes for Health Research; Canadian Cancer Society; Terry Fox Foundation; Genome Canada through the Ontario Genomics Institute; Ontario Institute for Cancer Research; Province of Ontario; Canada Research Chair; European Commission [GA-2013-609409]; Marie Curie Actions; Ontario Ministry of Health and Long Term Care (OMOHLTC) FX We thank Dr. M Roehrl for mass spectrometer support, A Khandani and P. A. Penttila for flow cytometry, and the Dick and Naldini laboratories for critical review. This work was supported by grants to L.N. from Telethon (TIGET grant), EU (FP7 GA 222878 PERSIST, ERC Advanced Grant 249845 TARGETING GENE THERAPY), and the Italian Ministry of Health and to J.E.D. from the Canadian Institutes for Health Research, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research with funds from the Province of Ontario, and a Canada Research Chair. E.M.S. is an EMBO Postdoctoral Fellow (ALTF 1595-2014) and is co-funded by the European Commission (LTFCOFUND2013, GA-2013-609409) and Marie Curie Actions. This research was funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC. NR 59 TC 18 Z9 18 U1 9 U2 26 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 FEB 8 PY 2016 VL 29 IS 2 BP 214 EP 228 DI 10.1016/j.ccell.2015.12.011 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD2FX UT WOS:000369739100013 PM 26832662 ER PT J AU Koskinas, KC Ughi, GJ Windecker, S Tearney, GJ Raber, L AF Koskinas, Konstantinos C. Ughi, Giovanni J. Windecker, Stephan Tearney, Guillermo J. Raeber, Lorenz TI Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment SO EUROPEAN HEART JOURNAL LA English DT Review DE Intracoronary imaging; Atherosclerosis; Vulnerable plaque; Coronary interventions ID OPTICAL COHERENCE TOMOGRAPHY; NEAR-INFRARED SPECTROSCOPY; INTRAVASCULAR ULTRASOUND GUIDANCE; ELUTING STENT IMPLANTATION; FRACTIONAL FLOW RESERVE; ACUTE MYOCARDIAL-INFARCTION; ENDOTHELIAL SHEAR-STRESS; ARTERY LESION MORPHOLOGY; INTENSIVE STATIN THERAPY; LIPID-LOWERING THERAPY AB While coronary atherosclerosis is a leading cause of mortality, evaluation of coronary lesions was previously limited to either indirect angiographic assessment of the lumen silhouette or post mortem investigations. Intracoronary (IC) imaging modalities have been developed that allow for visualization and characterization of coronary atheroma in living patients. Used alone or in combination, these modalities have enhanced our understanding of pathobiological mechanisms of atherosclerosis, identified factors responsible for disease progression, and documented the ability of various medications to reverse the processes of plaque growth and destabilization. These methodologies have established a link between in vivo plaque characteristics and subsequent coronary events, thereby improving individual risk stratification, paving the way for risk-tailored systemic therapies and raising the option for pre-emptive interventions. Moreover, IC imaging is increasingly used during coronary interventions to support therapeutic decision-making in angiographically inconclusive disease, guide and optimize procedural results in selected lesion and patient subsets, and unravel mechanisms underlying stent failure. This review aims to summarize current evidence regarding the role of IC imaging for diagnosis and risk stratification of coronary atherosclerosis, and to describe its clinical role for guiding percutaneous coronary interventions. Future perspectives for in-depth plaque characterization using novel techniques and multimodality imaging approaches are also discussed. C1 [Koskinas, Konstantinos C.; Windecker, Stephan; Raeber, Lorenz] Univ Hosp Bern, Dept Cardiol, CH-3010 Bern, Switzerland. [Ughi, Giovanni J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Tearney, Guillermo J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tearney, Guillermo J.] Harvard Massachusetts Inst Technol Hlth Sci & Tec, Cambridge, MA USA. RP Raber, L (reprint author), Univ Hosp Bern, Dept Cardiol, CH-3010 Bern, Switzerland. EM lorenz.raeber@insel.ch OI Ughi, Giovanni J./0000-0003-3354-0698 NR 113 TC 6 Z9 6 U1 0 U2 6 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 FEB 7 PY 2016 VL 37 IS 6 BP 524 EP U91 DI 10.1093/eurheartj/ehv642 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF3NE UT WOS:000371250400008 PM 26655874 ER PT J AU Tada, H Melander, O Louie, JZ Catanese, JJ Rowland, CM Devlin, JJ Kathiresan, S Shiffman, D AF Tada, Hayato Melander, Olle Louie, Judy Z. Catanese, Joseph J. Rowland, Charles M. Devlin, James J. Kathiresan, Sekar Shiffman, Dov TI Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history SO EUROPEAN HEART JOURNAL LA English DT Article DE Coronary heart disease risk; Genetic risk scores ID MIDDLE-AGED ADULTS; CARDIOVASCULAR-DISEASE; PROSPECTIVE COHORT; EVENTS; SUSCEPTIBILITY AB Aims Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD. Methods and results The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmo Diet and Cancer study-a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48-1.94; P-trend = 1.6 x 10(-15) and HR = 1.92 for GRS50; 95% CI: 1.67-2.20; P-trend = 6.2 x 10(-22)]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P x 3 x 10(-6)). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45-1.89) or GRS50 (HR = 1.87; 95% CI: 1.63-2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P<0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P<0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85-3.12) than those with low GRS50. Conclusion The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals. C1 [Tada, Hayato; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Tada, Hayato; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Tada, Hayato; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Tada, Hayato; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Melander, Olle] Skane Univ Hosp, Dept Internal Med, Malmo, Sweden. [Louie, Judy Z.; Catanese, Joseph J.; Rowland, Charles M.; Devlin, James J.; Kathiresan, Sekar; Shiffman, Dov] Quest Diagnost, Alameda, CA USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.; Kathiresan, S (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA.; Melander, O (reprint author), Lund Univ, Dept Clin Sci, Malmo, Sweden.; Melander, O (reprint author), Skane Univ Hosp, Dept Internal Med, Malmo, Sweden.; Shiffman, D (reprint author), Quest Diagnost, Alameda, CA USA. EM olle.melander@med.lu.se; sekar@broad.mit.edu; dov.shiffman@questdiagnostics.com FU Swedish Cancer Society; Swedish Medical Research Council; Swedish Dairy Association; Albert Pahlsson Foundation; Gunnar Nilsson Foundation; Malmo city council; Japanese Circulation Society; Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation; European Research Council [StG-282255]; Swedish Heart and Lung Foundation; Swedish Research Council; Novo Nordisk Foundation; Skane University Hospital donation funds; Medical Faculty, Lund University; Albert Pahlsson Research Foundation; Region Skane; King Gustav V and Queen Victoria Foundation; Marianne and Marcus Wallenberg Foundation; Quest Diagnostics FX The Malmo Diet and Cancer study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Albert Pahlsson and Gunnar Nilsson Foundations and the Malmo city council. H.T. is supported by a grant from the Japanese Circulation Society to study in the USA. S.K. is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, and the Donovan Family Foundation. O.M. is supported by the European Research Council (StG-282255), the Swedish Heart and Lung Foundation, Swedish Research Council; the Novo Nordisk Foundation, the Skane University Hospital donation funds; the Medical Faculty, Lund University; the Governmental funding of clinical research within the national health services, the Albert Pahlsson Research Foundation, Region Skane, the King Gustav V and Queen Victoria Foundation, and the Marianne and Marcus Wallenberg Foundation. O.M. and S.K. are the recipients of an investigator-initiated grant from Quest Diagnostics. Funding to pay the Open Access publication charges for this article was provided by Quest Diagnostics. NR 20 TC 22 Z9 22 U1 1 U2 7 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 FEB 7 PY 2016 VL 37 IS 6 BP 561 EP 567 DI 10.1093/eurheartj/ehv462 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF3NE UT WOS:000371250400012 PM 26392438 ER PT J AU McFarland, CP Clark, JB Lee, LO Grande, LJ Marx, BP Vasterling, JJ AF McFarland, Craig P. Clark, Justin B. Lee, Lewina O. Grande, Laura J. Marx, Brian P. Vasterling, Jennifer J. TI Event-based prospective memory among veterans: The role of posttraumatic stress disorder symptom severity in executing intentions SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article DE Prospective memory; posttraumatic stress disorder; event-based; anxiety ID OLDER-ADULTS; PTSD; PERFORMANCE; DEPRESSION; METAANALYSIS; ATTENTION; DEFICITS; DYSFUNCTION; INHIBITION; IMPAIRMENT AB Objective: Posttraumatic stress disorder (PTSD) has been linked with neuropsychological deficits in several areas, including attention, learning and memory, and cognitive inhibition. Although memory dysfunction is among the most commonly documented deficits associated with PTSD, our existing knowledge pertains only to retrospective memory. The current study investigated the relationship between PTSD symptom severity and event-based prospective memory (PM). Method: Forty veterans completed a computerized event-based PM task, a self-report measure of PTSD, and measures of retrospective memory. Results: Hierarchical regression analysis results revealed that PTSD symptom severity accounted for 16% of the variance in PM performance, F(3, 36) = 3.47, p < .05, after controlling for age and retrospective memory. Additionally, each of the three PTSD symptom clusters was related, to varying degrees, with PM performance. Conclusions: Results suggest that elevated PTSD symptoms may be associated with more difficulties completing tasks requiring PM. Further examination of PM in PTSD is warranted, especially in regard to its impact on everyday functioning. C1 [McFarland, Craig P.; Grande, Laura J.; Marx, Brian P.; Vasterling, Jennifer J.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA USA. [McFarland, Craig P.] Univ Montana, Dept Psychol, Missoula, MT 59812 USA. [Clark, Justin B.; Lee, Lewina O.; Marx, Brian P.; Vasterling, Jennifer J.] VA Boston Healthcare Syst, Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Boston, MA USA. [Lee, Lewina O.; Grande, Laura J.; Marx, Brian P.; Vasterling, Jennifer J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Lee, Lewina O.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Grande, Laura J.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders TRACTS, Boston, MA USA. RP McFarland, CP (reprint author), Univ Montana, Skaggs Bldg,Room 143, Missoula, MT 59812 USA. EM craig.mcfarland@umontana.edu NR 55 TC 1 Z9 1 U1 6 U2 15 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1380-3395 EI 1744-411X J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD FEB 7 PY 2016 VL 38 IS 2 BP 251 EP 260 DI 10.1080/13803395.2015.1102203 PG 10 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA DA5EO UT WOS:000367825800010 PM 26691304 ER PT J AU Freeman, E Semeere, A Wenger, M Bwana, M Asirwa, FC Busakhala, N Oga, E Jedy-Agba, E Kwaghe, V Iregbu, K Jaquet, A Dabis, F Yumo, HA Dusingize, JC Bangsberg, D Anastos, K Phiri, S Bohlius, J Egger, M Yiannoutsos, C Wools-Kaloustian, K Martin, J AF Freeman, Esther Semeere, Aggrey Wenger, Megan Bwana, Mwebesa Asirwa, F. Chite Busakhala, Naftali Oga, Emmanuel Jedy-Agba, Elima Kwaghe, Vivian Iregbu, Kenneth Jaquet, Antoine Dabis, Francois Yumo, Habakkuk Azinyui Dusingize, Jean Claude Bangsberg, David Anastos, Kathryn Phiri, Sam Bohlius, Julia Egger, Matthias Yiannoutsos, Constantin Wools-Kaloustian, Kara Martin, Jeffrey TI Pitfalls of practicing cancer epidemiology in resource-limited settings: the case of survival and loss to follow-up after a diagnosis of Kaposi's sarcoma in five countries across sub-Saharan Africa SO BMC CANCER LA English DT Article DE Survival; Mortality; Kaposi's sarcoma; HIV/AIDS; Cancer; Resource-limited settings; Africa; Loss to follow-up; Cohort ID SAMPLING-BASED APPROACH; ANTIRETROVIRAL THERAPY; WESTERN KENYA; MORTALITY; OUTCOMES; PROGRAM; HIV; REGISTRY; UGANDA; POPULATION AB Background: Survival after diagnosis is a fundamental concern in cancer epidemiology. In resource-rich settings, ambient clinical databases, municipal data and cancer registries make survival estimation in real-world populations relatively straightforward. In resource-poor settings, given the deficiencies in a variety of health-related data systems, it is less clear how well we can determine cancer survival from ambient data. Methods: We addressed this issue in sub-Saharan Africa for Kaposi's sarcoma (KS), a cancer for which incidence has exploded with the HIV epidemic but for which survival in the region may be changing with the recent advent of antiretroviral therapy (ART). From 33 primary care HIV Clinics in Kenya, Uganda, Malawi, Nigeria and Cameroon participating in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortia in 2009-2012, we identified 1328 adults with newly diagnosed KS. Patients were evaluated from KS diagnosis until death, transfer to another facility or database closure. Results: Nominally, 22 % of patients were estimated to be dead by 2 years, but this estimate was clouded by 45 % cumulative lost to follow-up with unknown vital status by 2 years. After adjustment for site and CD4 count, age <30 years and male sex were independently associated with becoming lost. Conclusions: In this community-based sample of patients diagnosed with KS in sub-Saharan Africa, almost half became lost to follow-up by 2 years. This precluded accurate estimation of survival. Until we either generally strengthen data systems or implement cancer-specific enhancements (e.g., tracking of the lost) in the region, insights from cancer epidemiology will be limited. C1 [Freeman, Esther] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Semeere, Aggrey] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Semeere, Aggrey; Wenger, Megan; Martin, Jeffrey] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bwana, Mwebesa] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Asirwa, F. Chite; Wools-Kaloustian, Kara] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Asirwa, F. Chite; Busakhala, Naftali] Moi Univ, AMPATH, Eldoret, Kenya. [Oga, Emmanuel; Jedy-Agba, Elima] Inst Human Virol, Abuja, Nigeria. [Kwaghe, Vivian] Univ Abuja Teaching Hosp, Abuja, Nigeria. [Iregbu, Kenneth] Natl Hosp Abuja, Abuja, Nigeria. [Jaquet, Antoine; Dabis, Francois] Univ Bordeaux, INSERM U897, Bordeaux, France. [Jaquet, Antoine; Dabis, Francois] Univ Bordeaux, ISPED, Bordeaux, France. [Yumo, Habakkuk Azinyui] R4D Int, Yaounde, Cameroon. [Dusingize, Jean Claude] Reg Alliance Sustainable Dev, Kigali, Rwanda. [Bangsberg, David] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Anastos, Kathryn] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Phiri, Sam] Lighthouse Trust Clin, Lilongwe, Malawi. [Bohlius, Julia; Egger, Matthias] Univ Bern, Bern, Switzerland. [Yiannoutsos, Constantin] Indiana Univ, Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA. RP Freeman, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Bartlett Hall 6R,55 Fruit St, Boston, MA 02114 USA. EM efreeman@mgh.harvard.edu OI Oga, Emmanuel/0000-0002-0744-5681 FU National Institutes of Health [U01 AI069911, U01 AI096299, U01 AI069919, U01 AI069924, D43 CA153717, U54 CA190153, P30 AI027763, T32 AR007098] FX This study was funded by the National Institutes of Health (U01 AI069911, U01 AI096299, U01 AI069919, U01 AI069924, D43 CA153717, U54 CA190153, P30 AI027763 and T32 AR007098). NR 39 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 6 PY 2016 VL 16 AR 65 DI 10.1186/s12885-016-2080-0 PG 7 WC Oncology SC Oncology GA DD6CN UT WOS:000370011600003 PM 26852390 ER PT J AU Ernst, M Kriston, L Romero, JM Frolich, AM Jansen, O Fiehler, J Buhk, JH AF Ernst, Marielle Kriston, Levente Romero, Javier M. Froelich, Andreas M. Jansen, Olav Fiehler, Jens Buhk, Jan-Hendrik TI Quantitative Evaluation of Performance in Interventional Neuroradiology: An Integrated Curriculum Featuring Theoretical and Practical Challenges SO PLOS ONE LA English DT Article ID SIMULATION; SKILLS; MAINTENANCE; OCCLUSION AB Purpose We sought to develop a standardized curriculum capable of assessing key competencies in Interventional Neuroradiology by the use of models and simulators in an objective, quantitative, and efficient way. In this evaluation we analyzed the associations between the practical experience, theoretical knowledge, and the skills lab performance of interventionalists. Materials and Methods We evaluated the endovascular skills of 26 participants of the Advanced Course in Endovascular Interventional Neuroradiology of the European Society of Neuroradiology with a set of three tasks (aneurysm coiling and thrombectomy in a virtual simulator and placement of an intra-aneurysmal flow disruptor in a flow model). Practical experience was assessed by a survey. Participants completed a written and oral examination to evaluate theoretical knowledge. Bivariate and multivariate analyses were performed. Results In multivariate analysis knowledge of materials and techniques in Interventional Neuroradiology was moderately associated with skills in aneurysm coiling and thrombectomy. Experience in mechanical thrombectomy was moderately associated with thrombectomy skills, while age was negatively associated with thrombectomy skills. We found no significant association between age, sex, or work experience and skills in aneurysm coiling. Conclusion Our study gives an example of how an integrated curriculum for reasonable and cost-effective assessment of key competences of an interventional neuroradiologist could look. In addition to traditional assessment of theoretical knowledge practical skills are measured by the use of endovascular simulators yielding objective, quantitative, and constructive data for the evaluation of the current performance status of participants as well as the evolution of their technical competency over time. C1 [Ernst, Marielle; Froelich, Andreas M.; Fiehler, Jens; Buhk, Jan-Hendrik] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Ctr Radiol & Endoscopy, Martinistr 52, D-20246 Hamburg, Germany. [Kriston, Levente] Univ Med Ctr Hamburg Eppendorf, Dept Med Psychol, Martinistr 52, D-20246 Hamburg, Germany. [Romero, Javier M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Neuroradiol, Boston, MA USA. [Jansen, Olav] Univ Kiel, Dept Radiol & Neuroradiol, Arnold Heller Str 3, D-24105 Kiel, Germany. RP Ernst, M (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Ctr Radiol & Endoscopy, Martinistr 52, D-20246 Hamburg, Germany. EM m.ernst@uke.de RI Kriston, Levente/D-1713-2013 OI Kriston, Levente/0000-0003-0748-264X FU Philips Healthcare FX The authors would like to thank all participants of the Advanced Course in Endovascular Interventional Neuroradiology of the European Society of Neuroradiology, cycle 2014-2015, and Philips Healthcare for the support and realization of the "Hermann Zeumer Research Laboratory" including a Philips Allura Clarity Angiography system. NR 17 TC 0 Z9 0 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 5 PY 2016 VL 11 IS 2 AR e0148694 DI 10.1371/journal.pone.0148694 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9PR UT WOS:000369554000160 PM 26848840 ER PT J AU Kristianto, J Litscher, SJ Johnson, MG Patel, F Patel, M Fisher, J Zastrow, RK Radcliff, AB Blank, RD AF Kristianto, Jasmin Litscher, Suzanne J. Johnson, Michael G. Patel, Forum Patel, Mital Fisher, Jacqueline Zastrow, Ryley K. Radcliff, Abigail B. Blank, Robert D. TI Congenic Strains Confirm the Pleiotropic Effect of Chromosome 4 QTL on Mouse Femoral Geometry and Biomechanical Performance SO PLOS ONE LA English DT Article ID QUANTITATIVE TRAIT LOCI; BONE-MINERAL DENSITY; CORTICAL BONE; SEX-DIFFERENCES; GENETIC COMPOSITION; CANDIDATE GENES; SKELETAL SIZE; BODY-SIZE; MICE; STRENGTH AB A pleiotropic quantitative trait locus (QTL) for bone geometry and mechanical performance in mice was mapped to distal chromosome 4 via an intercross of recombinant congenic mice HcB-8 and HcB-23. To study the QTL in isolation, we have generated C3H. B10-(rs6355453-rs13478087) (C. B. 4.3) and C3H. B10-(rs6369860-D4Mit170) (C. B. 4.2) congenic strains that harbor similar to 20 Mb and similar to 3 Mb, respectively, of chromosome 4 overlapping segments from C57BL/10ScSnA (B10) within the locus on a C3H/DiSnA (C3H) background. Using 3-point bend testing and standard beam equations, we phenotyped these mice for femoral mid-diaphyseal geometry and biomechanical performance. We analyzed the results via 2-way ANOVA, using sex and genotype as factors. In the C. B. 4.3 strain, we found that homozygous B10/B10 male mice had smaller cross sectional area (CSA) and reduced total displacement than homozygous C3H/C3H mice. Sex by genotype interaction was also observed for maximum load and stiffness for C3H/C3H and B10/B10 mice, respectively. In C. B. 4.2 strain, we found that homozygous B10/B10 mice had lower total displacement, post-yield displacement (PYD), stiffness, yield load and maximum load than mice harboring C3H allele. Sex by genotype interaction was observed in B10/B10 mice for perimeter, outer minor axis (OMA) and CSA. There were no significant differences in tissue level mechanical performance, which suggest that the QTL acts primarily on circumferential bone size. These data confirm the prior QTL mapping data and support other work demonstrating the importance of chromosome 4 QTL on bone modeling and bone responses to mechanical loading. C1 [Kristianto, Jasmin; Litscher, Suzanne J.; Johnson, Michael G.; Patel, Forum; Patel, Mital; Fisher, Jacqueline; Zastrow, Ryley K.; Radcliff, Abigail B.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Blank, Robert D.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Blank, Robert D.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Blank, Robert D.] Milwaukee VA Med Ctr, Milwaukee, WI USA. RP Kristianto, J (reprint author), Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. EM jkristianto@medicine.wisc.edu OI Blank, Robert Daniel/0000-0003-2950-1944 FU Office of Research and Development, Rehabilitation Research and Development Service [I21 RX1440]; Merit Review Award from the Office of Research and Development, Biomedical and Laboratory Research and Development Service, the Department of Veterans Affairs; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health [NIH AR54753]; NIH [AR54753] FX We would like to thank Marc Drezner and Baozhi Yuan for helpful discussions. This material is based on work supported in part by award I21 RX1440, by the Office of Research and Development, Rehabilitation Research and Development Service, and a Merit Review Award from the Office of Research and Development, Biomedical and Laboratory Research and Development Service, the Department of Veterans Affairs, and performed in the Geriatrics Research, Education, and Clinical Center at the William S. Middleton Memorial Veterans Hospital. The views expressed here are those of the authors, and the contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.; Research reported in this publication was supported in part by National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health under Award Number NIH AR54753. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.; Funded by NIH AR54753. www.nih.gov. (Robert Blank). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 2 Z9 2 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 FEB 5 PY 2016 VL 11 IS 2 AR e0148571 DI 10.1371/journal.pone.0148571 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9PR UT WOS:000369554000127 PM 26849124 ER PT J AU Alho, AC Kim, HT Chammas, MJ Reynolds, CG Matos, TR Forcade, E Whangbo, J Nikiforow, S Cutler, CS Koreth, J Ho, VT Armand, P Antin, JH Alyea, EP Lacerda, JF Soiffer, RJ Ritz, J AF Alho, Ana C. Kim, Haesook T. Chammas, Marie J. Reynolds, Carol G. Matos, Tiago R. Forcade, Edouard Whangbo, Jennifer Nikiforow, Sarah Cutler, Corey S. Koreth, John Ho, Vincent T. Armand, Philippe Antin, Joseph H. Alyea, Edwin P. Lacerda, Joao F. Soiffer, Robert J. Ritz, Jerome TI Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; RECENT THYMIC EMIGRANTS; IMMUNE-SYSTEM; HOMEOSTASIS; RECONSTITUTION; NAIVE; PROLIFERATION; LYMPHOCYTES; TOLERANCE; OUTCOMES AB The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4 Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. C1 [Alho, Ana C.; Chammas, Marie J.; Reynolds, Carol G.; Matos, Tiago R.; Forcade, Edouard; Whangbo, Jennifer; Nikiforow, Sarah; Cutler, Corey S.; Koreth, John; Ho, Vincent T.; Armand, Philippe; Antin, Joseph H.; Alyea, Edwin P.; Soiffer, Robert J.; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, 450 Brookline Ave, Boston, MA 02215 USA. [Alho, Ana C.; Matos, Tiago R.; Forcade, Edouard; Whangbo, Jennifer; Nikiforow, Sarah; Cutler, Corey S.; Koreth, John; Ho, Vincent T.; Armand, Philippe; Antin, Joseph H.; Alyea, Edwin P.; Soiffer, Robert J.; Ritz, Jerome] Harvard Univ, Sch Med, Boston, MA USA. [Alho, Ana C.; Lacerda, Joao F.] Univ Lisbon, Fac Med, Inst Med Mol, P-1699 Lisbon, Portugal. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Kim, Haesook T.; Ritz, Jerome] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02215 USA. [Kim, Haesook T.] Harvard Univ, Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, 450 Brookline Ave, Boston, MA 02215 USA. EM jerome_ritz@dfci.harvard.edu OI Matos, Tiago R./0000-0003-2864-8207 FU Harvard Medical School-Portugal Program in Translational Research [HMSP-ICT/0001/201]; National Institutes of Health, National Cancer Institute [CA183559, CA183560, CA142106] FX This work was supported by a Collaborative Research Grant from the Harvard Medical School-Portugal Program in Translational Research HMSP-ICT/0001/201, and National Institutes of Health, National Cancer Institute grants CA183559, CA183560, and CA142106. NR 47 TC 13 Z9 14 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 4 PY 2016 VL 127 IS 5 BP 646 EP 657 DI 10.1182/blood-2015-10-672345 PG 12 WC Hematology SC Hematology GA DI3IZ UT WOS:000373393600019 PM 26670634 ER PT J AU Tetteh, PW Basak, O Farin, HF Wiebrands, K Kretzschmar, K Begthel, H van den Born, M Korving, J de Sauvage, F van Es, JH van Oudenaarden, A Clevers, H AF Tetteh, Paul W. Basak, Onur Farin, Henner F. Wiebrands, Kay Kretzschmar, Kai Begthel, Harry van den Born, Maaike Korving, Jeroen de Sauvage, Frederic van Es, Johan H. van Oudenaarden, Alexander Clevers, Hans TI Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters SO CELL STEM CELL LA English DT Article ID IN-VIVO; SMALL-INTESTINE; EXPRESSION; CANCER; CRYPT; LGR5; MARKER; DEDIFFERENTIATION; TUMORIGENESIS; COMPARTMENT AB Intestinal crypts display robust regeneration upon injury. The relatively rare secretory precursors can replace lost stem cells, but it is unknown if the abundant enterocyte progenitors that express the Alkaline phosphate intestinal (Alpi) gene also have this capacity. We created an Alpi-IRES-CreERT2 (Alpi(CreER)) knockin allele for lineage tracing. Marked clones consist entirely of enterocytes and are all lost from villus tips within days. Genetic fate-mapping of Alpi(+) cells before or during targeted ablation of Lgr5-expressing stem cells generated numerous long-lived crypt-villus "ribbons,'' indicative of dedifferentiation of enterocyte precursors into Lgr5(+) stems. By single-cell analysis of dedifferentiating enterocytes, we observed the generation of Paneth-like cells and proliferative stem cells. We conclude that the highly proliferative, short-lived enterocyte precursors serve as a large reservoir of potential stem cells during crypt regeneration. C1 [Tetteh, Paul W.; Basak, Onur; Farin, Henner F.; Wiebrands, Kay; Kretzschmar, Kai; Begthel, Harry; van den Born, Maaike; Korving, Jeroen; van Es, Johan H.; van Oudenaarden, Alexander; Clevers, Hans] Royal Netherlands Acad Arts & Sci, Hubrecht Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Tetteh, Paul W.; Basak, Onur; Farin, Henner F.; Wiebrands, Kay; Kretzschmar, Kai; Begthel, Harry; van den Born, Maaike; Korving, Jeroen; van Es, Johan H.; van Oudenaarden, Alexander; Clevers, Hans] Univ Med Ctr, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [de Sauvage, Frederic] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA. [Tetteh, Paul W.] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02215 USA. [Farin, Henner F.] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, Paul Ehrlich Str 42-44, D-60596 Frankfurt, Germany. RP Clevers, H (reprint author), Royal Netherlands Acad Arts & Sci, Hubrecht Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.; Clevers, H (reprint author), Univ Med Ctr, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. EM h.clevers@hubrecht.eu OI Kretzschmar, Kai/0000-0002-4745-6684 FU Netherlands Organization for Scientific Research (NWO) personal grant; CBG fellowship; HFSPO; European Research Council [294325]; Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Vici award; LEDUCQ-TNE grant; CVON-HUSTCARE grants; EMBO FX The authors express their sincere gratitude to Stieneke van den Brink, Nobuo Sasaki, Norman Sachs, Helmuth Gehart, Carla Kroon-Veenboer, Lucas Kaaij, Anna van Oudenaarden, Lennart Kester, Reinier van der Linden, Stefan van der Elst, and Ewart de Bruijn for excellent technical assistance. P.W.T. was supported by a Netherlands Organization for Scientific Research (NWO) personal grant. O.B. was supported by a CBG fellowship. H.F. was supported by an EMBO long-term fellowship. K.K. is supported by long-term fellowships from EMBO and HFSPO. K.W. was supported by a European Research Council Advanced grant (ERC-AdG 294325-GeneNoiseControl) and a Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Vici award. J.H.v.E was supported by a LEDUCQ-TNE grant. M.v.d.B and H.B. were supported by CVON-HUSTCARE grants. NR 47 TC 31 Z9 31 U1 7 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD FEB 4 PY 2016 VL 18 IS 2 BP 203 EP 213 DI 10.1016/j.stem.2016.01.001 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DG8GT UT WOS:000372321700011 PM 26831517 ER PT J AU Hasegawa, T Uno, H Wei, LJ AF Hasegawa, Takahiro Uno, Hajime Wei, Lee-Jen TI Nivolumab in Nonsquamous Non-Small-Cell Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hasegawa, Takahiro] Shionogi, Osaka, Japan. [Uno, Hajime] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wei, Lee-Jen] Harvard Univ, Boston, MA 02115 USA. RP Hasegawa, T (reprint author), Shionogi, Osaka, Japan. EM wei@hsph.harvard.edu NR 1 TC 2 Z9 2 U1 2 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 4 PY 2016 VL 374 IS 5 BP 492 EP 492 DI 10.1056/NEJMc1514790 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DC6GX UT WOS:000369319100019 PM 26840145 ER PT J AU Keum, JW Shin, A Gillis, T Mysore, JS Abu Elneel, K Lucente, D Hadzi, T Holmans, P Jones, L Orth, M Kwak, S MacDonald, ME Gusella, JF Lee, JM AF Keum, Jae Whan Shin, Aram Gillis, Tammy Mysore, Jayalakshmi Srinidhi Abu Elneel, Kawther Lucente, Diane Hadzi, Tiffany Holmans, Peter Jones, Lesley Orth, Michael Kwak, Seung MacDonald, Marcy E. Gusella, James F. Lee, Jong-Min TI The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID REPEAT LENGTH; OF-ONSET; SCAN INVESTIGATIONS; DIABETES-MELLITUS; WEIGHT-LOSS; HD; METABOLISM; GENETICS; FEATURES; BRAINS AB Huntington disease (HD) is caused by an expanded HTT CAG repeat that leads in a length-dependent, completely dominant manner to onset of a characteristic movement disorder. HD also displays early mortality, so we tested whether the expanded CAG repeat exerts a dominant influence on age at death and on the duration of clinical disease. We found that, as with clinical onset, HD age at death is determined by expanded CAG-repeat length and has no contribution from the normal CAG allele. Surprisingly, disease duration is independent of the mutation's length. It is also unaffected by a strong genetic modifier of HD motor onset. These findings suggest two parsimonious alternatives. (1) HD pathogenesis is driven by mutant huntingtin, but before or near motor onset, sufficient CAG-driven damage occurs to permit CAG-independent processes and then lead to eventual death. In this scenario, some pathological changes and their clinical correlates could still worsen in a CAG-driven manner after disease onset, but these CAG-related progressive changes do not themselves determine duration. Alternatively, (2) HD pathogenesis is driven by mutant huntingtin acting in a CAG-dependent manner with different time courses in multiple cell types, and the cellular targets that lead to motor onset and death are different and independent. In this scenario, processes driven by HTT CAG length lead directly to death but not via the striatal pathology associated with motor manifestations. Each scenario has important ramifications for the design and testing of potential therapeutics, especially those aimed at preventing or delaying characteristic motor manifestations. C1 [Keum, Jae Whan; Shin, Aram; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi; Abu Elneel, Kawther; Lucente, Diane; MacDonald, Marcy E.; Gusella, James F.; Lee, Jong-Min] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Hadzi, Tiffany] GNS Healthcare Inc, One Charles Pk, Cambridge, MA 02142 USA. [Holmans, Peter; Jones, Lesley] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Genom,Dept Psychol Med, Cardiff CF24 4HQ, S Glam, Wales. [Orth, Michael] Univ Ulm, Dept Neurol, D-089081 Ulm, Germany. [Kwak, Seung] CHDI Fdn, Princeton, NJ 08540 USA. [MacDonald, Marcy E.; Lee, Jong-Min] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [MacDonald, Marcy E.; Gusella, James F.; Lee, Jong-Min] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Holmans, Peter; Jones, Lesley; Orth, Michael; Kwak, Seung; MacDonald, Marcy E.; Gusella, James F.; Lee, Jong-Min] Genet Modifiers Huntingtons Dis Consortium, New York, NY USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Lee, JM (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA.; Lee, JM (reprint author), Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA.; Lee, JM (reprint author), Genet Modifiers Huntingtons Dis Consortium, New York, NY USA. EM jlee51@mgh.harvard.edu OI Holmans, Peter/0000-0003-0870-9412 FU NIH [NINDS NS16367, U01NS082079, R01NS091161]; CHDI Foundation, Inc. FX The authors acknowledge and thank the Harvard Brain Tissue Resource Center at McLean Hospital (Dr. Francine Benes, Director), the New York Brain Bank at Columbia University (Dr. Jean-Paul Vonsattel, Director), the National Neurological Research Specimen Bank at the Department of Veterans Affairs Medical Center (Dr. Wallace Tourtellotte, Director), the Neuropathology Core of the MA Alzheimer Disease Research Center (Matt Frosch, Director), and the Harvard NeuroDiscovery Center Advanced Tissue Resources Core at Massachusetts General Hospital (Dr. Charles Vanderburg, Director) for providing Huntington disease postmortem brain tissues. We also thank Dr. Richard H. Myers (Boston University School of Medicine) for helpful comments on this manuscript. This work was supported by NIH grants NINDS NS16367, U01NS082079, and R01NS091161 and the CHDI Foundation, Inc. NR 42 TC 6 Z9 6 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 4 PY 2016 VL 98 IS 2 BP 287 EP 298 DI 10.1016/j.ajhg.2015.12.018 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DE3BR UT WOS:000370502300005 PM 26849111 ER PT J AU Aschard, H Vilhjalmsson, BJ Joshi, AD Price, AL Kraft, P AF Aschard, Hugues Vilhjalmsson, Bjarni J. Joshi, Amit D. Price, Alkes L. Kraft, Peter TI A Robust Example of Collider Bias in a Genetic Association Study Response SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter C1 [Aschard, Hugues; Joshi, Amit D.; Price, Alkes L.; Kraft, Peter] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Aschard, Hugues; Joshi, Amit D.; Price, Alkes L.; Kraft, Peter] Harvard Univ, TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Vilhjalmsson, Bjarni J.] Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark. [Joshi, Amit D.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Aschard, H (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Aschard, H (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. EM haschard@hsph.harvard.edu FU NCI NIH HHS [R35 CA197449] NR 6 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 4 PY 2016 VL 98 IS 2 BP 394 EP 395 DI 10.1016/j.ajhg.2015.12.020 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DE3BR UT WOS:000370502300017 PM 26849115 ER PT J AU Lin, CY Erkek, S Tong, YA Yin, LL Federation, AJ Zapatka, M Haldipur, P Kawauchi, D Risch, T Warnatz, HJ Worst, BC Ju, BS Orr, BA Zeid, R Polaski, DR Segura-Wang, M Waszak, SM Jones, DTW Kool, M Hovestadt, V Buchhalter, I Sieber, L Johann, P Chavez, L Groschel, S Ryzhova, M Korshunov, A Chen, WB Chizhikov, VV Millen, KJ Amstislavskiy, V Lehrach, H Yaspo, ML Eils, R Lichter, P Korbel, JO Pfister, SM Bradner, JE Northcott, PA AF Lin, Charles Y. Erkek, Serap Tong, Yiai Yin, Linlin Federation, Alexander J. Zapatka, Marc Haldipur, Parthiv Kawauchi, Daisuke Risch, Thomas Warnatz, Hans-Joerg Worst, Barbara C. Ju, Bensheng Orr, Brent A. Zeid, Rhamy Polaski, Donald R. Segura-Wang, Maia Waszak, Sebastian M. Jones, David T. W. Kool, Marcel Hovestadt, Volker Buchhalter, Ivo Sieber, Laura Johann, Pascal Chavez, Lukas Groeschel, Stefan Ryzhova, Marina Korshunov, Andrey Chen, Wenbiao Chizhikov, Victor V. Millen, Kathleen J. Amstislavskiy, Vyacheslav Lehrach, Hans Yaspo, Marie-Laure Eils, Roland Lichter, Peter Korbel, Jan O. Pfister, Stefan M. Bradner, James E. Northcott, Paul A. TI Active medulloblastoma enhancers reveal subgroup-specific cellular origins SO NATURE LA English DT Article ID LIBRARY PREPARATION PROTOCOL; TRANSCRIPTION FACTORS; SUPER-ENHANCERS; HUMAN GENOME; RHOMBIC LIP; IDENTITY; CELLS; EXPRESSION; LANDSCAPE; DISCOVERY AB Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins. C1 [Lin, Charles Y.; Federation, Alexander J.; Zeid, Rhamy; Polaski, Donald R.; Bradner, James E.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA. [Erkek, Serap; Segura-Wang, Maia; Waszak, Sebastian M.; Korbel, Jan O.] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany. [Erkek, Serap; Kawauchi, Daisuke; Worst, Barbara C.; Jones, David T. W.; Kool, Marcel; Sieber, Laura; Johann, Pascal; Chavez, Lukas; Pfister, Stefan M.; Northcott, Paul A.] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Tong, Yiai; Northcott, Paul A.] St Jude Childrens Res Hosp, Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Yin, Linlin; Chen, Wenbiao] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Zapatka, Marc; Hovestadt, Volker; Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Haldipur, Parthiv; Millen, Kathleen J.] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98105 USA. [Risch, Thomas; Warnatz, Hans-Joerg; Amstislavskiy, Vyacheslav; Lehrach, Hans; Yaspo, Marie-Laure] Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany. [Ju, Bensheng] St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cellular Therapy, 332 N Lauderdale St, Memphis, TN 38105 USA. [Orr, Brent A.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Jones, David T. W.; Kool, Marcel; Lichter, Peter; Pfister, Stefan M.] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Buchhalter, Ivo; Eils, Roland] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany. [Groeschel, Stefan] NCT Heidelberg, Dept Translat Oncol, D-69120 Heidelberg, Germany. [Ryzhova, Marina] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia. [Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany. [Korshunov, Andrey] Univ Hosp, Dept Neuropathol, D-69120 Heidelberg, Germany. [Chizhikov, Victor V.] Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Memphis, TN 38163 USA. [Millen, Kathleen J.] Univ Washington, Div Genet, Dept Pediat, Seattle, WA 98195 USA. [Eils, Roland] Heidelberg Univ, Inst Pharm & Mol Biotechnol & BioQuant, D-69117 Heidelberg, Germany. [Pfister, Stefan M.] Heidelberg Univ, Dept Pediat, D-69117 Heidelberg, Germany. [Lin, Charles Y.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA.; Northcott, PA (reprint author), German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany.; Pfister, SM (reprint author), Heidelberg Univ, Dept Pediat, D-69117 Heidelberg, Germany. EM s.pfister@dkfz-heidelberg.de; james_bradner@dfci.harvard.edu; paul.northcott@stjude.org RI Eils, Roland/B-6121-2009; Pfister, Stefan/F-6860-2013; OI Eils, Roland/0000-0002-0034-4036; Pfister, Stefan/0000-0002-5447-5322; Waszak, Sebastian/0000-0003-3042-9521; Buchhalter, Ivo/0000-0003-0764-5832; Hovestadt, Volker/0000-0002-3480-6649; Chavez, Lukas/0000-0002-8718-8848 FU Human Frontiers Science Program [LT000432/2014]; SNSF [P2ELP3_155365]; EMBO Long-Term Fellowship [ALTF 755-2014]; US Department of Defense CDMRP [CA120184] FX S.E. is a recipient of Human Frontiers Science Program long-term postdoctoral fellowship (LT000432/2014). S.M.W. received funding through a SNSF Early Postdoc Mobility Fellowship (P2ELP3_155365) and an EMBO Long-Term Fellowship (ALTF 755-2014). C.Y.L. is supported by a US Department of Defense CDMRP CA120184 postdoctoral fellowship. P.A.N. is a V Foundation V Scholar in Childhood Cancer Research. We thank Creative Science Studios (http://www.creativesciencestudios.com/) for assistance with artwork. We acknowledge J. Zhang and X. Zhou for their assistance in making this data accessible via the St. Jude PeCan Data Portal (https://pecan.stjude.org/dataset/northcott). NR 55 TC 16 Z9 16 U1 7 U2 31 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 FEB 4 PY 2016 VL 530 IS 7588 BP 57 EP + DI 10.1038/nature16546 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC6BK UT WOS:000369304500031 PM 26814967 ER PT J AU Rietman, A Stanley, TL Clish, C Mootha, V Mensink, M Grinspoon, SK Makimura, H AF Rietman, Annemarie Stanley, Takara L. Clish, Clary Mootha, Vamsi Mensink, Marco Grinspoon, Steven K. Makimura, Hideo TI Associations between plasma branched-chain amino acids, beta-aminoisobutyric acid and body composition SO JOURNAL OF NUTRITIONAL SCIENCE LA English DT Article DE Branched-chain amino acids; Visceral adiposity; beta-Aminoisobutyric acid; Subcutaneous adipose tissue; Lean body mass; Metabolomics ID INSULIN-RESISTANCE; ADIPOSE-TISSUE; METABOLISM; OBESITY; HUMANS; RISK; FAT; SENSITIVITY; PROFILES; ENZYME AB Plasma branched-chain amino acids (BCAA) are elevated in obesity and associated with increased cardiometabolic risk. beta-Aminoisobutyric acid (B-AIBA), a recently identified small molecule metabolite, is associated with decreased cardiometabolic risk. Therefore, we investigated the association of BCAA and B-AIBA with each other and with detailed body composition parameters, including abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A cross-sectional study was carried out with lean (n 15) and obese (n 33) men and women. Detailed metabolic evaluations, including measures of body composition, insulin sensitivity and plasma metabolomics were completed. Plasma BCAA were higher (1.6 (SE 0.08) (x10(7)) v. 1.3 (SE 0.06) (x10(7)) arbitrary units; P=0.005) in obese v. lean subjects. BCAA were positively associated with VAT (R 0.49; P=0.0006) and trended to an association with SAT (R 0.29; P=0.052). The association between BCAA and VAT, but not SAT, remained significant after controlling for age, sex and race on multivariate modelling (P<0.05). BCAA were also associated with parameters of insulin sensitivity (Matsuda index: R -0.50, P=0.0004; glucose AUC: R 0.53, P<0.001). BCAA were not associated with B-AIBA (R -0.04; P=0.79). B-AIBA was negatively associated with SAT (R -0.37; P=0.01) but only trended to an association with VAT (R 0.27; P=0.07). However, neither relationship remained significant after multivariate modelling (P>0.05). Plasma B-AIBA was associated with parameters of insulin sensitivity (Matsuda index R 0.36, P=0.01; glucose AUC: R -0.30, P = 0.04). Plasma BCAA levels were positively correlated with VAT and markers of insulin resistance. The results suggest a possible complex role of adipose tissue in BCAA homeostasis and insulin resistance. C1 [Rietman, Annemarie; Mensink, Marco] Wageningen Univ, Div Human Nutr, NL-6703 HD Wageningen, Netherlands. [Stanley, Takara L.; Grinspoon, Steven K.; Makimura, Hideo] Massachusetts Gen Hosp, Program Nutr Metab & Neuroendocrine Unit, Boston, MA 02114 USA. [Stanley, Takara L.; Mootha, Vamsi; Grinspoon, Steven K.; Makimura, Hideo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Stanley, Takara L.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Clish, Clary; Mootha, Vamsi] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Mootha, Vamsi] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Rietman, A (reprint author), Wageningen Univ, Div Human Nutr, NL-6703 HD Wageningen, Netherlands. EM annemarierietman@hotmail.com FU NCRR NIH HHS [M01 RR001066, UL1 RR025758]; NHLBI NIH HHS [R01 HL085268]; NIDDK NIH HHS [K23 DK087857, K23 DK089910, P30 DK040561] NR 27 TC 1 Z9 1 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 2048-6790 J9 J NUTR SCI JI J. Nutr. Sci. PD FEB 3 PY 2016 VL 5 AR e6 DI 10.1017/jns.2015.37 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DD6VF UT WOS:000370061900001 PM 27313851 ER PT J AU Amdur, RL Mukherjee, M Go, A Barrows, IR Ramezani, A Shoji, J Reilly, MP Gnanaraj, J Deo, R Roas, S Keane, M Master, S Teal, V Soliman, EZ Yang, P Feldman, H Kusek, JW Tracy, CM Raj, DS AF Amdur, Richard L. Mukherjee, Monica Go, Alan Barrows, Ian R. Ramezani, Ali Shoji, Jun Reilly, Muredach P. Gnanaraj, Joseph Deo, Raj Roas, Sylvia Keane, Martin Master, Steve Teal, Valerie Soliman, Elsayed Z. Yang, Peter Feldman, Harold Kusek, John W. Tracy, Cynthia M. Raj, Dominic S. CA CRIC Study Investigators TI Interleukin-6 Is a Risk Factor for Atrial Fibrillation in Chronic Kidney Disease: Findings from the CRIC Study SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; CORONARY-ARTERY-DISEASE; STAGE RENAL-DISEASE; HEMODIALYSIS-PATIENTS; ELEVATED INTERLEUKIN-6; PLASMA INTERLEUKIN-6; OXIDATIVE STRESS; INFLAMMATION; MORTALITY; INDIVIDUALS AB Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic kidney disease (CKD). In this study, we examined the association between inflammation and AF in 3,762 adults with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. AF was determined at baseline by self-report and electrocardiogram (ECG). Plasma concentrations of interleukin(IL)-1, IL-1 Receptor antagonist, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor-beta, high sensitivity C-Reactive protein, and fibrinogen, measured at baseline. At baseline, 642 subjects had history of AF, but only 44 had AF in ECG recording. During a mean follow-up of 3.7 years, 108 subjects developed new-onset AF. There was no significant association between inflammatory biomarkers and past history of AF. After adjustment for demographic characteristics, comorbid conditions, laboratory values, echocardiographic variables, and medication use, plasma IL-6 level was significantly associated with presence of AF at baseline (Odds ratio [OR], 1.61; 95% confidence interval [CI], 1.21 to 2.14; P = 0.001) and new-onset AF (OR, 1.25; 95% CI, 1.02 to 1.53; P = 0.03). To summarize, plasma IL-6 level is an independent and consistent predictor of AF in patients with CKD. C1 [Amdur, Richard L.] George Washington Univ, Med Fac Associates, Biostat Core, Washington, DC USA. [Mukherjee, Monica] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Go, Alan] Kaiser Permanente, Div Res, Oakland, CA USA. [Barrows, Ian R.] George Washington Univ, Sch Med, Washington, DC USA. [Ramezani, Ali; Shoji, Jun; Raj, Dominic S.] George Washington Univ, Sch Med, Div Renal Dis & Hypertens, Washington, DC USA. [Reilly, Muredach P.; Deo, Raj] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Gnanaraj, Joseph] Bridgeport Hosp, Bridgeport, CT USA. [Roas, Sylvia] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Keane, Martin] Temple Heart & Vasc Ctr, Philadelphia, PA USA. [Master, Steve] Univ Penn, Perelman Sch Med, Pathol & Lab Med, Philadelphia, PA 19104 USA. [Teal, Valerie; Yang, Peter; Feldman, Harold] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Tracy, Cynthia M.] George Washington Univ, Sch Med, Div Cardiol, Washington, DC USA. RP Raj, DS (reprint author), George Washington Univ, Sch Med, Div Renal Dis & Hypertens, Washington, DC USA. EM draj@mfa.gwu.edu FU National Institutes of Health [R01 DK073665-01A1, 1U01DK099914-01, 1U01DK099924-01]; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS [UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland GCRC [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago CTSA [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/NCRR UCSF-CTSI [UL1 RR-024131] FX Dr. Dominic S. Raj is supported by R01 DK073665-01A1, 1U01DK099914-01 and 1U01DK099924-01 from the National Institutes of Health. Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. NR 52 TC 3 Z9 3 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 3 PY 2016 VL 11 IS 2 AR e0148189 DI 10.1371/journal.pone.0148189 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9OF UT WOS:000369550200095 PM 26840403 ER PT J AU Buttenheim, AM Fiks, AG Burson, RC Wang, E Coffin, SE Metlay, JP Feemster, KA AF Buttenheim, Alison M. Fiks, Alexander G. Burson, Randall C., II Wang, Eileen Coffin, Susan E. Metlay, Joshua P. Feemster, Kristen A. TI A behavioral economics intervention to increase pertussis vaccination among infant caregivers: A randomized feasibility trial SO VACCINE LA English DT Article DE Vaccination; Diphtheria-tetanus-pertussis vaccine; Whooping cough; Infant; Pharmacy; Behavioral economics ID IMMUNIZATION PRACTICES; ADVISORY-COMMITTEE; PEDIATRIC OFFICE; PREGNANT-WOMEN; PUBLIC-HEALTH; UNITED-STATES; TDAP; PHARMACIST; CALIFORNIA; EPIDEMIC AB Objectives: The incidence of pertussis has tripled in the past five years. Infants can be protected by "cocooning," or vaccinating household contacts with the Tdap vaccine. However, Tdap coverage for adult caregivers of infants is low. This study evaluated the feasibility and impact of interventions informed by behavioral economics (retail pharmacy vouchers for Tdap vaccines and a celebrity public service announcement) to increase Tdap vaccination among caregivers of young infants. Methods: We conducted a randomized controlled feasibility trial among adults attending newborn well-child visits at an urban Philadelphia pediatric primary care clinic who were not previously vaccinated with Tdap. Participants were randomized to one of four conditions: ($5-off Tdap voucher vs. free voucher) x (watching a 1 min video public service announcement (PSA) about Tdap vaccination vs. no PSA). Tdap vaccination was assessed by tracking voucher redemption and following up with participants by phone. Results: Ninety-five adult caregivers of 74 infants were enrolled in the study (mean age 29.3 years; 61% male; relationship to newborn: 54% father, 33% mother, 13% grandparent or other; caregiver insurance status: 35% Medicaid, 34% private insurance, 32% uninsured). Only 1 subject redeemed the retail pharmacy Tdap voucher. Follow-up interviews suggest that, even with the voucher, significant barriers to vaccination remained including: delaying planned vaccination, perceived inconvenient pharmacy locations, and beliefs about pertussis risk and severity. Conclusions: Despite leveraging existing infrastructure for adult vaccination, results suggest that retail pharmacy vouchers delivered during a newborn visit are not an effective strategy for promoting Tdap. Alternate approaches are needed that prioritize convenience and provide an immediate opportunity to vaccinate when motivation is high. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Buttenheim, Alison M.] Univ Penn, Sch Nursing, Dept Family & Community Hlth, 416 Fagin Hall,435 Curie Blvd, Philadelphia, PA 19104 USA. [Fiks, Alexander G.] Childrens Hosp Philadelphia, Div Gen Pediat, CHOP North Room 1546,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Burson, Randall C., II] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Blockley Hall 333,423 Guardian Dr, Philadelphia, PA 19104 USA. [Wang, Eileen] Univ Penn, Sch Nursing, Dept Family & Community Hlth, 416 Fagin Hall,435 Curie Blvd, Philadelphia, PA 19104 USA. [Coffin, Susan E.] Childrens Hosp Philadelphia, Div Infect Dis, 3535 Market St,Room 1579, Philadelphia, PA 19104 USA. [Metlay, Joshua P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, 15 Parkman St, Boston, MA 02114 USA. [Feemster, Kristen A.] Childrens Hosp Philadelphia, Div Infect Dis, CHOP North Room 1511,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. RP Buttenheim, AM (reprint author), Univ Penn, Sch Nursing, Dept Family & Community Hlth, 416 Fagin Hall,435 Curie Blvd, Philadelphia, PA 19104 USA. EM abutt@nursing.upenn.edu; fiks@email.chop.edu; Randall.Burson@uphs.upenn.edu; eiwang@sas.upenn.edu; coffin@email.chop.edu; jmetlay@partners.org; feemster@email.chop.edu FU Leonard Davis Institute of Health Economics at University of Pennsylvania; Robert Wood Johnson Foundation Health and Society Scholars Program at University of Pennsylvania; National Cancer Institute [KM1CA1567151] FX The authors gratefully acknowledge the Pediatric Research Consortium of the Children's Hospital of Philadelphia for access to the research site and assistance with data collection. The authors also thank Maria Middleton and Valerie McGoldrick for research coordination and data collection. Finally, we thank our retail pharmacy partner. This study was funded by grants from the Leonard Davis Institute of Health Economics at the University of Pennsylvania and the Robert Wood Johnson Foundation Health and Society Scholars Program at the University of Pennsylvania, and the National Cancer Institute (KM1CA1567151). NR 39 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 3 PY 2016 VL 34 IS 6 BP 839 EP 845 DI 10.1016/j.vaccine.2015.11.068 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DD7ML UT WOS:000370108500019 PM 26686571 ER PT J AU Liu, CH Ren, J Liu, PK AF Liu, Christina H. Ren, Jiaqian Liu, Philip K. TI Amphetamine manipulates monoamine oxidase-A level and behavior using theranostic aptamers of transcription factors AP-1/NF-kB SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Article DE Acute stress; Addiction; Bipolar; Oxidative stress; Parkinson dementia; Protein-targeted delivery; Theranostics ID MAJOR DEPRESSIVE DISORDER; TRANSGENIC RATS EVIDENCE; GENE PROMOTER; MAO-A; DECOY OLIGODEOXYNUCLEOTIDES; FUNCTIONAL POLYMORPHISM; PANIC DISORDER; POINT MUTATION; LIVING BRAINS; ACUTE STRESS AB Background: Monoamine oxidase (MAO) enzymes play a critical role in controlling the catabolism of monoamine neurotransmitters and biogenic trace amines and behavior in humans. However, the mechanisms that regulate MAO are unclear. Several transcription factor proteins are proposed to modulate the transcription of MAO gene, but evidence supporting these hypotheses is controversial. We aimed to investigate the mechanism of gene transcription regulator proteins on amphetamine-induced behavior. We applied aptamers containing a DNA binding sequence, as well as a random sequence (without target) to study the modulation of amphetamine-induced MAO levels and hyperactivity in living mice. Methods: We pretreated in adult male C57black6 mice (Taconic Farm, Germantown, NY) (n >= 3 litters at a time), 2 to 3 months of age (23 +/- 2 gm body weight) with double-stranded (ds) DNA aptamers with sequence specific to activator protein-1 (5ECdsAP1), nuclear factor-kappa beta (5ECdsNF-kB), special protein-1 (5ECdsSP-1) or cyclicAMP responsive element binding (5ECdsCreB) protein binding regions, 5ECdsRan [a random sequence without target], single-stranded AP-1 (5ECssAP-1) (8 nmol DNA per kg) or saline (5 mu l, intracerebroventricular [icv] injection) control before amphetamine administration (4 mg/kg, i.p.). We then measured and analyzed locomotor activities and the level of MAO-A and MAO-B activity. Results: In the pathological condition of amphetamine exposure, we showed here that pretreatment with 5ECdsAP1 and 5ECdsNF-kB reversed the decrease of MAO-A activity (p < 0.05, t test), but not activity of the B isomer (MAO-B), in the ventral tegmental area (VTA) and substantia nigra (SN) of C57black6 mice. The change in MAO-A level coincided with a reversed amphetamine-induced restless behavior of mice. Pretreatments with saline, 5ECdsCreB, 5ECdsSP-1, 5ECdsRan or 5ECssAP-1 had no effect. Conclusion: Our data lead us to conclude that elevation of AP-1 or NF-kB indirectly decreases MAO-A protein levels which, in turn, diminishes MAO-A ability in the VTA of the mesolimbic dopaminergic pathway that has been implicated in cells under stress especially in the SN and VTA. This study has implications for design for the treatment of drug exposure and perhaps Parkinson's dementia. C1 [Liu, Christina H.; Ren, Jiaqian; Liu, Philip K.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Liu, Christina H.] NIH, 6707 Democracy Blvd,Suite 200, Bethesda, MD 20892 USA. RP Liu, PK (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM Philip.Liu@mgh.harvard.edu OI Liu, Philip K./0000-0003-2149-3564 FU [R01DA029889]; [R01EB013768]; [NS045776] FX We thank Drs. M. Schwartzchild for allowing us to use the locomotion detection device and Charng-Ming Liu for modified aptamer ds-sODN. We also thank Ms. N. Eusemann for assistance with editing the manuscript. This project was supported by research grants R01DA029889 and R01EB013768 to PKL, NS045776 to the MGH Neuroscience Center. NR 45 TC 1 Z9 1 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1021-7770 EI 1423-0127 J9 J BIOMED SCI JI J. Biomed. Sci. PD FEB 3 PY 2016 VL 23 AR 21 DI 10.1186/s12929-016-0239-2 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DC8WN UT WOS:000369500700001 PM 26841904 ER PT J AU Tong, B Hornak, AJ Maison, SF Ohlemiller, KK Liberman, MC Simmons, DD AF Tong, Benton Hornak, Aubrey J. Maison, Stephane F. Ohlemiller, Kevin K. Liberman, M. Charles Simmons, Dwayne D. TI Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium homeostasis; hearing loss; outer hair cell; parvalbumin ID OUTER HAIR-CELLS; CALCIUM-BINDING PROTEINS; HEARING-LOSS; BETA-PARVALBUMIN; INNER-EAR; ELECTROMOTILITY; ORGAN; CYTOSKELETAL; EXPRESSION; CORTI AB Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70-80 dB threshold shifts in auditory brainstem responses. Thus, Ocm is not critical for cochlear development but does play an essential role for cochlear function in the adult mouse. C1 [Tong, Benton; Ohlemiller, Kevin K.] Washington Univ, Sch Med, Dept Otolaryngol, St Louis, MO 63110 USA. [Hornak, Aubrey J.; Simmons, Dwayne D.] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. [Maison, Stephane F.; Liberman, M. Charles] Harvard Univ, Sch Med, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Maison, Stephane F.; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Simmons, DD (reprint author), Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. EM dd.simmons@g.ucla.edu FU National Institute on Deafness and Other Communication Disorders [DC004086, DC013304, R01 DC00188, P30 DC05209]; Fulbright Scholar Award FX We thank the Mouse ES and Mouse Genetics Cores at Washington University and University of California, Los Angeles, and Drs. R. Thalmann, I. Thalmann, and D. Ornitz (Washington University) for their advice and technical assistance. We also acknowledge Dr. C.-L. Hseh for karyotyping and the Washington University Mouse Genetics Core for injection services. This research was supported by National Institute on Deafness and Other Communication Disorders Grants DC004086 and DC013304 (D.D.S.) and R01 DC00188 and P30 DC05209 (M.C.L.), and a 2015-2016 Fulbright Scholar Award (D.D.S.). NR 36 TC 2 Z9 2 U1 2 U2 2 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 FEB 3 PY 2016 VL 36 IS 5 BP 1631 EP 1635 DI 10.1523/JNEUROSCI.3311-15.2016 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DC4HR UT WOS:000369182200018 PM 26843644 ER PT J AU Breitkopf, SB Yang, XM Begley, MJ Kulkarni, M Chiu, YH Turke, AB Lauriol, J Yuan, M Qi, J Engelman, JA Hong, PY Kontaridis, MI Cantley, LC Perrimon, N Asara, JM AF Breitkopf, Susanne B. Yang, Xuemei Begley, Michael J. Kulkarni, Meghana Chiu, Yu-Hsin Turke, Alexa B. Lauriol, Jessica Yuan, Min Qi, Jie Engelman, Jeffrey A. Hong, Pengyu Kontaridis, Maria I. Cantley, Lewis C. Perrimon, Norbert Asara, John M. TI A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2 SO SCIENTIFIC REPORTS LA English DT Article ID TYROSINE-PHOSPHATASE SHP2; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; HEMATOPOIETIC-CELLS; REGULATORY SUBUNIT; MASS-SPECTROMETRY; INSULIN-RECEPTOR; MYELOMA CELLS; ACTIVATION; KINASE AB Using a series of immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) experiments and reciprocal BLAST, we conducted a fly-human cross-species comparison of the phosphoinositide-3-kinase (PI3K) interactome in a drosophila S2R+ cell line and several NSCLC and human multiple myeloma cell lines to identify conserved interacting proteins to PI3K, a critical signaling regulator of the AKT pathway. Using H929 human cancer cells and drosophila S2R+ cells, our data revealed an unexpected direct binding of Corkscrew, the drosophila ortholog of the non-receptor protein tyrosine phosphatase type II (SHP2) to the Pi3k21B (p60) regulatory subunit of PI3K (p50/p85 human ortholog) but no association with Pi3k92e, the human ortholog of the p110 catalytic subunit. The p85-SHP2 association was validated in human cell lines, and formed a ternary regulatory complex with GRB2-associated-binding protein 2 (GAB2). Validation experiments with knockdown of GAB2 and Far-Western blots proved the direct interaction of SHP2 with p85, independent of adaptor proteins and transfected FLAG-p85 provided evidence that SHP2 binding on p85 occurred on the SH2 domains. A disruption of the SHP2-p85 complex took place after insulin/IGF1 stimulation or imatinib treatment, suggesting that the direct SHP2-p85 interaction was both independent of AKT activation and positively regulates the ERK signaling pathway. C1 [Breitkopf, Susanne B.; Yang, Xuemei; Begley, Michael J.; Yuan, Min; Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. [Breitkopf, Susanne B.; Asara, John M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Begley, Michael J.] Pfizer, Ctr Therapeut Innovat, Boston, MA USA. [Kulkarni, Meghana; Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA 02115 USA. [Chiu, Yu-Hsin] Novartis, Cambridge, MA USA. [Turke, Alexa B.; Qi, Jie; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Thorac Canc, Charlestown, MA USA. [Lauriol, Jessica; Kontaridis, Maria I.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Hong, Pengyu] Brandeis Univ, Dept Comp Sci, Waltham, MA USA. [Kontaridis, Maria I.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Cantley, Lewis C.] Weill Cornell Med Coll, Ctr Canc, New York, NY USA. RP Asara, JM (reprint author), Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA.; Asara, JM (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM jasara@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NIH [5P01CA120964, 1S10OD010612, 5P30CA006516, R01GM041890, R01HL102368, R01HL114775]; American Heart Association FX We acknowledge NIH grants 5P01CA120964 (J.M.A, N.P., L.C.C.), 1S10OD010612 (J.M.A), 5P30CA006516 (J.M.A.) and R01GM041890 (LCC), R01HL102368 (M.I.K.), R01HL114775 (M.I.K) and American Heart Association Postdoctoral fellowship to J.L. NP is an investigator of the Howard Hughes Medical Institute. NR 55 TC 1 Z9 1 U1 3 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 FEB 3 PY 2016 VL 6 AR 20471 DI 10.1038/srep20471 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD3AF UT WOS:000369792600001 PM 26839216 ER PT J AU Li, ZJ Liu, ML Lan, L Zeng, F Makris, N Liang, YL Guo, TP Wu, F Gao, YJ Dong, MK Yang, J Li, Y Gong, QY Liang, FR Kong, J AF Li, Zhengjie Liu, Mailan Lan, Lei Zeng, Fang Makris, Nikos Liang, Yilin Guo, Taipin Wu, Feng Gao, Yujie Dong, Mingkai Yang, Jie Li, Ying Gong, Qiyong Liang, Fanrong Kong, Jian TI Altered periaqueductal gray resting state functional connectivity in migraine and the modulation effect of treatment SO SCIENTIFIC REPORTS LA English DT Article ID KNEE OSTEOARTHRITIS PATIENTS; RANDOMIZED CONTROLLED-TRIAL; CHRONIC PAIN; OPIOID ANALGESIA; HUMAN BRAIN; ACUPUNCTURE; ACTIVATION; MIDBRAIN; PET; PROJECTIONS AB The aims of this study were to 1) compare resting state functional connectivity (rs-fc) of the periaqueductal gray (PAG), a key region in the descending pain modulatory system (DPMS) between migraine without aura (MwoA) patients and healthy controls (HC), and 2) investigate how an effective treatment can influence the PAG rs-fc in MwoA patients. One hundred MwoA patients and forty-six matched HC were recruited. Patients were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting state fMRI data were collected and seed based functional connectivity analysis was applied. Compared with HC, MwoA patients showed reduced rs-fc between the PAG and rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC), key regions in the DPMS and other pain related brain regions. The reduced rs-fc between the PAG and rACC/mPFC was associated with increased migraine headache intensity at the baseline. After treatments, rs-fc between the PAG and the rACC in MwoA patients significantly increased. The changes of rs-fc among the PAG, rACC and ventral striatum were significantly associated with headache intensity improvement. Impairment of the DPMS is involved in the neural pathophysiology of migraines. Impaired DPMS in migraine patients can be normalized after effective treatment. C1 [Li, Zhengjie; Lan, Lei; Zeng, Fang; Guo, Taipin; Wu, Feng; Gao, Yujie; Dong, Mingkai; Yang, Jie; Li, Ying; Liang, Fanrong] Chengdu Univ Tradit Chinese Med, Teaching Hosp 3, Chengdu, Sichuan, Peoples R China. [Li, Zhengjie] Xiamen Univ, Coll Med, Dept Tradit Chinese Med, Xiamen, Fujian, Peoples R China. [Liu, Mailan] Hunan Univ Chinese Med, Acupuncture & Tuina Sch, Changsha, Hunan, Peoples R China. [Makris, Nikos; Kong, Jian] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Makris, Nikos; Kong, Jian] Harvard Univ, Sch Med, Charlestown, MA USA. [Makris, Nikos; Kong, Jian] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Liang, Yilin] Wellesley Coll, Neurosci Program, Wellesley, MA 02181 USA. [Gong, Qiyong] Sichuan Univ, West China Hosp, Huaxi MR Res Ctr, Chengdu 610064, Sichuan, Peoples R China. RP Zeng, F; Liang, FR (reprint author), Chengdu Univ Tradit Chinese Med, Teaching Hosp 3, Chengdu, Sichuan, Peoples R China. EM zeng_fang@126.com; acuresearch@126.com FU State Key Program for Basic Research of China [2012CB518501]; National Natural Science Foundation of China [81273154, 81473602]; Program for New Century Talents in the University of Ministry of Education of China; Youth Foundation of Sichuan Province [2012JQ0052]; NCCIH/NIH [R01AT006364, R01AT008563, R21AT008707, P01 AT006663] FX The authors would like to thank Wei Qin, Jinbo Sun, Jixin Liu, Minghao Dong, Qizhu Wu and Xiaoqi Huang from Xidian University and the West China Hospital of Sichuan University for their assistance in this study. This study was supported by grants from the State Key Program for Basic Research of China (2012CB518501), the National Natural Science Foundation of China (No.81273154 and No.81473602), the Program for New Century Talents in the University of Ministry of Education of China (2013) and the Youth Foundation of Sichuan Province (No.2012JQ0052). Jian Kong is supported by R01AT006364 (NCCIH/NIH), R01AT008563, (NCCIH/NIH), R21AT008707 (NCCIH/NIH) and P01 AT006663 (NCCIH/NIH). NR 55 TC 9 Z9 10 U1 5 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 3 PY 2016 VL 6 AR 20298 DI 10.1038/srep20298 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD3CX UT WOS:000369799900001 PM 26839078 ER PT J AU Arena, S Siravegna, G Mussolin, B Kearns, JD Wolf, BB Misale, S Lazzari, L Bertotti, A Trusolino, L Adjei, AA Montagut, C Di Nicolantonio, F Nering, R Bardelli, A AF Arena, Sabrina Siravegna, Giulia Mussolin, Benedetta Kearns, Jeffrey D. Wolf, Beni B. Misale, Sandra Lazzari, Luca Bertotti, Andrea Trusolino, Livio Adjei, Alex A. Montagut, Clara Di Nicolantonio, Federica Nering, Rachel Bardelli, Alberto TI MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; METASTATIC BREAST-CANCER; KINASE DOMAIN; THERAPY; TRASTUZUMAB; PERTUZUMAB; COMBINATIONS; INHIBITION; CRIZOTINIB AB The anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are used to treat RAS wild-type colorectal cancers (CRCs), but their efficacy is limited by the emergence of acquired drug resistance. After EGFR blockade, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. We hypothesized that EGFR ECD-resistant variants could be targeted by the recently developed oligoclonal antibody MM-151 that binds multiple regions of the EGFR ECD. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade. These data provide molecular rationale for the clinical use of MM-151 in patients who become resistant to cetuximab or panitumumab as a result of EGFR ECD mutations. C1 [Arena, Sabrina; Siravegna, Giulia; Mussolin, Benedetta; Misale, Sandra; Lazzari, Luca; Bertotti, Andrea; Trusolino, Livio; Di Nicolantonio, Federica; Bardelli, Alberto] IRCCS, Candiolo Canc Inst Fdn Piemonte Oncol FPO, I-10060 Turin, Italy. [Arena, Sabrina] FIRC Inst Mol Oncol IFOM, I-20139 Milan, Italy. [Arena, Sabrina; Siravegna, Giulia; Lazzari, Luca; Bertotti, Andrea; Trusolino, Livio; Di Nicolantonio, Federica; Bardelli, Alberto] Univ Torino, Dept Oncol, I-10060 Turin, Italy. [Kearns, Jeffrey D.; Wolf, Beni B.; Nering, Rachel] Merrimack Pharmaceut Inc, Cambridge, MA 02139 USA. [Adjei, Alex A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Montagut, Clara] Hosp Mar, Med Oncol Dept, Barcelona 08003, Spain. [Montagut, Clara] Hosp Mar, FIMIM, Med Res Inst, Canc Res Program, Barcelona 08003, Spain. [Wolf, Beni B.] Blueprint Med, Cambridge, MA 02139 USA. [Misale, Sandra] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Arena, S; Bardelli, A (reprint author), IRCCS, Candiolo Canc Inst Fdn Piemonte Oncol FPO, I-10060 Turin, Italy.; Arena, S (reprint author), FIRC Inst Mol Oncol IFOM, I-20139 Milan, Italy.; Arena, S; Bardelli, A (reprint author), Univ Torino, Dept Oncol, I-10060 Turin, Italy. EM sabrina.arena@ircc.it; alberto.bardelli@unito.it RI Di Nicolantonio, Federica/A-2503-2011; OI Di Nicolantonio, Federica/0000-0001-9618-2010; ARENA, Sabrina/0000-0002-1318-2494 FU European Community [602901, 635342-2]; Innovative Medicines Initiative (IMI) [115749]; AIRC (Associazione Italiana per la Ricerca sul Cancro) [9970]; Fondazione Piemontese per la Ricerca sul Cancro-ONLUS; Ministero dell'Istruzione, dell'Universita e della Ricerca-progetto PRIN; AIRC [14205, 16788, 15571]; Fundacio Cellex; [PI15/00457]; [DTS15/00048] FX This study was supported by European Community's Seventh Framework Programme under grant agreement no. 602901 MErCuRIC (A. Bardelli and F.D.N.) and grant agreement no. 635342-2 MoTriColor (A. Bardelli); Innovative Medicines Initiative (IMI) contract no. 115749 CANCER-ID (A. Bardelli); AIRC (Associazione Italiana per la Ricerca sul Cancro) 2010 Special Program Molecular Clinical Oncology 5 per mille, Project no. 9970 (A. Bardelli and L.T.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2010 e 2011 Ministero della Salute (A. Bardelli, F.D.N., and L.T.); Ministero dell'Istruzione, dell'Universita e della Ricerca-progetto PRIN 2010-2011 (A. Bardelli); and AIRC Investigator Grants, project 14205 (L.T.), project 16788 (A. Bardelli), and project 15571 (A. Bertotti). C.M. was supported by PI15/00457, DTS15/00048, and Fundacio Cellex. NR 48 TC 10 Z9 11 U1 0 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 3 PY 2016 VL 8 IS 324 AR 324ra14 DI 10.1126/scitranslmed.aad5640 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DC4CC UT WOS:000369166600003 PM 26843189 ER PT J AU Wright, C Gupta, CN Chen, J Patel, V Calhoun, VD Ehrlich, S Wang, L Bustillo, JR Perrone-Bizzozero, NI Turner, JA AF Wright, C. Gupta, C. N. Chen, J. Patel, V. Calhoun, V. D. Ehrlich, S. Wang, L. Bustillo, J. R. Perrone-Bizzozero, N. I. Turner, J. A. TI Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; INDEPENDENT COMPONENT ANALYSIS; FUNCTIONAL CONNECTIVITY; ADULT NEUROGENESIS; BETA-CATENIN; RISK; MIR-137; IMPACT; CELLS; BRAIN AB Evidence suggests that microRNA-137 (miR-137) is involved in the genetic basis of schizophrenia. Risk variants within the miR-137 host gene (MIR137HG) influence structural and functional brain-imaging measures, and miR-137 itself is predicted to regulate hundreds of genes. We evaluated the influence of a MIR137HG risk variant (rs1625579) in combination with variants in miR-137-regulated genes TCF4, PTGS2, MAPK1 and MAPK3 on gray matter concentration (GMC). These genes were selected based on our previous work assessing schizophrenia risk within possible miR-137-regulated gene sets using the same cohort of subjects. A genetic risk score (GRS) was determined based on genotypes of these four schizophrenia risk-associated genes in 221 Caucasian subjects (89 schizophrenia patients and 132 controls). The effects of the rs1625579 genotype with the GRS of miR-137-regulated genes in a three-way interaction with diagnosis on GMC patterns were assessed using a multivariate analysis. We found that schizophrenia subjects homozygous for the MIR137HG risk allele show significant decreases in occipital, parietal and temporal lobe GMC with increasing miR-137-regulated GRS, whereas those carrying the protective minor allele show significant increases in GMC with GRS. No correlations of GMC and GRS were found in control subjects. Variants within or upstream of genes regulated by miR-137 in combination with the MIR137HG risk variant may influence GMC in schizophrenia-related regions in patients. Given that the genes evaluated here are involved in protein kinase A signaling, dysregulation of this pathway through alterations in miR-137 biogenesis may underlie the gray matter loss seen in the disease. C1 [Wright, C.; Gupta, C. N.; Chen, J.; Patel, V.; Calhoun, V. D.; Turner, J. A.] Mind Res Network, Albuquerque, NM USA. [Wright, C.; Calhoun, V. D.; Bustillo, J. R.; Perrone-Bizzozero, N. I.] Univ New Mexico, Dept Neurosci, Albuquerque, NM 87131 USA. [Calhoun, V. D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Ehrlich, S.] Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Translat Dev Neurosci Sect, D-01062 Dresden, Germany. [Ehrlich, S.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ehrlich, S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Wang, L.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Wang, L.] Northwestern Univ, Feinberg Sch Med, Dept Radiol, Chicago, IL 60611 USA. [Bustillo, J. R.; Perrone-Bizzozero, N. I.] Univ New Mexico, Dept Psychiat & Behav Sci, Albuquerque, NM 87131 USA. [Turner, J. A.] Georgia State Univ, Dept Psychol, Univ Plaza, Atlanta, GA 30303 USA. [Turner, J. A.] Georgia State Univ, Neurosci Inst, Atlanta, GA 30303 USA. RP Perrone-Bizzozero, NI (reprint author), Univ New Mexico, Sch Med, Dept Neurosci & Psychiat & Behav Sci, Albuquerque, NM 87131 USA. EM nbizzozero@salud.unm.edu FU National Institutes of Health [5R01MH094524-03, P50 MH071616, R01 MH056584, 1R01 MH084803, 1U01 MH097435]; Department of Energy [DE-FG02-99ER62764, 5P20RR021938/P20GM103472, R01EB005846] FX This work was supported by The National Institutes of Health (5R01MH094524-03 to VDC and JAT). The MCIC data set was collected through support from the Department of Energy (DE-FG02-99ER62764 to VDC) and the National Institutes of Health (5P20RR021938/P20GM103472 and R01EB005846 to VDC). The NU data set was shared through support from the National Institutes of Health grants (P50 MH071616, R01 MH056584, 1R01 MH084803 to LW) and 1U01 MH097435 (LW and JAT). We thank the participants who enrolled in the studies used in this analysis, as well as Marilee Morgan for assistance with genotyping. NR 73 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD FEB 2 PY 2016 VL 6 AR e724 DI 10.1038/tp.2015.211 PG 8 WC Psychiatry SC Psychiatry GA DJ0KP UT WOS:000373892200001 PM 26836412 ER PT J AU Fernandez-Nogueira, P Bragado, P Almendro, V Ametller, E Rios, J Choudhury, S Mancino, M Gascon, P AF Fernandez-Nogueira, Patricia Bragado, Paloma Almendro, Vanessa Ametller, Elisabet Rios, Jose Choudhury, Sibgat Mancino, Mario Gascon, Pedro TI Differential expression of neurogenes among breast cancer subtypes identifies high risk patients SO ONCOTARGET LA English DT Article DE breast cancer; neurogenes; neuropeptides; neurotransmitters; tumor microenvironment ID AMYLOID PRECURSOR PROTEIN; NERVE GROWTH-FACTOR; PANCREATIC-CANCER; PROSTATE-CANCER; MOLECULAR PORTRAITS; ALZHEIMERS-DISEASE; GENE-EXPRESSION; MAMMARY-GLAND; CELL-LINES; STEM-CELLS AB The nervous system is now recognized to be a relevant component of the tumor microenvironment. Receptors for neuropeptides and neurotransmitters have been identified in breast cancer. However, very little is known about the role of neurogenes in regulating breast cancer progression. Our purpose was to identify neurogenes associated with breast cancer tumorigenesis with a potential to be used as biomarker and/or targets for treatment. We used three databases of human genes: GeneGo, GeneCards and Eugenes to generate a list of 1266 relevant neurogenes. Then we used bioinformatics tools to interrogate two published breast cancer databases SAGE and MicMa (n = 96) and generated a list of 7 neurogenes that are differentially express among breast cancer subtypes. The clinical potential was further investigated using the GOBO database (n = 1881). We identified 6 neurogenes that are differentially expressed among breast cancer subtypes and whose expression correlates with prognosis. Histamine receptor1 (HRH1), neuropilin2 (NRP2), ephrin-B1 (EFNB1), neural growth factor receptor (NGFR) and amyloid precursor protein (APP) were differentially overexpressed in basal and HER2-enriched tumor samples and syntaxin 1A (STX1A) was overexpressed in HER2-enriched and luminal B tumors. Analysis of HRH1, NRP2, and STX1A expression using the GOBO database showed that their expression significantly correlated with a shorter overall survival (p < 0.0001) and distant metastasis-free survival (p < 0.0001). In contrast, elevated co-expression of NGFR, EFNB1 and APP was associated with longer overall (p < 0.0001) and metastasis-free survival (p < 0.0001). We propose that HRH1, NRP2, and STX1A can be used as prognostic biomarkers and therapeutic targets for basal and HER2-enriched breast cancer subtypes. C1 [Fernandez-Nogueira, Patricia; Bragado, Paloma; Ametller, Elisabet; Mancino, Mario; Gascon, Pedro] Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain. [Ametller, Elisabet; Mancino, Mario; Gascon, Pedro] Inst Invest Biomed August Pi & Sunyer Barcelona, Barcelona, Spain. [Fernandez-Nogueira, Patricia; Gascon, Pedro] Univ Barcelona, Dept Med, Barcelona, Spain. [Almendro, Vanessa; Choudhury, Sibgat] Harvard Univ, Brigham & Womens Hosp, Med Sch,Dana Farber Canc Inst, Div Med Oncol,Dept Med, Boston, MA 02115 USA. [Rios, Jose] Hosp Clin Barcelona, IDIBAPS, Med Stat Core Facil, Barcelona, Spain. [Rios, Jose] Univ Autonoma Barcelona, Fac Med, Biostat Unit, E-08193 Barcelona, Spain. RP Mancino, M; Gascon, P (reprint author), Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain.; Mancino, M; Gascon, P (reprint author), Inst Invest Biomed August Pi & Sunyer Barcelona, Barcelona, Spain.; Gascon, P (reprint author), Univ Barcelona, Dept Med, Barcelona, Spain. EM mmancino@clinic.ub.es; gascon@clinic.ub.es FU Cellex Foundation; Instituto de Salud Carlos III (ISCIII)-Subdirecion General de Evaluacion y Fomento de Investigacion; Fondo Europeo de Desarollo Regional (FEDER) (The Fondo de Investigacion Sanitaria) [PI12/01706]; Fondo Europeo de Desarollo Regional (FEDER) (RTICC) [RD12/00360055]; APIF fellowship from the University of Barcelona; School of Medicine; Sara Borrell Fellowship program from ISCIII FX This work was supported by grants from the Cellex Foundation and from the Instituto de Salud Carlos III (ISCIII)-Subdirecion General de Evaluacion y Fomento de Investigacion, Fondo Europeo de Desarollo Regional (FEDER) (The Fondo de Investigacion Sanitaria (PI12/01706) and RTICC, RD12/00360055). P.F-N. is supported by an APIF fellowship from the University of Barcelona, School of Medicine. M.M. is supported by the Sara Borrell Fellowship program from ISCIII. The group is recognized as a consolidated research group by AGAUR (2014_SGR_530). NR 77 TC 2 Z9 2 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 2 PY 2016 VL 7 IS 5 BP 5313 EP 5326 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD5HD UT WOS:000369952800017 PM 26673618 ER PT J AU Zaynagetdinov, R Sherrill, TP Gleaves, LA Hunt, P Han, W McLoed, AG Saxon, JA Tanjore, H Gulleman, PM Young, LR Blackwell, TS AF Zaynagetdinov, Rinat Sherrill, Taylor P. Gleaves, Linda A. Hunt, Pierre Han, Wei McLoed, Allyson G. Saxon, Jamie A. Tanjore, Harikrishna Gulleman, Peter M. Young, Lisa R. Blackwell, Timothy S. TI Chronic NF-kappa B activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs SO ONCOTARGET LA English DT Article DE NF-kappa B; COPD; lung cancer; macrophage; tregs ID OBSTRUCTIVE PULMONARY-DISEASE; REGULATORY T-CELLS; RETINOIC ACID; BRONCHIAL BIOPSIES; MACROPHAGES; CARCINOGENESIS; EXPRESSION; BETA; TUMORIGENESIS; INFLAMMATION AB Nuclear Factor (NF)-kappa B is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated I kappa B kinase beta (IKK beta) in airway epithelium (IKTA), we found that sustained NF-kappa B signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4(+)/CD25(+)/FoxP3(+) regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8(+) lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3(+) Tregs ex vivo through expression of TGF beta and IL-10. Targeting of TGF beta and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-kappa B pathway links COPD and lung cancer through generation and maintenance of a pro-tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells. C1 [Zaynagetdinov, Rinat; Sherrill, Taylor P.; Gleaves, Linda A.; Hunt, Pierre; Han, Wei; Tanjore, Harikrishna; Young, Lisa R.; Blackwell, Timothy S.] Vanderbilt Univ, Dept Med, Sch Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA. [McLoed, Allyson G.; Saxon, Jamie A.; Blackwell, Timothy S.] Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37232 USA. [Blackwell, Timothy S.] US Dept Vet Affairs, Nashville, TN 37232 USA. [Gulleman, Peter M.; Young, Lisa R.] Vanderbilt Univ, Dept Pediat, Sch Med, Div Pulm Med, Nashville, TN 37232 USA. RP Zaynagetdinov, R (reprint author), Vanderbilt Univ, Dept Med, Sch Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA. EM rinat.z.zaynagetdinov@vanderbilt.edu FU Lung Cancer Initiative of North Carolina; National Institutes of Health [T32HL094296, R01 HL119503]; Department of Veterans Affairs Merit Review Award [1101BX002378]; Vanderbilt-Ingram Cancer Center Spore Grant; Free to Breathe FX This work was supported by a Grant from the Lung Cancer Initiative of North Carolina and Free to Breathe (R.Z.), by National Institutes of Health Grants T32HL094296 (R.Z.) and R01 HL119503 (L.R.Y), by the Department of Veterans Affairs Merit Review Award 1101BX002378 (T.S.B), and by a Vanderbilt-Ingram Cancer Center Spore Grant 2010 (T.S.B). NR 30 TC 2 Z9 2 U1 3 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 2 PY 2016 VL 7 IS 5 BP 5470 EP 5482 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD5HD UT WOS:000369952800028 PM 26756215 ER PT J AU Santhanakrishnan, R Wang, N Larson, MG Magnani, JW McManus, DD Lubitz, SA Ellinor, PT Cheng, S Vasan, RS Lee, DS Wang, TJ Levy, D Benjamin, EJ Ho, JE AF Santhanakrishnan, Rajalakshmi Wang, Na Larson, Martin G. Magnani, Jared W. McManus, David D. Lubitz, Steven A. Ellinor, Patrick T. Cheng, Susan Vasan, Ramachandran S. Lee, Douglas S. Wang, Thomas J. Levy, Daniel Benjamin, Emelia J. Ho, Jennifer E. TI Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction SO CIRCULATION LA English DT Article DE atrial fibrillation; epidemiology; heart failure; mortality; ventricular function; left ID VENTRICULAR SYSTOLIC DYSFUNCTION; PROGNOSTIC-SIGNIFICANCE; RISK; MORTALITY; PREVALENCE; DISEASE; STROKE; METAANALYSIS; COMMUNITY; FIBROSIS AB Background Atrial fibrillation (AF) and heart failure (HF) frequently coexist and together confer an adverse prognosis. The association of AF with HF subtypes has not been well described. We sought to examine differences in the temporal association of AF and HF with preserved versus reduced ejection fraction. Methods and Results We studied Framingham Heart Study participants with new-onset AF or HF between 1980 and 2012. Among 1737 individuals with new AF (mean age, 7512 years; 48% women), more than one third (37%) had HF. Conversely, among 1166 individuals with new HF (mean age, 79 +/- 11 years; 53% women), more than half (57%) had AF. Prevalent AF was more strongly associated with incident HF with preserved ejection fraction (multivariable-adjusted hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.48-3.70; no AF as referent) versus HF with reduced ejection fraction (HR, 1.32; 95% CI, 0.83-2.10), with a trend toward difference between HF subtypes (P for difference=0.06). Prevalent HF was associated with incident AF (HR, 2.18; 95% CI, 1.26-3.76; no HF as referent). The presence of both AF and HF portended greater mortality risk compared with neither condition, particularly among individuals with new HF with reduced ejection fraction and prevalent AF (HR, 2.72; 95% CI, 2.12-3.48) compared with new HF with preserved ejection fraction and prevalent AF (HR, 1.83; 95% CI, 1.41-2.37; P for difference=0.02). Conclusions AF occurs in more than half of individuals with HF, and HF occurs in more than one third of individuals with AF. AF precedes and follows HF with both preserved and reduced ejection fraction, with some differences in temporal association and prognosis. Future studies focused on underlying mechanisms of these dual conditions are warranted. C1 [Santhanakrishnan, Rajalakshmi; Magnani, Jared W.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Boston, MA 02215 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Magnani, Jared W.; Cheng, Susan; Vasan, Ramachandran S.; Lee, Douglas S.; Benjamin, Emelia J.; Ho, Jennifer E.] NHLBI, Bethesda, MD USA. [Larson, Martin G.; Magnani, Jared W.; Cheng, Susan; Vasan, Ramachandran S.; Benjamin, Emelia J.; Ho, Jennifer E.] Boston Univ, Framingham Heart Study, Boston, MA USA. [McManus, David D.; Benjamin, Emelia J.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Boston, MA 02125 USA. [Lubitz, Steven A.; Ellinor, Patrick T.; Ho, Jennifer E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.; Ho, Jennifer E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Broad Inst Harvard, Program Med Populat Genet, Cambridge, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] MIT, Cambridge, MA 02139 USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiol,Dept Med, Boston, MA USA. [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON M5S 1A1, Canada. [Lee, Douglas S.] Univ Toronto, Toronto Gen Hosp, Toronto, ON M5S 1A1, Canada. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. [Levy, Daniel] NHLBI, Div Intramural Res, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. RP Ho, JE (reprint author), Massachusetts Gen Hosp, CPZN 185 Cambridge St,3224, Boston, MA 02114 USA. EM jho1@mgh.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; National Institutes of Health [K23-HL116780, 1R01HL128914, 2R01HL092577, 3R01HL092577-06S1]; Boston University School of Medicine, Department of Medicine Career Investment Award (Boston, MA); National Institutes of Health/National Heart, Lung and Blood Institute [K23HL114724]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105] FX This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I). This work was supported by the National Institutes of Health (K23-HL116780 to Dr Ho, 1R01HL128914 to Dr Benjamin, 2R01HL092577 and 3R01HL092577-06S1 to Drs Benjamin and Ellinor). Dr Ho is supported by a Boston University School of Medicine, Department of Medicine Career Investment Award (Boston, MA). Dr Lubitz is supported by National Institutes of Health/National Heart, Lung and Blood Institute K23HL114724 and Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. NR 44 TC 18 Z9 19 U1 1 U2 6 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 FEB 2 PY 2016 VL 133 IS 5 BP 484 EP 492 DI 10.1161/CIRCULATIONAHA.115.018614 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DD1IB UT WOS:000369673400006 PM 26746177 ER PT J AU Tonelli, M Karumanchi, SA Thadhani, R AF Tonelli, Marcello Karumanchi, S. Ananth Thadhani, Ravi TI Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease SO CIRCULATION LA English DT Review DE dialysis; heart diseases; kidney diseases; stroke ID CHRONIC KIDNEY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; SUDDEN CARDIAC DEATH; STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; CONGESTIVE-HEART-FAILURE; ACUTE CORONARY SYNDROME; IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; LEFT-VENTRICULAR HYPERTROPHY; PRESERVED EJECTION FRACTION AB Patients with chronic kidney disease and end-stage renal disease are at 5- to 10-fold higher risk for developing cardiovascular disease (CVD) than age-matched controls. Clinically, CVD in this population manifests as coronary artery disease, arrhythmias, stroke, or congestive heart failure. Beyond the traditional risk factors (eg, diabetes mellitus and hypertension), uremia-specific factors that arise from accumulating toxins also contribute to the pathogenesis of CVD. In this review, we summarize the literature on the epidemiology of both traditional and uremia-related CVD and focus on postulated mechanisms of the latter. In the context of current and emerging diagnostics and therapies for CVD, we highlight what we interpret as major gaps in the medical management of this growing population that need to be addressed with targeted epidemiological and translational research. Finally, we describe the global challenges associated with the recognition and management of uremia-related CVD in developed and developing nations. C1 [Tonelli, Marcello] Univ Calgary, Dept Med, Calgary, AB T2N 1N4, Canada. [Karumanchi, S. Ananth] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med & Obstet & Gynecol, Boston, MA USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD USA. [Thadhani, Ravi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA USA. RP Tonelli, M (reprint author), Univ Calgary, 7th Floor,TRW Bldg,3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM tonelli.admin@ucalgary.ca RI Tonelli, Marcello/B-3028-2009 FU Population Health Scholar award from Alberta Innovates Health Solutions; Collaborative Research and Innovation Opportunity award; National Institutes of Health [K24 DK094872, R01 DK094486] FX Dr Tonelli was supported by a Population Health Scholar award from Alberta Innovates Health Solutions. This work was partially funded by an Collaborative Research and Innovation Opportunity award to the Interdisciplinary Collaborative Disease Collaboration (www.icdc.ca). Dr Thadhani is supported by National Institutes of Health grants K24 DK094872 and R01 DK094486. NR 236 TC 7 Z9 7 U1 5 U2 16 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 FEB 2 PY 2016 VL 133 IS 5 BP 518 EP 536 DI 10.1161/CIRCULATIONAHA.115.018713 PG 19 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DD1IB UT WOS:000369673400010 PM 26831434 ER PT J AU Hassan, A Ahlskog, JE Matsumoto, JY Milber, JM Bower, JH Wilkinson, JR AF Hassan, Anhar Ahlskog, J. Eric Matsumoto, Joseph Y. Milber, Joshua M. Bower, James H. Wilkinson, Jayne R. TI Orthostatic tremor Clinical, electrophysiologic, and treatment findings in 184 patients SO NEUROLOGY LA English DT Article ID MYOCLONUS AB Objective:To evaluate the clinical, electrophysiologic, and treatment outcome features of orthostatic tremor (OT) in a large case series.Methods:We performed medical record review of 184 patients who met clinical and electrodiagnostic criteria for OT from 1976 to 2013 at the Mayo Clinic. Demographic, clinical, electrophysiologic, and treatment data were extracted.Results:The majority of OT cases were female (63.6%) and mean age at onset was 59.3 years (range 13-85 years). Diagnosis was delayed by a mean of 7.2 years (range 0-44 years). The average tremor frequency was 15.7 Hz (range 12.5-20 Hz), and transmitted to the arms on weight-bearing (95.5%). Patients reported a spectrum of progressive orthostatic leg symptoms, relieved by sitting or leaning. Falls were reported in 24.1%. Coexistent neurologic disorders included essential tremor (22.8%), other tremor (4.9%), and parkinsonism (8.7%). Family history of OT was noted in 4.9%. Of 46 medications trialed, 24 failed to provide any benefit. Benzodiazepines provided at least mild benefit in 55.9%, and moderate to marked benefit in 31.5%; -blockers (31.0%) and anticonvulsants (25.0%) provided mild benefit, and the remainder were largely ineffective. Medication benefit waned over time. Deep brain stimulation (DBS) was effective in 2 cases.Conclusion:OT predominantly affects female seniors, and the diagnosis should be considered with any orthostatic-induced leg symptoms, and confirmed by surface EMG. Benzodiazepines are the most efficacious treatment, followed by -blockers and anticonvulsants. DBS should be further explored for treatment. C1 [Hassan, Anhar; Ahlskog, J. Eric; Matsumoto, Joseph Y.; Bower, James H.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Milber, Joshua M.] SUNY Downstate Coll Med, Brooklyn, NY USA. [Wilkinson, Jayne R.] Univ Penn, Philadelphia, PA 19104 USA. [Wilkinson, Jayne R.] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Philadelphia, PA USA. RP Hassan, A (reprint author), Mayo Clin, Dept Neurol, Rochester, MN USA. EM hassan.anhar@mayo.edu NR 15 TC 7 Z9 7 U1 1 U2 1 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 FEB 2 PY 2016 VL 86 IS 5 BP 458 EP 464 DI 10.1212/WNL.0000000000002328 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DD1HZ UT WOS:000369673200010 PM 26747880 ER PT J AU Prentice-Mott, HV Meroz, Y Carlson, A Levine, MA Davidson, MW Irimia, D Charras, GT Mahadevan, L Shah, JV AF Prentice-Mott, Harrison V. Meroz, Yasmine Carlson, Andreas Levine, Michael A. Davidson, Michael W. Irimia, Daniel Charras, Guillaume T. Mahadevan, L. Shah, Jagesh V. TI Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE confined cell migration; moesin; microtubules; chemotaxis; cell polarization ID POLYMORPHONUCLEAR LEUKOCYTES; NEUTROPHIL POLARIZATION; EUKARYOTIC CHEMOTAXIS; CHEMICAL GRADIENTS; MIGRATION; MOESIN; CORTEX; NETWORK; SIGNALS; EZRIN AB Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues. C1 [Prentice-Mott, Harrison V.; Levine, Michael A.; Shah, Jagesh V.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Prentice-Mott, Harrison V.; Levine, Michael A.; Shah, Jagesh V.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Prentice-Mott, Harrison V.; Meroz, Yasmine; Carlson, Andreas; Mahadevan, L.] Harvard Univ, Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Irimia, Daniel] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02129 USA. [Charras, Guillaume T.] UCL, London Ctr Nanotechnol, London WC1H 0AH, England. [Charras, Guillaume T.] UCL, Dept Cell & Dev Biol, Mortimer St, London WC1E 6BT, England. [Mahadevan, L.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Mahadevan, L.] Harvard Univ, Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Mahadevan, L.] Harvard Univ, Kavli Inst Nanobio Sci & Technol, Cambridge, MA 02138 USA. RP Shah, JV (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA.; Shah, JV (reprint author), Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA.; Mahadevan, L (reprint author), Harvard Univ, Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA.; Mahadevan, L (reprint author), Harvard Univ, Dept Phys, Cambridge, MA 02138 USA.; Mahadevan, L (reprint author), Harvard Univ, Organism & Evolutionary Biol, Cambridge, MA 02138 USA.; Mahadevan, L (reprint author), Harvard Univ, Kavli Inst Nanobio Sci & Technol, Cambridge, MA 02138 USA. EM lm@seas.harvard.edu; jagesh_shah@hms.harvard.edu RI Carlson, Andreas/G-9884-2016 OI Carlson, Andreas/0000-0002-3068-9983 FU BioMEMS Resource Center Grant [P41 EB002503]; Biological and Biotechnological Sciences Research Council Grant [BB/F021402]; Brigham and Women's Renal Division funds; National Science Foundation [BMMB 15-36616]; MacArthur Fellowship; Weizmann Institute of Science-National Postdoctoral Award Program for Advancing Women in Science FX The authors thank the members of the J. V. S. and L. M. laboratories and Tim Mitchison for valuable discussions. Microfabrication work was supported by BioMEMS Resource Center Grant P41 EB002503. This work was supported by Biological and Biotechnological Sciences Research Council Grant BB/F021402 (to G. T. C.), Brigham and Women's Renal Division funds (to J. V. S.), National Science Foundation Grant BMMB 15-36616 (to J. V. S. and L. M.), and a MacArthur Fellowship (to L. M.). Y. M. is an Awardee of the Weizmann Institute of Science-National Postdoctoral Award Program for Advancing Women in Science. NR 37 TC 3 Z9 3 U1 6 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 2 PY 2016 VL 113 IS 5 BP 1267 EP 1272 DI 10.1073/pnas.1513289113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2YO UT WOS:000369085100058 PM 26764383 ER PT J AU Carpio, MA Michaud, M Zhou, WP Fisher, JK Walensky, LD Katz, SG AF Carpio, Marcos A. Michaud, Michael Zhou, Wenping Fisher, Jill K. Walensky, Loren D. Katz, Samuel G. TI REPLY TO FERNANDEZ-MARRERO ET AL.: Role of BOK at the intersection of endoplasmic reticulum stress and apoptosis regulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID FAMILY-MEMBER BOK C1 [Carpio, Marcos A.; Michaud, Michael; Zhou, Wenping; Katz, Samuel G.] Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 USA. [Fisher, Jill K.; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Fisher, Jill K.; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA. RP Katz, SG (reprint author), Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 USA.; Walensky, LD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.; Walensky, LD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA. EM Loren_Walensky@dfci.harvard.edu; samuel.katz@yale.edu FU NHLBI NIH HHS [K08 HL103847, 5K08HL103847]; NIH HHS [S10 OD020142] NR 4 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 FEB 2 PY 2016 VL 113 IS 5 BP E494 EP E495 DI 10.1073/pnas.1521979113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC2YO UT WOS:000369085100002 PM 26811485 ER PT J AU Boutin, M Sun, Y Shacka, JJ Auray-Blais, C AF Boutin, Michel Sun, Ying Shacka, John J. Auray-Blais, Christiane TI Tandem Mass Spectrometry Multiplex Analysis of Glucosylceramide and Galactosylceramide Isoforms in Brain Tissues at Different Stages of Parkinson Disease SO ANALYTICAL CHEMISTRY LA English DT Article ID NEURONOPATHIC GAUCHER-DISEASE; ALPHA-SYNUCLEIN; GLUCOCEREBROSIDASE; ACCUMULATION; QUANTITATION; DEFICIENCY; QUADRUPOLE; BIOMARKERS; PLASMA; MODEL AB Previous studies demonstrated that Parkinson disease (PD) is associated with a decreased activity of the glucocerebrosidase (GCase) enzyme in brain tissues. The objective of this study was to determine if GCase deficiency is associated with the accumulation of its glucosylceramide (GluCer) substrate in PD brain tissues. An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed, optimized, and validated for the multiplex analysis of GluCer isoforms (C18:0, C20:0, C22:0, C24:1, and C24:0) in brain tissue samples. These molecules were chromatographically separated from their isobaric galactosylceramide (GalCer) counterparts using normal phase chromatography. The analysis was performed by tandem mass spectrometry in the multiple reaction monitoring (MRM) acquisition mode. Limits of detection ranging from 0.4 to 1.1 nmol/g brain tissue were established for the different GluCer isoforms analyzed. For the first time, GluCer isoform levels were analyzed in temporal cortex brain tissue samples from 26 PD patients who were divided into three PD disease stages (IIa, III, and IV) according to the Unified Staging System for Lewy Body Disorders. These specimens were compared with brain tissue samples from 12 controls and 6 patients with Incidental Lewy Body Disease. No significant GluCer concentration differences were observed between the 5 sample groups. The GluCer isoform levels were also normalized with their matching GalCer isoforms. The normalized results showed a trend for GluCer levels which increased with PD severity. However, the differences observed between the groups were not significant, owing likely to the high standard deviations measured. C1 [Boutin, Michel; Auray-Blais, Christiane] Univ Sherbrooke, Div Med Genet, Dept Pediat, Ctr Rech,CHUS,Fac Med & Hlth Sci, 3001,12th Ave North, Sherbrooke, PQ J1H 5N4, Canada. [Sun, Ying] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, R Bldg Room 1401,3333 Burnet Ave, Cincinnati, OH 45229 USA. [Shacka, John J.] Univ Alabama Birmingham, Dept Pathol, Mol & Cellular Pathol Div, 1670 Univ Blvd,VH G019H, Birmingham, AL 35294 USA. [Shacka, John J.] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. RP Auray-Blais, C (reprint author), Univ Sherbrooke, Div Med Genet, Dept Pediat, Ctr Rech,CHUS,Fac Med & Hlth Sci, 3001,12th Ave North, Sherbrooke, PQ J1H 5N4, Canada. EM christiane.auray-blais@usherbrooke.ca FU Michael J. Fox Foundation for Parkinson's Research FX This research was funded by the Michael J. Fox Foundation for Parkinson's Research. We are grateful to Waters Corporation for their continued scientific support and partnership. We would like to thank Michael P. Nelson, Ph.D. at University of Alabama at Birmingham for his support in preparing the brain tissue samples. We would like to sincerely thank Dr. Joe T. R. Clarke for his expertise and insight and Marie-Pierre Garant for statistical analysis support. NR 25 TC 2 Z9 2 U1 6 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD FEB 2 PY 2016 VL 88 IS 3 BP 1856 EP 1863 DI 10.1021/acs.analchem.5b04227 PG 8 WC Chemistry, Analytical SC Chemistry GA DC8LM UT WOS:000369471100053 PM 26735924 ER PT J AU Turcotte, R Mattson, JM Wu, JW Zhang, YH Lin, CP AF Turcotte, Raphael Mattson, Jeffrey M. Wu, Juwell W. Zhang, Yanhang Lin, Charles P. TI Molecular Order of Arterial Collagen Using Circular Polarization Second-Harmonic Generation Imaging SO BIOPHYSICAL JOURNAL LA English DT Article ID MICROSCOPY; TENDON AB Second-harmonic generation (SHG) originates from the interaction between upconverted fields from individual scatterers. This renders SHG microscopy highly sensitive to molecular distribution. Here, we aim to take advantage of the difference in SHG between aligned and partially aligned molecules to probe the degree of molecular order during biomechanical testing, independently of the absolute orientation of the scattering molecules. Toward this goal, we implemented a circular polarization SHG imaging approach and used it to quantify the intensity change associated with collagen fibers straightening in the arterial wall during mechanical stretching. We were able to observe the delayed alignment of collagen fibers during mechanical loading, thus demonstrating a simple method to characterize molecular distribution using intensity information alone. C1 [Turcotte, Raphael; Wu, Juwell W.; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Turcotte, Raphael; Wu, Juwell W.; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Turcotte, Raphael; Zhang, Yanhang] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Mattson, Jeffrey M.; Zhang, Yanhang] Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. RP Lin, CP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA.; Lin, CP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. EM lin@helix.mgh.harvard.edu FU NIH [U01 HL099997, R01 HL098028]; FRQNT PhD Fellowship; Wellman Center for Photomedicine Graduate Student Fellowship FX This work is supported in part by NIH grant Nos. U01 HL099997 (to C.L.P.) and NIH R01 HL098028 (to Y.Z.). R.T. was supported by a FRQNT PhD Fellowship and a Wellman Center for Photomedicine Graduate Student Fellowship. NR 17 TC 2 Z9 2 U1 5 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 2 PY 2016 VL 110 IS 3 BP 530 EP 533 DI 10.1016/j.bpj.2015.12.030 PG 4 WC Biophysics SC Biophysics GA DC8KH UT WOS:000369467800003 PM 26806883 ER PT J AU Merrins, MJ Poudel, C McKenna, JP Ha, J Sherman, A Bertram, R Satin, LS AF Merrins, Matthew J. Poudel, Chetan McKenna, Joseph P. Ha, Joon Sherman, Arthur Bertram, Richard Satin, Leslie S. TI Phase Analysis of Metabolic Oscillations and Membrane Potential in Pancreatic Islet beta-Cells SO BIOPHYSICAL JOURNAL LA English DT Article ID PULSATILE INSULIN-SECRETION; PURINE NUCLEOTIDE CYCLE; GLYCOLYTIC PATHWAY; CA2+; GLUCOSE; CALCIUM; MODEL; DEHYDROGENASE; ACTIVATION; MECHANISMS AB Metabolism in islet beta-cells displays oscillations that can trigger pulses of electrical activity and insulin secretion. There has been a decades-long debate among islet biologists about whether metabolic oscillations are intrinsic or occur in response to oscillations in intracellular Ca2+ that result from bursting electrical activity. In this article, the dynamics of oscillatory metabolism were investigated using five different optical reporters. Reporter activity was measured simultaneously with membrane potential bursting to determine the phase relationships between the metabolic oscillations and electrical activity. Our experimental findings suggest that Ca2+ entry into beta-cells stimulates the rate of mitochondrial metabolism, accounting for the depletion of glycolytic intermediates during each oscillatory burst. We also performed Ca2+ clamp tests in which we clamped membrane potential with the K-ATP channel-opener diazoxide and KCl to fix Ca2+ at an elevated level. These tests confirm that metabolic oscillations do not require Ca2+ oscillations, but show that Ca2+ plays a larger role in shaping metabolic oscillations than previously suspected. A dynamical picture of the mechanisms of oscillations emerged that requires the restructuring of contemporary mathematical beta-cell models, including our own dual oscillator model. In the companion article, we modified our model to account for these new data. C1 [Merrins, Matthew J.; Poudel, Chetan] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Endocrinol Diabet & Metab, Madison, WI USA. [Merrins, Matthew J.; Poudel, Chetan] Univ Wisconsin, Dept Biomol Chem, Sch Med & Publ Hlth, Madison, WI USA. [Merrins, Matthew J.; Poudel, Chetan] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [McKenna, Joseph P.; Bertram, Richard] Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. [McKenna, Joseph P.; Bertram, Richard] Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA. [McKenna, Joseph P.; Bertram, Richard] Florida State Univ, Program Mol Biophys, Tallahassee, FL 32306 USA. [Ha, Joon; Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Satin, Leslie S.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Satin, Leslie S.] Univ Michigan, Brehm Diabet Ctr, Ann Arbor, MI 48109 USA. RP Satin, LS (reprint author), Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA.; Satin, LS (reprint author), Univ Michigan, Brehm Diabet Ctr, Ann Arbor, MI 48109 USA. EM lsatin@umich.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK46409, K01-DK101683]; NIH FX This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases, including grants R01-DK46409 to L.S.S. and K01-DK101683 to M.J.M. A.S. and J.H. were supported by the Intramural Research Program of the NIH. NR 39 TC 4 Z9 4 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 2 PY 2016 VL 110 IS 3 BP 691 EP 699 DI 10.1016/j.bpj.2015.12.029 PG 9 WC Biophysics SC Biophysics GA DC8KH UT WOS:000369467800018 PM 26840733 ER PT J AU McKenna, JP Ha, J Merrins, MJ Satin, LS Sherman, A Bertram, R AF McKenna, Joseph P. Ha, Joon Merrins, Matthew J. Satin, Leslie S. Sherman, Arthur Bertram, Richard TI Ca2+ Effects on ATP Production and Consumption Have Regulatory Roles on Oscillatory Islet Activity SO BIOPHYSICAL JOURNAL LA English DT Article ID PANCREATIC BETA-CELLS; PULSATILE INSULIN-SECRETION; METABOLIC OSCILLATIONS; GLYCOLYTIC OSCILLATIONS; ELECTRICAL-ACTIVITY; GLUCOSE-METABOLISM; CALCIUM; PHOSPHOFRUCTOKINASE; MODEL; MEMBRANE AB Pancreatic islets respond to elevated blood glucose by secreting pulses of insulin that parallel oscillations in beta-cell metabolism, intracellular Ca2+ concentration, and bursting electrical activity. The mechanisms that maintain an oscillatory response are not fully understood, yet several models have been proposed. Only some can account for experiments supporting that metabolism is intrinsically oscillatory in beta-cells. The dual oscillator model (DOM) implicates glycolysis as the source of oscillatory metabolism. In the companion article, we use recently developed biosensors to confirm that glycolysis is oscillatory and further elucidate the coordination of metabolic and electrical signals in the insulin secretory pathway. In this report, we modify the DOM by incorporating an established link between metabolism and intracellular Ca2+ to reconcile model predictions with experimental observations from the companion article. With modification, we maintain the distinguishing feature of the DOM, oscillatory glycolysis, but introduce the ability of Ca2+ influx to reshape glycolytic oscillations by promoting glycolytic efflux. We use the modified model to explain measurements from the companion article and from previously published experiments with islets. C1 [McKenna, Joseph P.; Bertram, Richard] Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. [Ha, Joon; Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Merrins, Matthew J.] Univ Wisconsin, Dept Med, Div Endocrinol Diabet & Metab, Sch Med & Publ Hlth, Madison, WI USA. [Merrins, Matthew J.] Univ Wisconsin, Dept Biomol Chem, Sch Med & Publ Hlth, Madison, WI USA. [Merrins, Matthew J.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Satin, Leslie S.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Satin, Leslie S.] Univ Michigan, Brehm Diabet Ctr, Ann Arbor, MI 48109 USA. [Bertram, Richard] Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA. [Bertram, Richard] Florida State Univ, Program Mol Biophys, Tallahassee, FL 32306 USA. RP Bertram, R (reprint author), Florida State Univ, Dept Math, Tallahassee, FL 32306 USA.; Bertram, R (reprint author), Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA.; Bertram, R (reprint author), Florida State Univ, Program Mol Biophys, Tallahassee, FL 32306 USA. EM bertram@math.fsu.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK46409, K01-DK101683]; Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) FX This work was partially supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (grant No. R01-DK46409 to L.S.S. and grant No. K01-DK101683 to M.J.M.). A.S. and J.H. were supported by the Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases). NR 46 TC 1 Z9 1 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 2 PY 2016 VL 110 IS 3 BP 733 EP 742 DI 10.1016/j.bpj.2015.11.3526 PG 10 WC Biophysics SC Biophysics GA DC8KH UT WOS:000369467800022 PM 26840737 ER PT J AU Bradley, SM O'Donnell, CI Grunwald, GK Liu, CF Hebert, PL Maddox, TM Jesse, RL Fihn, SD Rumsfeld, JS Ho, PM AF Bradley, Steven M. O'Donnell, Colin I. Grunwald, Gary K. Liu, Chuan-Fen Hebert, Paul L. Maddox, Thomas M. Jesse, Robert L. Fihn, Stephan D. Rumsfeld, John S. Ho, P. Michael TI Facility Level Variation in Hospitalization, Mortality, and Costs in the 30 Days After Percutaneous Coronary Intervention: Insights on Short- Term Healthcare Value From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System (VA CART) Program Response SO CIRCULATION LA English DT Letter C1 [Bradley, Steven M.; O'Donnell, Colin I.; Grunwald, Gary K.; Maddox, Thomas M.; Rumsfeld, John S.; Ho, P. Michael] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. [Bradley, Steven M.; Maddox, Thomas M.; Rumsfeld, John S.; Ho, P. Michael] Univ Colorado, Sch Med, Aurora, CO USA. [O'Donnell, Colin I.; Grunwald, Gary K.] Univ Colorado, Sch Publ Hlth, Aurora, CO USA. [Liu, Chuan-Fen; Hebert, Paul L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Jesse, Robert L.; Fihn, Stephan D.] US Dept Vet Affairs, Vet Hlth Adm, Washington, DC USA. RP Bradley, SM (reprint author), VA Eastern Colorado Hlth Care Syst, Denver, CO USA.; Bradley, SM (reprint author), Univ Colorado, Sch Med, Aurora, CO USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 2 PY 2016 VL 133 IS 5 BP E377 EP E377 DI 10.1161/CIRCULATIONAHA.115.019552 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DD1IC UT WOS:000369673500005 PM 26831442 ER PT J AU Wasfy, JH Dominici, F Yeh, RW AF Wasfy, Jason H. Dominici, Francesca Yeh, Robert W. TI Facility Level Variation in Hospitalization, Mortality, and Costs in the 30 Days After Percutaneous Coronary Intervention: Insights on Short-Term Healthcare Value From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System (VA CART) Program SO CIRCULATION LA English DT Letter C1 [Wasfy, Jason H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. [Dominici, Francesca] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA USA. [Yeh, Robert W.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Smith Ctr Outcomes Res Cardiol, Boston, MA 02215 USA. RP Wasfy, JH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. FU NCI NIH HHS [P01 CA134294]; NHLBI NIH HHS [K23 HL118138]; NIGMS NIH HHS [R01 GM111339] NR 3 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 2 PY 2016 VL 133 IS 5 BP E376 EP E376 DI 10.1161/CIRCULATIONAHA.115.017851 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DD1IC UT WOS:000369673500004 PM 26831441 ER PT J AU Wang, F Kaplan, JL Gold, BD Bhasin, MK Ward, NL Kellermayer, R Kirschner, BS Heyman, MB Dowd, SE Cox, SB Dogan, H Steven, B Ferry, GD Cohen, SA Baldassano, RN Moran, CJ Garnett, EA Drake, L Otu, HH Mirny, LA Libermann, TA Winter, HS Korolev, KS AF Wang, Feng Kaplan, Jess L. Gold, Benjamin D. Bhasin, Manoj K. Ward, Naomi L. Kellermayer, Richard Kirschner, Barbara S. Heyman, Melvin B. Dowd, Scot E. Cox, Stephen B. Dogan, Haluk Steven, Blaire Ferry, George D. Cohen, Stanley A. Baldassano, Robert N. Moran, Christopher J. Garnett, Elizabeth A. Drake, Lauren Otu, Hasan H. Mirny, Leonid A. Libermann, Towia A. Winter, Harland S. Korolev, Kirill S. TI Detecting Microbial Dysbiosis Associated with Pediatric Crohn Disease Despite the High Variability of the Gut Microbiota SO CELL REPORTS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; RIBOSOMAL-RNA GENE; INTESTINAL MICROBIOTA; BACTERIAL; MICROORGANISMS; COMMUNITIES; DIVERSITY; RICHNESS; DATABASE; COLITIS AB The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis. C1 [Wang, Feng; Korolev, Kirill S.] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Kaplan, Jess L.; Moran, Christopher J.; Drake, Lauren; Winter, Harland S.] Harvard Univ, Sch Med, Dept Pediat, MassGen Hosp Children, Boston, MA 02114 USA. [Gold, Benjamin D.; Cohen, Stanley A.] Childrens Healthcare Atlanta LLC, Atlanta, GA 30342 USA. [Gold, Benjamin D.; Cohen, Stanley A.] GI Care Kids LLC, Atlanta, GA 30342 USA. [Bhasin, Manoj K.; Libermann, Towia A.] Beth Israel Deaconess Med Ctr, BIDMC Genom Prote Bioinformat & Syst Biol Ctr, Boston, MA 02115 USA. [Bhasin, Manoj K.; Libermann, Towia A.] Beth Israel Deaconess Med Ctr, Dept Med, Div Interdisciplinary Med & Biotechnol, Boston, MA 02115 USA. [Bhasin, Manoj K.; Libermann, Towia A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ward, Naomi L.; Steven, Blaire] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Kellermayer, Richard; Ferry, George D.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Kirschner, Barbara S.] Univ Chicago, Comer Childrens Hosp, Dept Pediat, Chicago, IL 60637 USA. [Heyman, Melvin B.; Garnett, Elizabeth A.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Dowd, Scot E.; Cox, Stephen B.] Mol Res MR DNA, Shallowater, TX 79363 USA. [Dogan, Haluk; Otu, Hasan H.] Univ Nebraska, Dept Elect & Comp Engn, Lincoln, NE 68588 USA. [Baldassano, Robert N.] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. [Mirny, Leonid A.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Korolev, Kirill S.] Boston Univ, Dept Phys, 590 Commonwealth Ave, Boston, MA 02215 USA. RP Korolev, KS (reprint author), Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA.; Winter, HS (reprint author), Harvard Univ, Sch Med, Dept Pediat, MassGen Hosp Children, Boston, MA 02114 USA.; Korolev, KS (reprint author), Boston Univ, Dept Phys, 590 Commonwealth Ave, Boston, MA 02215 USA. EM hwinter@partners.org; korolev@bu.edu FU Boston University; B. Hasso Family Foundation; Karen and Brock Wagner family; [NIH-R03 DK064544] FX Support was provided by the startup fund from Boston University (to K.S.K.; supported K.S.K. and F.W.). Some of the analysis was carried out on the Shared Computing Cluster at BU. Martin Schlaff (philanthropic support) and the B. Hasso Family Foundation provided support (to H.S.W.). The Houston Men of Distinction and the Gutsy Kids Fund was provided and supported by the Karen and Brock Wagner family (to R.K.). The authors would also like to acknowledge Antone Opekun for his work on this project. The PIBD-CC study was supported by NIH-R03 DK064544 (principal investigator, B.D. Gold; Role of Infectious Agents in Pediatric Crohn's Disease). NR 56 TC 4 Z9 4 U1 4 U2 10 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 FEB 2 PY 2016 VL 14 IS 4 BP 945 EP 955 DI 10.1016/j.celrep.2015.12.088 PG 11 WC Cell Biology SC Cell Biology GA DC3FH UT WOS:000369104500023 PM 26804920 ER PT J AU Guo, GJ Pinello, L Han, XP Lai, SJ Shen, L Lin, TW Zou, KY Yuan, GC Orkin, SH AF Guo, Guoji Pinello, Luca Han, Xiaoping Lai, Shujing Shen, Li Lin, Ta-Wei Zou, Keyong Yuan, Guo-Cheng Orkin, Stuart H. TI Serum-Based Culture Conditions Provoke Gene Expression Variability in Mouse Embryonic Stem Cells as Revealed by Single-Cell Analysis SO CELL REPORTS LA English DT Article ID MESSENGER-RNA-SEQ; SELF-RENEWAL; TRANSCRIPTIONAL HETEROGENEITY; GROUND-STATE; PLURIPOTENCY; MECHANISMS; NOISE AB Variation in gene expression is an important feature of mouse embryonic stem cells (ESCs). However, the mechanisms responsible for global gene expression variation in ESCs are not fully understood. We performed single-cell mRNA-seq analysis of mouse ESCs and uncovered significant heterogeneity in ESCs cultured in serum. We define highly variable gene clusters with distinct chromatin states and show that bivalent genes are prone to expression variation. At the same time, we identify an ESC-priming pathway that initiates the exit from the naive ESC state. Finally, we provide evidence that a large proportion of intracellular network variability is due to the extracellular culture environment. Serum-free culture reduces cellular heterogeneity and transcriptome variation in ESCs. C1 [Guo, Guoji; Han, Xiaoping; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Hematol Oncol, 44 Binney St, Boston, MA 02115 USA. [Guo, Guoji; Han, Xiaoping; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Pinello, Luca; Yuan, Guo-Cheng] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Guo, Guoji; Han, Xiaoping; Lai, Shujing] Zhejiang Univ, Sch Med, Ctr Stem Cell & Regenerat Med, Hangzhou 310058, Zhejiang, Peoples R China. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Lin, Ta-Wei] Boston Childrens Hosp, Mol Genet Core Facil, Boston, MA 02115 USA. [Zou, Keyong] Boston Open Labs, Cambridge, MA 02138 USA. [Shen, Li] Zhejiang Univ, Sch Med, Inst Life Sci, Hangzhou 310058, Zhejiang, Peoples R China. RP Guo, GJ; Orkin, SH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Hematol Oncol, 44 Binney St, Boston, MA 02115 USA.; Guo, GJ; Orkin, SH (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02115 USA.; Yuan, GC (reprint author), Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Guo, GJ (reprint author), Zhejiang Univ, Sch Med, Ctr Stem Cell & Regenerat Med, Hangzhou 310058, Zhejiang, Peoples R China.; Orkin, SH (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA. EM ggj@zju.edu.cn; gcyuan@jimmy.harvard.edu; stuart_orkin@dfci.harvard.edu FU NIH [R01HG5085]; Harvard Stem Cell Institute; 1000 Talent Plan from China; Fundamental Research Funds for the Central Universities; NHGRI Career Development Award [K99HG008399] FX We thank Y. Fujiwara, M. Nguyen, H.E. Benjamin, A. Saadatpour, E. Marco, and Z. Shao for help on experiments and Y. Zhang, Z. Li, H. Ouyang, Y. Zhou, and J. Ji for insightful discussions on the project. This work was supported by funding from NIH and the Harvard Stem Cell Institute (S.H.O). S.H.O. is an investigator of the Howard Hughes Medical Institute (HHMI). G.-C. Y. is supported by NIH grant R01HG5085. G.G. is supported by the 1000 Talent Plan from China and the Fundamental Research Funds for the Central Universities. L.P. is supported by NHGRI Career Development Award K99HG008399. NR 37 TC 5 Z9 6 U1 3 U2 11 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 FEB 2 PY 2016 VL 14 IS 4 BP 956 EP 965 DI 10.1016/j.celrep.2015.12.089 PG 10 WC Cell Biology SC Cell Biology GA DC3FH UT WOS:000369104500024 PM 26804902 ER PT J AU Lee, CT Tao, CY Stoupel, J AF Lee, Chun-Teh Tao, Chih-Yun Stoupel, Janet TI The Effect of Subepithelial Connective Tissue Graft Placement on Esthetic Outcomes After Immediate Implant Placement: Systematic Review SO JOURNAL OF PERIODONTOLOGY LA English DT Review DE Dental implants; esthetics, dental; evidence-based dentistry; periodontics; treatment outcome ID FRESH EXTRACTION SOCKETS; SINGLE-TOOTH REPLACEMENT; FOLLOW-UP; ROOT-COVERAGE; CASE SERIES; GINGIVAL DIMENSIONS; KERATINIZED GINGIVA; RIDGE AUGMENTATION; PROSPECTIVE COHORT; CLINICAL-TRIAL AB Background: Immediate implantation, despite many advantages, carries a risk of gingival recession, papilla loss, collapse of ridge contour, and other esthetic complications. Soft tissue graft placement combined with immediate implantation may be used to reduce these concerns. This review aims to systematically analyze clinical esthetic outcomes of the immediate implant combined with soft tissue graft (IMITG). Methods: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews were used. The electronic search was conducted using MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 to October 2014. Quality assessments of selected articles were performed. Mid-buccal gingival level, interproximal gingival level, facial gingival thickness, gingival ridge dimension, and width of keratinized gingiva were the esthetic outcomes reviewed. Weighted mean difference of mid-buccal gingival level (WDBGL), papilla index score (WDPIS), and width of keratinized gingiva (WDKG) between initial and last measurements were calculated. Other esthetic outcomes were assessed by the descriptive analysis. Results: Ten studies with a minimum of 6-month follow-up were included, and reported esthetic outcomes were analyzed. Mid-buccal gingival level (WDBGL, 0.07 mm; 95% confidence interval [CI] = -0.44 to 0.59; P = 0.12) and interproximal gingival level did not significantly change after IMITG (WDPIS in the mesial site, 0.31; 95% CI = -0.01 to 0.64; P = 0.06; and WDPIS in the distal site, 0.29; 95% CI = -0.06 to 0.65; P = 0.11). Width of keratinized gingiva significantly increased after IMITG (WDKG, 1.27 mm; 95% CI = -0.08 to 2.46; P = 0.04). Facial gingival thickness and gingival ridge dimension could be increased after IMITG. Conclusions: Because of the heterogeneity and limited number of selected studies, no conclusive statement could be made regarding the benefit of IMITG on esthetic outcomes. More randomized controlled trials are needed to provide definite clinical evidence. C1 [Lee, Chun-Teh] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Tao, Chih-Yun] Univ Texas Hlth Sci Ctr Houston, Dept Periodont & Dent Hyg, Houston, TX 77030 USA. [Stoupel, Janet] Natl Taiwan Univ, Sch Dent, Dept Dent, Taipei 10764, Taiwan. [Stoupel, Janet] Columbia Univ, Coll Dent Med, Sect Oral & Diagnost Sci, Div Periodont, 630 W 168th St, New York, NY 10032 USA. RP Stoupel, J (reprint author), Columbia Univ, Coll Dent Med, Sect Oral & Diagnost Sci, Div Periodont, 630 W 168th St, New York, NY 10032 USA. EM js108@cumc.columbia.edu NR 66 TC 1 Z9 1 U1 8 U2 19 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD FEB 2 PY 2016 VL 87 IS 2 BP 156 EP 167 DI 10.1902/jop.2015.150383 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DC3PZ UT WOS:000369132500011 PM 26469808 ER PT J AU Mao, ZG Wu, JH Dong, TT Wu, MX AF Mao, Zhigang Wu, Jeffrey H. Dong, Tingting Wu, Mei X. TI Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10 SO SCIENTIFIC REPORTS LA English DT Article ID HYPERBARIC-OXYGEN THERAPY; LASER THERAPY; FOOT ULCERS; RATS; SKIN; ANGIOGENESIS; COENZYME-Q10; INJURY; TRIAL; CARE AB Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68 similar to 103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study. C1 [Mao, Zhigang] Shanghai Jiao Tong Univ, Sch Med, ShangHai People Hosp 9, Shanghai 200030, Peoples R China. [Mao, Zhigang; Wu, Jeffrey H.; Dong, Tingting; Wu, Mei X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Wu, MX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. EM mwu5@mgh.harvard.edu FU Department of Defense/Air Force Office of Scientific Research Military Photomedicine Program [W81XWH-13-2-0067]; Department of Defense; CDMRP/BAA; Wellman Center; [FA9550-11-1-0331]; [FA9550-13-1-0068] FX The authors would like to thank all the members in the Photopathology Core at Wellman Center for experimental assistance with histopathology and microscopy and members in Dr. Hamblin's and Dr. Wu's groups at Wellman Center for Photomedicine for stimulating discussions. This work is supported in part by FA9550-11-1-0331 and FA9550-13-1-0068, Department of Defense/Air Force Office of Scientific Research Military Photomedicine Program, W81XWH-13-2-0067, Department of Defense, CDMRP/BAA, and Wellman Center found to MXW. NR 34 TC 3 Z9 3 U1 4 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 2 PY 2016 VL 6 AR 20084 DI 10.1038/srep20084 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC3RG UT WOS:000369135800002 PM 26830658 ER PT J AU Murphy, SA Cannon, CP Blazing, MA Giugliano, RP White, JA Lokhnygina, Y Reist, C Im, K Bohula, EA Isaza, D Lopez-Sendon, J Dellborg, M Kher, U Tershakovec, AM Braunwald, E AF Murphy, Sabina A. Cannon, Christopher P. Blazing, Michael A. Giugliano, Robert P. White, Jennifer A. Lokhnygina, Yuliya Reist, Craig Im, KyungAh Bohula, Erin A. Isaza, Daniel Lopez-Sendon, Jose Dellborg, Mikael Kher, Uma Tershakovec, Andrew M. Braunwald, Eugene TI Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome The IMPROVE-IT Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ezetimibe; low-density lipoprotein cholesterol; simvastatin; total events ID MODERATE STATIN THERAPY; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIALS; END-POINTS; HIGH-RISK; ATORVASTATIN; METAANALYSIS; CHOLESTEROL; SIMVASTATIN; EFFICACY AB BACKGROUND Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin. OBJECTIVES This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy. METHODS All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization >= 30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis. RESULTS Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005). CONCLUSIONS Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878) (C) 2016 by the American College of Cardiology Foundation. C1 [Murphy, Sabina A.; Cannon, Christopher P.; Giugliano, Robert P.; Im, KyungAh; Bohula, Erin A.; Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Murphy, Sabina A.; Cannon, Christopher P.; Giugliano, Robert P.; Im, KyungAh; Bohula, Erin A.; Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. [Blazing, Michael A.; White, Jennifer A.; Lokhnygina, Yuliya; Reist, Craig] Duke Clin Res Inst, Durham, NC USA. [Isaza, Daniel] Fdn Cardioinfantil, Inst Cardiol, Bogota, Cundinamarca, Colombia. [Lopez-Sendon, Jose] Hosp Univ La Paz, Dept Cardiol, Madrid, Spain. [Dellborg, Mikael] Univ Gothenburg, Ostra & Sahlgrenska Acad, Sahlgrenska Univ Hospital, Gothenburg, Sweden. [Kher, Uma; Tershakovec, Andrew M.] Merck & Co Inc, Kenilworth, NJ USA. RP Murphy, SA (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM smurphy15@partners.org FU Merck and Co., Inc.; Merck and Co.; Amarin; Accumentrics; Arisaph; Janssen; Boehringer-Ingelheim; GlaxoSmithKline; Merck; Takeda; Bristol-Myers Squibb; CSL Behring; Essentialis; Kowa; Lipimedix; Pfizer; Regeneron; Sanofi; Amgen; Novartis; AstraZeneca; Daiichi-Sankyo; CVS Caremark; Sanofi Aventis; Medicines Company; Menarini International; Bayer; Medscape FX The IMPROVE-IT study was sponsored by Merck and Co., Inc. Ms. Murphy has received fees from Merck and Co. and Amarin. Dr. Cannon has received grant support from Accumentrics, Arisaph, and Janssen; grant support and personal fees from Boehringer-Ingelheim, GlaxoSmithKline, Merck, and Takeda; and personal fees from Bristol-Myers Squibb, CSL Behring, Essentialis, Kowa, Lipimedix, Pfizer, Regeneron, and Sanofi. Dr. Blazing received support from Merck during the conduct of the study; and has received personal fees from Merck, Sanofi, Amgen, Novartis, AstraZeneca, and Pfizer. Dr. Giugliano received grant support from Merck during the conduct of the study; has received grant support and personal fees from Amgen; and personal fees from Merck, Daiichi-Sankyo, Pfizer, CVS Caremark, Regeneron, and Sanofi. Dr. Bohula has received fees from Merck. Dr. Lopez-Sendon has received research grants form Merck, AstraZeneca, and GlaxoSmithKline; and honoraria from AstraZeneca and Sanofi. Dr. Dellborg has received honoraria from Merck, AstraZeneca, and Servier; and advisory board fees from Merck, AstraZeneca, Pfizer, and Amgen. Drs. Kher and Tershakovec are employees of Merck Sharp & Dohme Corp., and hold stock/stock options in the company. Dr. Braunwald received support from Merck during the conduct of the study; and has received personal fees from Daiichi-Sankyo, Sanofi Aventis, The Medicines Company, Menarini International, Bayer, and Medscape. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 25 TC 23 Z9 23 U1 3 U2 9 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 FEB 2 PY 2016 VL 67 IS 4 BP 353 EP 361 DI 10.1016/j.jacc.2015.10.077 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DB6HO UT WOS:000368615600001 PM 26821621 ER PT J AU Chen-Scarabelli, C Scarabelli, TM AF Chen-Scarabelli, Carol Scarabelli, Tiziano M. TI Cyclosporine A Prior to Primary PCI in STEMI Patients The Coup de Grace to Post-Conditioning? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardioprotection; coronary occlusion; infarct size; mitochondrial permeability transition pores; myocardial reperfusion injury ID ELEVATION MYOCARDIAL-INFARCTION; REPERFUSION; INJURY; TRIAL; CARDIOPROTECTION C1 [Chen-Scarabelli, Carol; Scarabelli, Tiziano M.] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Scarabelli, Tiziano M.] Univ Alabama Birmingham, Div Cardiovasc Dis, 1530 3rd Ave,South Tinsley Harrison Tower, Birmingham, AL 35294 USA. RP Scarabelli, TM (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, 1530 3rd Ave,South Tinsley Harrison Tower, Birmingham, AL 35294 USA. EM tscarabelli@uabmc.edu NR 14 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 2 PY 2016 VL 67 IS 4 BP 375 EP 378 DI 10.1016/j.jacc.2015.11.024 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DB6HO UT WOS:000368615600004 PM 26821624 ER PT J AU Keenan, T Zhao, W Rasheed, A Ho, WK Malik, R Felix, JF Young, R Shah, N Samuel, M Sheikh, N Mucksavage, ML Shah, O Li, J Morley, M Laser, A Mallick, NH Zaman, KS Ishaq, M Rasheed, SZ Memon, FUR Ahmed, F Hanif, B Lakhani, MS Fahim, M Ishaq, M Shardha, NK Ahmed, N Mahmood, K Iqbal, W Akhtar, S Raheel, R O'Donnell, CJ Hengstenberg, C Marz, W Kathiresan, S Samani, N Goel, A Hopewell, JC Chambers, J Cheng, YC Sharma, P Yang, Q Rosand, J Boncoraglio, GB Kazmi, SU Hakonarson, H Kottgen, A Kalogeropoulos, A Frossard, P Kamal, A Dichgans, M Cappola, T Reilly, MP Danesh, J Rader, DJ Voight, BF Saleheen, D AF Keenan, Tanya Zhao, Wei Rasheed, Asif Ho, Weang K. Malik, Rainer Felix, Janine F. Young, Robin Shah, Nabi Samuel, Maria Sheikh, Nasir Mucksavage, Megan L. Shah, Omar Li, Jin Morley, Michael Laser, Annika Mallick, Nadeem Hayat Zaman, Khan Shah Ishaq, Mohammad Rasheed, Syed Zahed Memon, Fazal-ur-Rehman Ahmed, Faisal Hanif, Bashir Lakhani, Muhammad Shakir Fahim, Muhammad Ishaq, Madiha Shardha, Naresh Kumar Ahmed, Naveeduddin Mahmood, Khalid Iqbal, Waseem Akhtar, Saba Raheel, Rabia O'Donnell, Christopher J. Hengstenberg, Christian Maerz, Winifred Kathiresan, Sekar Samani, Nilesh Goel, Anuj Hopewell, Jemma C. Chambers, John Cheng, Yu-Ching Sharma, Pankaj Yang, Qiong Rosand, Jonathan Boncoraglio, Giorgio B. Kazmi, Shahana Urooj Hakonarson, Hakon Koettgen, Anna Kalogeropoulos, Andreas Frossard, Philippe Kamal, Ayeesha Dichgans, Martin Cappola, Thomas Reilly, Muredach P. Danesh, John Rader, Daniel J. Voight, Benjamin F. Saleheen, Danish TI Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE genetic; pleiotropy; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; URIC-ACID; BLOOD-PRESSURE; GENETIC-VARIANTS; COMMON VARIANTS; ISCHEMIC-STROKE; ARTERY-DISEASE; INCREASED RISK; LOCI AB BACKGROUND Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. OBJECTIVES Through a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). METHODS This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. RESULTS Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. CONCLUSIONS Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions. (C) 2016 by the American College of Cardiology Foundation. C1 [Keenan, Tanya; Zhao, Wei; Mucksavage, Megan L.; Shah, Omar; Kathiresan, Sekar; Reilly, Muredach P.; Rader, Daniel J.; Saleheen, Danish] Univ Penn, Translat Med & Human Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Keenan, Tanya; Kathiresan, Sekar] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rasheed, Asif; Shah, Nabi; Samuel, Maria; Fahim, Muhammad; Ishaq, Madiha; Shardha, Naresh Kumar; Akhtar, Saba; Raheel, Rabia; Frossard, Philippe; Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Ho, Weang K.; Young, Robin; Sheikh, Nasir; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Malik, Rainer; Dichgans, Martin] Univ Munich, Med Ctr, Inst Stroke & Dementia Res ISD, Munich, Germany. [Felix, Janine F.] Erasmus MC, Dept Epidemiol, Univ Med Ctr Rotterdam, Amsterdam, Netherlands. [Felix, Janine F.] NGI NCHA, Leiden, Netherlands. [Li, Jin; Hakonarson, Hakon] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Morley, Michael] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Laser, Annika] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Laser, Annika] Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Mallick, Nadeem Hayat] Punjab Inst Cardiol, Lahore, Pakistan. [Zaman, Khan Shah] Natl Inst Cardiovasc Dis, Karachi, Pakistan. [Ishaq, Mohammad; Rasheed, Syed Zahed] Karachi Inst Heart Dis, Karachi, Pakistan. [Memon, Fazal-ur-Rehman] Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan. [Ahmed, Faisal] Liaquat Natl Hosp, Dept Cardiol, Karachi, Pakistan. [Hanif, Bashir; Lakhani, Muhammad Shakir] Tabba Heart Inst, Dept Cardiol, Karachi, Pakistan. [Ahmed, Naveeduddin] Liaquat Natl Hosp, Dept Neurol, Karachi, Pakistan. [Mahmood, Khalid] Dow Univ Hlth Sci, Civil Hosp, Dept Med, Karachi, Pakistan. [Iqbal, Waseem] Lahore Gen Hosp, Dept Med, Lahore, Pakistan. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hengstenberg, Christian] Univ Hosp Regensburg, Internal Med Cardiol 2, Regensburg, Germany. [Maerz, Winifred] Med Univ Graz, Clin Inst Med, Graz, Austria. [Maerz, Winifred] Med Univ Graz, Chem Lab Diagnost, Graz, Austria. [Maerz, Winifred] Heidelberg Univ, Mannheim Med Fac, Med Clin 5, Mannheim, Germany. [Maerz, Winifred] Synlab Lab Serv GmbH, Synlab Acad, Mannheim, Germany. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Samani, Nilesh] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Clin Sci Wing, Leicester, Leics, England. [Goel, Anuj] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hopewell, Jemma C.] Univ Oxford, Div Cardiovasc Sci, Oxford, England. [Chambers, John] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Cheng, Yu-Ching] Univ Maryland, Sch Med, Dept Med, Baltimore VA Med Ctr, Baltimore, MD 21201 USA. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, London, England. [Sharma, Pankaj] Hammersmith Hosp, London, England. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Div Neurocrit Care, Boston, MA 02114 USA. [Boncoraglio, Giorgio B.] Fdn IRCCS Ist Neurol, Dept Cerebrovasc Dis, Milan, Italy. [Kazmi, Shahana Urooj] Univ Karachi, Dept Microbiol, Karachi, Pakistan. [Koettgen, Anna] Univ Freiburg, Renal Div, Univ Med Ctr Freiburg, Hugstetter Str 55, D-79106 Freiburg, Germany. [Koettgen, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Kalogeropoulos, Andreas] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Kamal, Ayeesha] Aga Khan Univ, Div Neurol, Dept Med, Karachi, Pakistan. [Cappola, Thomas; Reilly, Muredach P.] Univ Penn, Cardiovasc Div, Perelman Sch Med, Philadelphia, PA 19104 USA. [Voight, Benjamin F.] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Voight, Benjamin F.] Univ Penn, Dept Genet, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. RP Voight, BF (reprint author), Univ Penn, Dept Syst Pharmacol & Translat Therapeut, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Voight, BF (reprint author), Univ Penn, Dept Genet, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Saleheen, D (reprint author), Univ Penn, Dept Biostat & Epidemiol, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bvoight@upenn.edu; saleheen@mail.med.upenn.edu RI Boncoraglio, Giorgio/B-8647-2011; OI Zhao, Wei/0000-0002-8301-9297 FU Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8]; [FP6 LSHM-CT-2007-037273] FX For the CEDIR (Cerebrovascular Diseases Registry) (Milano, Italy), the authors would like to acknowledge: Eugenio A. Parati and Emilio Ciusani from Fondazione IRCCS Istituto Neurologico "Carlo Besta" of Milan, who contributed to collection and genotyping of cases within CEDIR (Cerebrovascular Diseases Registry), funded by Annual Research Funding of the Italian Ministry of Health (Grant Numbers: RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8). Simona Barlera and Maria Grazia Franzosi from Istituto di Ricerche Farmacologiche "Mario Negri" of Milan contributed to collection and genotyping of the PROCARDIS controls, funded by FP6 LSHM-CT-2007-037273. NR 49 TC 8 Z9 8 U1 5 U2 11 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 FEB 2 PY 2016 VL 67 IS 4 BP 407 EP 416 DI 10.1016/j.jacc.2015.10.086 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DB6HO UT WOS:000368615600009 PM 26821629 ER PT J AU Ignatiadis, M Azim, HA Desmedt, C Veys, I Larsimont, D Salgado, R Lyng, MB Viale, G Leyland-Jones, B Giobbie-Hurder, A Kammler, R Dell'Orto, P Rothe, F Laios, I Ditzel, HJ Regan, MM Piccart, M Michiels, S Sotiriou, C AF Ignatiadis, Michail Azim, Hatem A., Jr. Desmedt, Christine Veys, Isabelle Larsimont, Denis Salgado, Roberto Lyng, Maria B. Viale, Giuseppe Leyland-Jones, Brian Giobbie-Hurder, Anita Kammler, Rosita Dell'Orto, Patrizia Rothe, Francoise Laios, Ioanna Ditzel, Henrik J. Regan, Meredith M. Piccart, Martine Michiels, Stefan Sotiriou, Christos TI The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence SO JAMA ONCOLOGY LA English DT Article ID POSTMENOPAUSAL WOMEN; GENE-EXPRESSION; ADJUVANT CHEMOTHERAPY; INTERNATIONAL KI67; RANDOMIZED-TRIAL; PREDICTIVE-VALUE; CLINICAL-TRIAL; WORKING GROUP; FOLLOW-UP; TAMOXIFEN AB IMPORTANCE The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required. OBJECTIVE To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation. DESIGN, SETTING, AND PARTICIPANTS This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log 2-transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value. INTERVENTIONS Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67. MAIN OUTCOMES AND MEASURES Distant recurrence-free interval (DRFI). RESULTS Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic information to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99%(95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94%(95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87%(95% CI, 80%-94%). CONCLUSIONS AND RELEVANCE Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade, the GG assay can identify a higher proportion of endocrine-only treated patients with very low risk of distant recurrence at 10 years. C1 [Ignatiadis, Michail; Azim, Hatem A., Jr.; Desmedt, Christine; Salgado, Roberto; Rothe, Francoise; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab, Brussels, Belgium. [Ignatiadis, Michail; Piccart, Martine; Sotiriou, Christos] Univ Libre Bruxelles, Med Oncol Clin, Inst Jules Bordet, Dept Med, Brussels, Belgium. [Veys, Isabelle] Univ Libre Bruxelles, Inst Jules Bordet, Dept Breast & Gynecol Surg, Brussels, Belgium. [Larsimont, Denis; Laios, Ioanna] Univ Libre Bruxelles, Inst Jules Bordet, Dept Pathol, Brussels, Belgium. [Lyng, Maria B.; Ditzel, Henrik J.] Univ Southern Denmark, Inst Mol Med, Odense, Denmark. [Lyng, Maria B.; Ditzel, Henrik J.] Danish Breast Canc Cooperat Grp, Copenhagen, Denmark. [Viale, Giuseppe; Dell'Orto, Patrizia] Univ Milan, European Inst Oncol, Dept Pathol, Milan, Italy. [Leyland-Jones, Brian] Avera Canc Inst, Sioux Falls, SD USA. [Giobbie-Hurder, Anita; Regan, Meredith M.] Dana Farber Canc Inst, Int Breast Canc Study Grp, Ctr Stat, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kammler, Rosita] Coordinating Ctr, Int Breast Canc Study, Bern, Switzerland. [Kammler, Rosita] Cent Pathol Off, Bern, Switzerland. [Ditzel, Henrik J.] Odense Univ Hosp, Dept Oncol, Odense, Denmark. [Ditzel, Henrik J.] Odense Univ Hosp, AgeCare, Odense, Denmark. [Michiels, Stefan] Gustave Roussy, Serv Biostat & Epidemiol, Villejuif, France. [Michiels, Stefan] Univ Paris Sud, CESP, INSERM U1018, Villejuif, France. RP Sotiriou, C (reprint author), Inst Jules Bordet, Breast Canc Translat Res Lab BCTL, Blvd Waterloo,121, B-1000 Brussels, Belgium. EM christos.sotiriou@bordet.be OI Ditzel, Henrik J./0000-0003-3927-5135; Desmedt, Christine/0000-0002-5223-5579 FU Breast Cancer Research Foundation (BCRF); Les Amis de l'Institut Bordet; Novartis; Swedish Cancer Society; Cancer Council Australia; Australian New Zealand Breast Cancer Trials Group; Frontier Science and Technology Research Foundation; Swiss Group for Clinical Cancer Research (SAKK); US National Institutes of Health (NIH) [CA-75362]; Cancer Research Switzerland/Oncosuisse FX This study was supported by grants from the Breast Cancer Research Foundation (BCRF), and Les Amis de l'Institut Bordet. The BIG 1-98 trial was sponsored by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Support for the IBCSG was provided by the Swedish Cancer Society, Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), US National Institutes of Health (NIH) (grant No. CA-75362), and Cancer Research Switzerland/Oncosuisse. NR 31 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD FEB PY 2016 VL 2 IS 2 BP 217 EP 224 DI 10.1001/jamaoncol.2015.4377 PG 8 WC Oncology SC Oncology GA DW5JL UT WOS:000383680200015 PM 26633571 ER PT J AU Johnson, DB Sullivan, RJ Ott, PA Carlino, MS Khushalani, NI Ye, F Guminski, A Puzanov, I Lawrence, DP Buchbinder, EI Mudigonda, T Spencer, K Bender, C Lee, J Kaufman, HL Menzies, AM Hassel, JC Mehnert, JM Sosman, JA Long, GV Clark, JI AF Johnson, Douglas B. Sullivan, Ryan J. Ott, Patrick A. Carlino, Matteo S. Khushalani, Nikhil I. Ye, Fei Guminski, Alexander Puzanov, Igor Lawrence, Donald P. Buchbinder, Elizabeth I. Mudigonda, Tejaswi Spencer, Kristen Bender, Carolin Lee, Jenny Kaufman, Howard L. Menzies, Alexander M. Hassel, Jessica C. Mehnert, Janice M. Sosman, Jeffrey A. Long, Georgina V. Clark, Joseph I. TI Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders SO JAMA ONCOLOGY LA English DT Article ID METASTATIC MELANOMA; ADVERSE EVENTS; PHASE-II; RHEUMATOID-ARTHRITIS; SAFETY; CTLA-4; TRANSPLANTATION; DEFICIENT; BLOCKADE; EFFICACY AB IMPORTANCE Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE Ipilimumab therapy. MAIN OUTCOMES AND MEASURES Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring. C1 [Johnson, Douglas B.; Puzanov, Igor; Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Sullivan, Ryan J.; Lawrence, Donald P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ott, Patrick A.; Buchbinder, Elizabeth I.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Carlino, Matteo S.; Lee, Jenny] Westmead & Blacktown Hosp, Dept Med, Crown Princess Mary Canc Ctr, Sydney, NSW, Australia. [Carlino, Matteo S.; Guminski, Alexander; Menzies, Alexander M.; Long, Georgina V.] Univ Sydney, Dept Med, Sydney, NSW, Australia. [Khushalani, Nikhil I.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Ye, Fei] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA. [Guminski, Alexander; Lee, Jenny; Menzies, Alexander M.; Long, Georgina V.] Melanoma Inst Australia, Dept Med, Sydney, NSW, Australia. [Mudigonda, Tejaswi] Vanderbilt Univ, Med Ctr, Sch Med, Nashville, TN 37232 USA. [Spencer, Kristen; Mehnert, Janice M.] Rutgers Canc Inst New Jersey, Dept Med, New Brunswick, NJ USA. [Bender, Carolin; Hassel, Jessica C.] Univ Heidelberg Hosp, Dept Med, Heidelberg, Germany. [Kaufman, Howard L.] Rutgers Canc Inst New Jersey, Dept Surg, New Brunswick, NJ USA. [Clark, Joseph I.] Loyola Univ, Med Ctr, Dept Med, Maywood, IL 60153 USA. RP Johnson, DB (reprint author), Vanderbilt Univ, Med Ctr, 2220 Pierce Ave,777 Preston Res Bldg, Nashville, TN 37232 USA. EM douglas.b.johnson@vanderbilt.edu FU National Institutes of Health (NIH) grant [K12 CA0906525] FX This stuty was supported by National Institutes of Health (NIH) grant K12 CA0906525 (Dr Johnson). NR 32 TC 37 Z9 37 U1 6 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD FEB PY 2016 VL 2 IS 2 BP 234 EP 240 DI 10.1001/jamaoncol.2015.4368 PG 7 WC Oncology SC Oncology GA DW5JL UT WOS:000383680200018 PM 26633184 ER PT J AU Konstantinidis, IT Arkadopoulos, N Ferrone, CR AF Konstantinidis, Ioannis T. Arkadopoulos, Nikolaos Ferrone, Cristina R. TI Surgical management of intrahepatic cholangiocarcinoma in the modern era: advances and challenges SO CHINESE CLINICAL ONCOLOGY LA English DT Review DE Intrahepatic cholangiocarcinoma (ICC); surgical resection; minimally invasive approaches; intraarterial therapies (IATs); proton beam therapy (PBT); multimodality treatment ID LAPAROSCOPIC LIVER RESECTION; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; BILIARY-TRACT CANCER; PROTON-BEAM THERAPY; PHASE-II TRIAL; STEREOTACTIC BODY RADIOTHERAPY; HEPATOCELLULAR-CARCINOMA; UNRESECTABLE CHOLANGIOCARCINOMA; MULTIINSTITUTIONAL ANALYSIS; Y-90 RADIOEMBOLIZATION AB Intrahepatic cholangiocarcinoma (ICC) is one of the few gastrointestinal cancers with increasing incidence and mortality worldwide. Unlike hepatocellular carcinoma (HCC) which arises usually in a cirrhotic environment ICC frequently arises in the context of normal hepatic parenchyma. Surgical resection represents the mainstay of curative treatment, with minimally invasive approaches being increasingly utilized. Despite good surgical outcomes, most patients suffer from disease recurrence and eventually succumb to their disease. Effective adjuvant treatments are therefore needed. For unresectable disease hepatic artery utilization techniques are becoming more widely used. New treatments for non metastatic disease such as proton beam therapy (PBT) are also emerging. Systemic chemotherapy is also changing and targeted biologic agents are being added to conventional chemotherapeutic agents. C1 [Konstantinidis, Ioannis T.; Ferrone, Cristina R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Konstantinidis, Ioannis T.] Univ Arizona, Dept Surg, Tucson, AZ 85721 USA. [Konstantinidis, Ioannis T.; Arkadopoulos, Nikolaos] Univ Athens, Sch Med, Attikon Hosp, Dept Surg 4, Athens, Greece. RP Ferrone, CR (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang 460,15 Parkman St, Boston, MA 02114 USA. EM cferrone@partners.org NR 90 TC 0 Z9 0 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2304-3865 EI 2304-3873 J9 CHIN CLIN ONCOL JI Chin. Clin. Oncol. PD FEB PY 2016 VL 5 IS 1 AR UNSP 9 DI 10.3978/j.issn.2304-3865.2016.02.06 PG 11 WC Oncology SC Oncology GA EB7OL UT WOS:000387577700009 PM 26932433 ER PT J AU Rachh, P Wilkins, G Capodilupo, TA Kilroy, S Schnider, M Repper-Delisi, J AF Rachh, Pratik Wilkins, Gianna Capodilupo, Theresa A. Kilroy, Susan Schnider, Maureen Repper-Delisi, Jennifer TI Redesigning the Patient Observer Model to Achieve Increased Efficiency and Staff Engagement on a Surgical Trauma Inpatient Unit SO JOINT COMMISSION JOURNAL ON QUALITY AND PATIENT SAFETY LA English DT Article ID SITTER-REDUCTION PROGRAM; CONSTANT OBSERVATION; OLDER PERSONS; DELIRIUM; CARE; FALLS; SETTINGS; QUALITY; COSTS AB Background: Provision of safe and efficient observer care to inpatients whose behavior puts them at risk for injury is a clinically challenging and costly endeavor for hospitals. At Massachusetts General Hospital (MGH; Boston), process improvement strategies were deployed to provide staff with an improved clinical model for patient observation, unitbased responsibility for allocating resources, and strategies to maintain a safer environment. Methods: In a surgical trauma unit at MGH, a team of nursing leaders and clinicians created an innovative process to identify, assess, and develop best practices for ensuring patient safety in the hospital environment. Patients with delirium were identified as the most prevalent and concerning patient group, and specific interventions were developed to address their unique needs. From December 2012 through June 2014, the team successfully piloted the best practices (July 16, 2013-September 30, 2013) and implemented them. Results: The baseline outcome metric of patient observer direct-care hours decreased from a median of 208 hours/week (January 1, 2012-July 13, 2013) to a median of 112 hours/week (July 14, 2013-June 28, 2014); a 46% decrease in utilization. Fall rate (falls per 1,000 patient-days) remained unchanged postimplementation, and staff satisfaction with the patient observer model increased from 9% to 72%, while costs associated with providing observer care remained stable. Conclusions: Providing the inpatient unit staff with the knowledge and tools needed to optimally manage patients with at-risk behaviors, including delirium, significantly decreased the number of staff hours spent at the bedside providing observation, did not negatively affect the unit fall rate, and increased staff engagement at no additional expense to the unit. C1 [Rachh, Pratik; Wilkins, Gianna] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Rachh, Pratik] Emory Univ, Dept Radiol & Imaging Sci, Atlanta, GA 30322 USA. [Capodilupo, Theresa A.] Massachusetts Gen Hosp, Dept Patient Care Serv, Boston, MA 02114 USA. RP Wilkins, G (reprint author), Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. EM gwilkins@partners.org NR 38 TC 0 Z9 0 U1 1 U2 1 PU JOINT COMMISSION RESOURCES INC PI OAK BROOK PA 1515 W 22 ST, STE 1300W, OAK BROOK, IL 60523 USA SN 1553-7250 EI 1938-131X J9 JT COMM J QUAL PATIE JI Jt. Comm. J. Qual. Patient Saf. PD FEB PY 2016 VL 42 IS 2 BP 77 EP + PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB7FJ UT WOS:000387551600004 PM 26803036 ER PT J AU Carson, AP Muntner, P Selvin, E Carnethon, MR Li, XL Gross, MD Garvey, WT Lewis, CE AF Carson, April P. Muntner, Paul Selvin, Elizabeth Carnethon, Mercedes R. Li, Xuelin Gross, Myron D. Garvey, W. Timothy Lewis, Cora E. TI Do glycemic marker levels vary by race? Differing results from a cross-sectional analysis of individuals with and without diagnosed diabetes SO BMJ OPEN DIABETES RESEARCH & CARE LA English DT Article ID HEMOGLOBIN A(1C) LEVELS; GLYCATED ALBUMIN; ALTERNATIVE MARKERS; BLOOD-GLUCOSE; RISK; 1,5-ANHYDROGLUCITOL; FRUCTOSAMINE; ADULTS; ASSOCIATION; MELLITUS AB Objective: It is well known that A1c varies by race. However, racial differences in other biomarkers of hyperglycemia are less well characterized. The objective of this study was to determine whether average levels of glycemic markers differ by race in adults with and without diagnosed diabetes, before and after accounting for postchallenge glucose. Research design and methods: This cross-sectional study included 2692 middle-aged men and women (5.5% with diagnosed diabetes; 44% African-American; and 56% white) from the Coronary Artery Risk Development in Young Adults Study (2005-2006) who had fasting glucose, 2-hour postchallenge glucose, A1c, glycated albumin, fructosamine, and 1,5-anhydroglucitol (1,5-AG) measured. Multiple linear regression was used to evaluate racial differences in mean levels of each glycemic marker stratified by the diabetes status and adjusted for sociodemographics, cardiovascular factors, and postchallenge glucose. Results: Among those with diagnosed diabetes, racial differences were not observed for any of the glycemic markers. In contrast, among those without diagnosed diabetes, African-Americans had higher mean levels than whites of A1c (beta=0.19% points; 95% CI 0.14 to 0.24), glycated albumin (beta=0.82% points; 95% CI 0.68 to 0.97), fructosamine (beta=8.68 mu mol/L; 95% CI 6.68 to 10.68), and 2-hour glucose (beta=3.50 mg/dL; 95% CI 0.10 to 6.90) after multivariable adjustment, whereas there were no statistically significant racial difference in 1,5-AG. The racial differences observed for A1c, glycated albumin, and fructosamine persisted after further adjustment for fasting and 2-hour glucose and were of similar magnitude (SD units). Conclusions: Racial differences in glycemic marker levels were evident among middle-aged adults without diagnosed diabetes even after adjustment for postchallenge glucose. Whether these racial differences in biomarkers of hyperglycemia affect the risk of complications warrants additional study. C1 [Carson, April P.; Muntner, Paul] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Selvin, Elizabeth] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Li, Xuelin; Lewis, Cora E.] Univ Alabama Birmingham, Sch Med, Div Prevent Med, Birmingham, AL USA. [Gross, Myron D.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Sch Hlth Profess, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. RP Carson, AP (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. EM apcarson@uab.edu FU NCATS NIH HHS [UL1 TR000165, UL1 TR001417]; NHLBI NIH HHS [HHSN268200900041C, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, R01 HL053560]; NIDDK NIH HHS [K01 DK095928, F32 DK009528, K24 DK106414, P30 DK079626] NR 33 TC 3 Z9 3 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2052-4897 J9 BMJ OPEN DIAB RES CA JI BMJ Open Diab. Res. Care PD FEB PY 2016 VL 4 IS 1 AR e000213 DI 10.1136/bmjdrc-2016-000213 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA1DQ UT WOS:000386333100047 PM 27335652 ER PT J AU Spasovski, G Busic, M Delmonico, F AF Spasovski, Goce Busic, Mirela Delmonico, Francis TI Improvement in kidney transplantation in the Balkans after the Istanbul Declaration: where do we stand today? SO CLINICAL KIDNEY JOURNAL LA English DT Review DE deceased donation; Declaration of Istanbul; kidney transplantation; living donation; SEE Health Network ID ORGAN DONATION; RENAL-TRANSPLANTATION AB Due to the limited access to kidney transplantation (KTx) in developing countries, desperate patients have engaged in the purchase and sale of kidneys. In 2004, the World Health Assembly urged member states to protect the poor and vulnerable from being exploited through practices of illegal organ trafficking that had become widespread throughout the world. In 2008, the international transplant community convened a summit of transplant professionals, legal experts and ethicists to combat organ trafficking, transplant tourism and transplant commercialism that resulted in the Declaration of Istanbul (DOI). The South-Eastern Europe Health Network (SEEHN) represents a nine country multigovernmental collaboration on health systems. The Regional Health Development Centre on Organ Donation and Transplant Medicine (RHDC) was established in 2011 in Croatia to facilitate cooperation among south-eastern European countries to improve organ transplantation within the Balkan region. Since 2011, a collaboration between the RHDC, the Custodian Group of the DOI (DICG) and SEEHN professionals has enhanced strategic planning and definition of country-specific action plan priorities on organ donation and transplantation. Data of kidney transplantation provided in this report show a significant increase in transplantation activities in a 4-year period in Macedonia, Moldova, Bosnia and Hercegovina, Romania and Montenegro. The success of the donation and transplantation programmes was influenced by the engagement of key professionals and the establishment of organizational infrastructure with the implementation of an appropriate funding model. In conclusion, the DOI has provided an ethical framework for engagement of health professionals from south-eastern European countries. The newly established SEEHN RHDC as a technical coordinating body greatly contributed in building institutional capacity and strengthening regional collaboration between health authorities and professionals within these countries for improvement of transplant activities in the Balkans. C1 [Spasovski, Goce] Univ Skopje, Dept Nephrol, Skopje, Macedonia. [Spasovski, Goce] South Eastern Europe Hlth Network Reg Hlth Dev Ct, Steering Comm, Skopje, Macedonia. [Busic, Mirela] Minist Hlth, South Eastern Europe Hlth Network Reg Hlth Dev Ct, Zagreb, Croatia. [Delmonico, Francis] Harvard Med Sch, Massachusetts Gen Hosp, Transplant Ctr, Boston, MA USA. RP Spasovski, G (reprint author), Univ Skopje, Dept Nephrol, Skopje, Macedonia.; Spasovski, G (reprint author), South Eastern Europe Hlth Network Reg Hlth Dev Ct, Steering Comm, Skopje, Macedonia. EM spasovski.goce@gmail.com NR 16 TC 1 Z9 1 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1753-0784 EI 1753-0792 J9 CLIN KIDNEY J JI Clin. Kidney J. PD FEB PY 2016 VL 9 IS 1 BP 172 EP 175 DI 10.1093/ckj/sfv116 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DZ8OC UT WOS:000386128800027 PM 26798481 ER PT J AU Auriel, E Charidimou, A Gurol, E Ni, J Van Etten, ES Martinez-Ramirez, S Boulouis, G Piazza, F Di Francesco, JC Frosch, MP Pontes-Neto, OM Shoamanesh, A Reijmer, Y Vashkevich, A Ayres, AM Schwab, KM Viswanathan, A Greenberg, SM AF Auriel, Eitan Charidimou, Andreas Gurol, Edip Ni, Jun Van Etten, Ellis S. Martinez-Ramirez, Sergi Boulouis, Gregoire Piazza, Fabrizio Di Francesco, Jacopo C. Frosch, Matthew P. Pontes-Neto, Octavio M. Shoamanesh, Ashkan Reijmer, Yael Vashkevich, Anastasia Ayres, Alison M. Schwab, Kristin M. Viswanathan, Anand Greenberg, Steven M. TI Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation SO JAMA NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; SUPERFICIAL SIDEROSIS; IMAGING ABNORMALITIES; STEREOTACTIC BIOPSY; HEMORRHAGE; BAPINEUZUMAB; LESIONS AB IMPORTANCE Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an important diagnosis to reach in clinical practice because many patients with the disease respond to immunosuppressive therapy. Reliable noninvasive diagnostic criteria for CAA-ri would allow some patients to avoid the risk of brain biopsy. OBJECTIVE To test the sensitivity and specificity of clinical and neuroimaging-based criteria for CAA-ri. DESIGN, SETTING, AND PARTICIPANTS We modified the previously proposed clinicoradiological criteria and retrospectively analyzed clinical medical records and magnetic resonance imaging fluid-attenuated inversion recovery and gradient-echo scans obtained from individuals with CAA-ri and noninflammatory CAA. At 2 referral centers between October 1, 1995, and May 31, 2013, and between January 1, 2009, and December 31, 2011, participants included 17 individuals with pathologically confirmed CAA-ri and 37 control group members with pathologically confirmed noninflammatory CAA. The control group was further divided into those with past lobar intracerebral hemorrhage (ICH) (n = 21) and those with cerebral microbleeds only and no history of ICH (n = 16). The dates of our analysis were September 1, 2012, to August 31, 2015. MAIN OUTCOMES AND MEASURES The sensitivity and specificity of prespecified criteria for probable CAA-ri (requiring asymmetric white matter hyperintensities extending to the subcortical white matter) and possible CAA-ri (not requiring the white matter hyperintensities to be asymmetric). RESULTS The 17 patients in the CAA-ri group were a mean (SD) of 68 (8) years and 8 (47%) were women. In the CAA-ri group, 14 of 17 (82%) met the criteria for both probable and possible CAA-ri. In the control group having noninflammatory CAA with lobar ICH, 1 of 21 (5%) met the criteria for possible CAA-ri, and none met the criteria for probable CAA-ri. In the control group having noninflammatory CAA with no ICH, 11 of 16 (69%) met the criteria for possible CAA-ri, and 1 of 16 (6%) met the criteria for probable CAA-ri. These findings yielded a sensitivity and specificity of 82% and 97%, respectively, for the probable criteria and a sensitivity and specificity of 82% and 68%, respectively, for the possible criteria. CONCLUSIONS AND RELEVANCE Our data suggest that a reliable diagnosis of CAA-ri can be reached from basic clinical and magnetic resonance imaging information alone, with good sensitivity and excellent specificity. C1 [Auriel, Eitan; Charidimou, Andreas; Gurol, Edip; Ni, Jun; Van Etten, Ellis S.; Martinez-Ramirez, Sergi; Boulouis, Gregoire; Pontes-Neto, Octavio M.; Shoamanesh, Ashkan; Reijmer, Yael; Vashkevich, Anastasia; Ayres, Alison M.; Schwab, Kristin M.; Viswanathan, Anand; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Ste 300, Boston, MA 02114 USA. [Auriel, Eitan; Charidimou, Andreas; Gurol, Edip; Ni, Jun; Van Etten, Ellis S.; Martinez-Ramirez, Sergi; Boulouis, Gregoire; Frosch, Matthew P.; Pontes-Neto, Octavio M.; Shoamanesh, Ashkan; Reijmer, Yael; Vashkevich, Anastasia; Ayres, Alison M.; Schwab, Kristin M.; Viswanathan, Anand; Greenberg, Steven M.] Harvard Med Sch, 175 Cambridge St,Ste 300, Boston, MA 02114 USA. [Auriel, Eitan; Piazza, Fabrizio; Di Francesco, Jacopo C.; Greenberg, Steven M.] Univ Milano Bicocca, Inflammatory Cerebral Amyloid Angiopathy & Alzhei, Monza, Italy. [Piazza, Fabrizio; Di Francesco, Jacopo C.] Univ Milano Bicocca, Milan Ctr Neurosci, Sch Med & Surg, Monza, Italy. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Neuropathol Serv, Boston, MA 02114 USA. [Shoamanesh, Ashkan] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Ste 300, Boston, MA 02114 USA.; Greenberg, SM (reprint author), Harvard Med Sch, 175 Cambridge St,Ste 300, Boston, MA 02114 USA. EM sgreenberg@partners.org RI Piazza, Fabrizio/L-2094-2016; OI Piazza, Fabrizio/0000-0002-3385-3224; DiFrancesco, Jacopo C./0000-0002-4102-1188; Boulouis, Gregoire/0000-0001-8422-9205 FU National Institutes of Health [R01AG26484]; University of Milano-Bicocca [12-1-2002100-2015]; Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease Biomarkers-Italy Study Group of the Italian Society of Neurology for the Study of Dementia FX This project was supported by grant R01AG26484 from the National Institutes of Health (Dr Greenberg), by competitive research fund 12-1-2002100-2015 from the University of Milano-Bicocca, and by The Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease Biomarkers-Italy Study Group of the Italian Society of Neurology for the Study of Dementia. NR 25 TC 11 Z9 13 U1 2 U2 3 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 FEB PY 2016 VL 73 IS 2 BP 197 EP 202 DI 10.1001/jamaneurol.2015.4078 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DZ4QY UT WOS:000385845500011 PM 26720093 ER PT J AU Davis, SR Worsley, R Miller, KK Parish, SJ Santoro, N AF Davis, Susan R. Worsley, Roisin Miller, Karen K. Parish, Sharon J. Santoro, Nanette TI Androgens and Female Sexual Function and Dysfunction-Findings From the Fourth International Consultation of Sexual Medicine SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Androgens; Testosterone; Dehydroepiandrosterone; Female Sexual Function and Dysfunction ID SURGICALLY MENOPAUSAL WOMEN; PLACEBO-CONTROLLED-TRIAL; HORMONE-BINDING GLOBULIN; INTRAVAGINAL DEHYDROEPIANDROSTERONE PRASTERONE; PREMATURE OVARIAN FAILURE; BREAST-CANCER INCIDENCE; QUALITY-OF-LIFE; POSTMENOPAUSAL WOMEN; TESTOSTERONE PATCH; DESIRE DISORDER AB Introduction: Androgens have been implicated as important for female sexual function and dysfunction. Aim: To review the role of androgens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of androgen therapy for female sexual dysfunction (FSD). Methods: We searched the literature using online databases for studies pertaining to androgens and female sexual function. Major reviews were included and their findings were summarized to avoid replicating their content. Main Outcome Measures: Quality of data published in the literature and recommendations were based on the GRADES system. Results: The literature supports an important role for androgens in female sexual function. There is no blood androgen level below which women can be classified as having androgen deficiency. Clinical trials have consistently demonstrated that transdermal testosterone (T) therapy improves sexual function and sexual satisfaction in women who have been assessed as having hypoactive sexual desire disorder. The use of T therapy is limited by the lack of approved formulations for women and long-term safety data. Most studies do not support the use of systemic dehydroepiandrosterone therapy for the treatment of FSD in women with normally functioning adrenals or adrenal insufficiency. Studies evaluating the efficacy and safety of vaginal testosterone and dehydroepiandrosterone for the treatment of vulvovaginal atrophy are ongoing. Conclusion: Available data support an important role of androgens in female sexual function and dysfunction and efficacy of transdermal T therapy for the treatment of some women with FSD. Approved T formulations for women are generally unavailable. In consequence, the prescribing of T mostly involves off-label use of T products formulated for men and individually compounded T formulations. Long-term studies to determine the safety of T therapy for women and possible benefits beyond that of sexual function are greatly needed. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. C1 [Davis, Susan R.; Worsley, Roisin] Monash Univ, Sch Publ Hlth & Prevent Med, Womens Hlth Res Program, Level 6,99 Commercial Rd, Melbourne, Vic 3004, Australia. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Res Program Womens Hlth, Boston, MA 02114 USA. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine & Pituitary Clin Ctr, Boston, MA 02114 USA. [Parish, Sharon J.] Weill Cornell Med Coll, New York, NY USA. [Santoro, Nanette] Univ Colorado, Sch Med, Aurora, CO USA. RP Davis, SR (reprint author), Monash Univ, Sch Publ Hlth & Prevent Med, Womens Hlth Res Program, Level 6,99 Commercial Rd, Melbourne, Vic 3004, Australia. EM Susan.Davis@monash.edu OI Worsley, Roisin/0000-0001-9201-1222 FU National Health and Medical Research Council [1041853] FX S.R.D. is a National Health and Medical Research Council Research Fellow (grant 1041853). NR 101 TC 5 Z9 5 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD FEB PY 2016 VL 13 IS 2 BP 168 EP 178 DI 10.1016/j.jsxm.2015.12.033 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DX9OX UT WOS:000384726100004 PM 26953831 ER PT J AU Ionescu, DF Fava, M Kim, DJH Baer, L Shelton, RC Cusin, C AF Ionescu, Dawn F. Fava, Maurizio Kim, Daniel Ju Hyung Baer, Lee Shelton, Richard C. Cusin, Cristina TI A placebo-controlled crossover study of iloperidone augmentation for residual anger and irritability in major depressive disorder SO THERAPEUTIC ADVANCES IN PSYCHOPHARMACOLOGY LA English DT Article DE anger; augmentation; iloperidone; irritability; major depressive disorder ID ANTIDEPRESSANT TREATMENT; QUESTIONNAIRE; SCHIZOPHRENIA; ATTACKS; SCALE; AGGRESSION; SYMPTOMS; EFFICACY; BINDING AB Background: Even when patients experience remission with antidepressants, many continue to report anger attacks and excessive irritability despite continued treatment. Iloperidone antagonizes 5-HT-2a, D2, and alpha-1 receptors, which can have anti-aggressive effects. We examined iloperidone's safety and efficacy as an augmentation agent in outpatients with partially remitted major depressive disorder (MDD) with residual symptoms of anger and irritability. Methods: A total of 13 outpatients with partially remitted MDD [currently treated with selective serotonin reuptake inhibitors (SSRIs)] received four weeks of iloperidone or placebo, followed by one week of washout. Patients were then crossed over to the other treatment arm for 4 weeks. Treatment arms were randomized and double blind; and two sites were used for the study. Analyses compared treatment response using the Symptom Questionnaire (SQ) Anger/Hostility Subscale as the primary outcome measure. Results: There was no significant differential effect of iloperidone x weeks on the SQ Anger/Hostility Subscore over the course of the study, compared with placebo x weeks, regardless of administration order (p = 0.77). Conclusions: Iloperidone did not significantly outperform placebo on measures of anger or irritability in patients with partially remitted MDD and residual anger/irritability. C1 [Fava, Maurizio] Harvard Med Sch, Depress Clin & Res Program, Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. [Ionescu, Dawn F.; Kim, Daniel Ju Hyung; Baer, Lee; Cusin, Cristina] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Ionescu, Dawn F.; Baer, Lee; Cusin, Cristina] Harvard Med Sch, Boston, MA USA. [Shelton, Richard C.] Univ Alabama Birmingham, Dept Psychiat, Birmingham, AL USA. RP Fava, M (reprint author), Harvard Med Sch, Depress Clin & Res Program, Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. EM mfava@partners.org RI Ionescu, Dawn/K-5675-2015 NR 25 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2045-1253 J9 THER ADV PSYCHOPHARM JI Ther. Adv. Psychopharm. PD FEB PY 2016 VL 6 IS 1 BP 4 EP 12 DI 10.1177/2045125315618621 PG 9 WC Psychiatry SC Psychiatry GA DY3EY UT WOS:000384974800002 PM 26913173 ER PT J AU Berry, ABL Butler, KA Harrington, C Braxton, MO Walker, AJ Pete, N Johnson, T Oberle, MW Haselkorn, J Nichol, WP Haselkorn, M AF Berry, Andrew B. L. Butler, Keith A. Harrington, Craig Braxton, Melissa O. Walker, Amy J. Pete, Nikki Johnson, Trevor Oberle, Mark W. Haselkorn, Jodie Nichol, W. Paul Haselkorn, Mark TI Using conceptual work products of health care to design health IT SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Model-based design; Health IT; Electronic health record; Workflow; Conceptual work products; Case management; Information architecture; User interface; Human-computer interaction ID TASK-ANALYSIS; FRAMEWORK AB This paper introduces a new, model -based design method for interactive health information technology (IT) systems. This method extends workflow models with models of conceptual work products. When the health care work being modeled is substantially cognitive, tacit, and complex in nature, graphical workflow models can become too complex to be useful to deigners. Conceptual models complement and simplify workflows by providing an explicit specification for the information product they must produce. We illustrate how conceptual work products can be modeled using standard software modeling language, which allows them to provide fundamental requirements for what the workflow must accomplish and the information that a new system should provide. Developers can use these specifications to envision how health IT could enable an effective cognitive strategy as a workflow with precise information requirements. We illustrate the new method with a study conducted in an outpatient multiple sclerosis (MS) clinic. This study shows specifically how the different phases of the method can be carried out, how the method allows for iteration across phases, and how the method generated a health IT design for case management of MS that is efficient and easy to use. (C) 2015 Elsevier Inc. All rights reserved. C1 [Berry, Andrew B. L.; Butler, Keith A.; Braxton, Melissa O.; Pete, Nikki; Johnson, Trevor; Haselkorn, Mark] Univ Washington, Dept Human Ctr Design & Engn, Coll Engn, Campus Box 352315, Seattle, WA 98195 USA. [Harrington, Craig] Univ Texas Houston, Sch Biomed Informat, 7000 Fannin St,Suite 600, Houston, TX 77030 USA. [Walker, Amy J.] Univ Washington, Sch Nursing, 1959 NE Pacific St, Seattle, WA 98195 USA. [Oberle, Mark W.] Univ Washington, Sch Publ Hlth, Box 357230, Seattle, WA 98195 USA. [Haselkorn, Jodie; Nichol, W. Paul] Vet Affairs Puget Sound Hlth Care Syst, 1660 South Columbian Way, Seattle, WA 98108 USA. RP Butler, KA (reprint author), Univ Washington, Dept Human Ctr Design & Engn, Coll Engn, Campus Box 352315, Seattle, WA 98195 USA. EM ablberry@uw.edu; Keith.A.Butler@gmail.com; craig.j.harrington@uth.tmc.edu; braxtm@uw.edu; walkeraj@uw.edu; peten@uw.edu; trevorj@uw.edu; moberle@uw.edu; Jodie.Haselkorn@va.gov; Paul.Nichol@va.gov; markh@uw.edu FU Agency for Healthcare Research and Quality [R01HS021233]; VA Puget Sound Health Care System, Seattle, Washington FX This project was supported by Grant Number R01HS021233 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. This material is the result of work supported by resources from the VA Puget Sound Health Care System, Seattle, Washington. We gratefully acknowledge participation by the VHA MS COE West and VHA Office of Informatics and Analytics. The research with human subjects was conducted in accordance with UW IRB 40065, VA IRB MIRB0553, and UT-Houston IRB HSC-SBMI-14-0136. We would like to thank Dr. Lucas McCarthy for his analysis of data feasibility, Dr. Chris Esposito for programming P-CMS, Christina Chung for assistance with data collection and analysis, Yi-Chen Sung for assistance designing prototypes and figures, and Tongfang Sun for assistance with manuscript preparation. NR 36 TC 1 Z9 1 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2016 VL 59 BP 15 EP 30 DI 10.1016/j.jbi.2015.10.014 PG 16 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA DX9HJ UT WOS:000384703900002 PM 26528606 ER PT J AU Faibish, D Suzuki, M Bartlett, JD AF Faibish, D. Suzuki, M. Bartlett, J. D. TI Appropriate real-time PCR reference genes for fluoride treatment studies performed in vitro or in vivo SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Fluoride; Reference genes; Real-time PCR; Fluorosis; Gene expression ID POLYMERASE-CHAIN-REACTION; ENDOPLASMIC-RETICULUM STRESS; FLUOROTIC ENAMEL MATRIX; ACTIN MESSENGER-RNA; RT-PCR; HOUSEKEEPING GENES; BETA-ACTIN; RENAL CLEARANCE; RIBOSOMAL-RNA; RAT INCISOR AB Objective: Quantitative real-time PCR (qPCR) is routinely performed for experiments designed to identify the molecular mechanisms involved in the pathogenesis of dental fluorosis. Expression of reference gene (s) is expected to remain unchanged in fluoride-treated cells or in rodents relative to the corresponding untreated controls. The aim of this study was to select optimal reference genes for fluoride experiments performed in vitro and in vivo. Design: Five candidate genes were evaluated: B2m, Eef1al, Gapdh, Hprt and Tbp. For in vitro experiments, LS8 cells derived from mouse enamel organ were treated with 0,1, 3 and/or 5 mM sodium fluoride (NaF) for 6 or 18 h followed by RNA isolation. For in vivo experiments, six-week old rats were treated with 0 or 100 ppm fluoride as NaF for six weeks at which time RNA was isolated from enamel organs. RNA from cells and enamel organs were reverse-transcribed and stability of gene expression for the candidate reference genes was evaluated by qPCR in treated versus non-treated samples. Results: The most stably expressed genes in vitro according to geNorm were B2m and Tbp, and according to Normfinder were Hprt and Gapdh. The most stable genes in vivo were Eef1al and Gapdh. Expression of Ddit3, a gene previously shown to be induced by fluoride, was demonstrated to be accurately calculated only when using an optimal reference gene. Conclusions: This study identifies suitable reference genes for relative quantification of gene expression by qPCR after fluoride treatment both in cultured cells and in the rodent enamel organ. (C) 2015 Elsevier Ltd. All rights reserved. C1 Dept Mineralized Tissue Biol, 245 First St, Cambridge, MA 02142 USA. Harvard Sch Dent Med, Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. [Suzuki, M.] OSU Coll Dent Off Res, Biosci, 4139 Postle Hall,305 W 12th Ave Columbus, Columbus, OH 43210 USA. RP Bartlett, JD (reprint author), OSU Coll Dent Off Res, Res, 4139 Postle Hall,305 W 12th Ave Columbus, Columbus, OH 43210 USA.; Bartlett, JD (reprint author), OSU Coll Dent Off Res, Biosci, 4139 Postle Hall,305 W 12th Ave Columbus, Columbus, OH 43210 USA. EM dfaibish@forsyth.org; suzuki.94@osu.edu; bartlett.196@osu.edu FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [T32DE007327, R01DE018106] FX Research reported in this publication was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health (DF) T32DE007327, (JDB) R01DE018106. NR 60 TC 2 Z9 2 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 EI 1879-1506 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD FEB PY 2016 VL 62 BP 33 EP 42 DI 10.1016/j.archoralbio.2015.11.004 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DX6ST UT WOS:000384514100005 PM 26615575 ER PT J AU Wiesner, T Kutzner, H Cerroni, L Mihm, MC Busam, KJ Murali, R AF Wiesner, Thomas Kutzner, Heinz Cerroni, Lorenzo Mihm, Martin C., Jr. Busam, Klaus J. Murali, Rajmohan TI Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy SO PATHOLOGY LA English DT Article DE Biomarkers; BAPI; BRAF; classification; diagnosis; genetics; genomics; melanocytic tumours; melanoma; molecular biology; pathology; precision oncology; RAS; Spitz tumours; spitzoid neoplasms; targeted therapy ID IN-SITU HYBRIDIZATION; GERMLINE BAP1 MUTATIONS; TERT PROMOTER MUTATIONS; COPY NUMBER ABERRATIONS; LYMPH-NODE BIOPSY; CELL LUNG-CANCER; MALIGNANT-MELANOMA; UVEAL MELANOMA; FUSION GENE; ALK FUSIONS AB Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy. C1 [Wiesner, Thomas] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 415 E 68th St, New York, NY 10065 USA. [Wiesner, Thomas; Kutzner, Heinz; Cerroni, Lorenzo] Med Univ Graz, Dept Dermatol & Venereol, Graz, Austria. [Kutzner, Heinz] Dermatopathol Friedrichshafen, Friedrichshafen, Germany. [Mihm, Martin C., Jr.] Harvard Med Sch, Dana Farber Canc Inst, Melanoma Ctr, Boston, MA USA. [Busam, Klaus J.; Murali, Rajmohan] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Murali, Rajmohan] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA. RP Wiesner, T (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 415 E 68th St, New York, NY 10065 USA. EM wiesnert@me.com FU Jubilaeumsfonds of the Oesterreichische Nationalbank OeNB [15461]; Harry J. Lloyd Trust - Translational Research Grant; Klaus Wolff Fellowship; National Institutes of Health (MSK Cancer Center Support Grant) [P30 CA008748] FX Thomas Wiesner is funded by the Jubilaeumsfonds of the Oesterreichische Nationalbank OeNB (#15461), a Harry J. Lloyd Trust - Translational Research Grant, and a Klaus Wolff Fellowship. The work is also supported by the National Institutes of Health (P30 CA008748; MSK Cancer Center Support Grant). The authors state that there are no conflicts of interest to disclose. NR 128 TC 4 Z9 4 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD FEB PY 2016 VL 48 IS 2 BP 113 EP 131 DI 10.1016/j.pathol.2015.12.007 PG 19 WC Pathology SC Pathology GA DW0GC UT WOS:000383317900003 PM 27020384 ER PT J AU Kachooei, AR Tarabochia, M Jupiter, JB AF Kachooei, Amir Reza Tarabochia, Matthew Jupiter, Jesse B. TI Distal Radius Volar Rim Fracture Fixation Using DePuy-Synthes Volar Rim Plate SO JOURNAL OF WRIST SURGERY LA English DT Article DE volar rim fracture; volar rim plate; distal radius fracture ID LUNATE FACET; INTRAARTICULAR FRACTURES AB Background To assess the results of distal radius fractures with the involvement of the volar rim fixed with the DePuy-Synthes Volar Rim Plate. Case Description We searched for the patients with volar rim fracture and/or volar rim fractures as part of a complex fracture fixed with a volar rim plate. Ten patients met the inclusion criteria: three patients with type 23B3, six patients with type 23C, and one patient with very distal type 23A. The mean follow-up was 14 months (range: 2-26). Fractures healed in all patients. Of the three patients with isolated volar rim fractures (type 23B3), two patients had no detectable deficits in motion. These patients had an average Gartland and Werley score of 9 (range: 2-14). Of the other seven patients (six with type 23C and one with type 23A fracture), three patients healed with full range of motion and four had some deficits in range of motion. Two patients had excellent results, three had good results, and two had fair results using the Gartland and Werley categorical rating. One patient healed with a shortened radius and ulnar impingement requiring a second surgery for ulnar head resection arthroplasty. Literature Review Results after nonoperative treatment of volar rim fractures are not satisfactory and often require subsequent corrective osteotomy. Satisfactory outcomes are achieved when the fragments are well reduced and secured regardless of the device type. Clinical Relevance Volar rim plates give an adequate buttress of the volar radius distal to volar projection of the lunate facet and do not interfere with wrist mobility. Furthermore, the dorsal fragments can be fixed securely through the volar approach eliminating the need for a secondary posterior incision. However, patients should be informed of the potential problems and the need to remove the plate if symptoms develop. C1 [Kachooei, Amir Reza] Mashhad Univ Med Sci, Orthoped Res Ctr, Mashhad, Iran. [Kachooei, Amir Reza; Tarabochia, Matthew; Jupiter, Jesse B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. RP Jupiter, JB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. EM jjupiter1@partners.org NR 14 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2163-3916 EI 2163-3924 J9 J WRIST SURG JI J. WRIST SURG. PD FEB PY 2016 VL 5 IS 1 BP 2 EP 8 DI 10.1055/s-0035-1570740 PG 7 WC Orthopedics SC Orthopedics GA DT5WB UT WOS:000381552700002 PM 26855829 ER PT J AU Galovski, TE Harik, JM Blain, LM Elwood, L Gloth, C Fletcher, TD AF Galovski, Tara E. Harik, Juliette M. Blain, Leah M. Elwood, Lisa Gloth, Chelsea Fletcher, Thomas D. TI Augmenting Cognitive Processing Therapy to Improve Sleep Impairment in PTSD: A Randomized Controlled Trial SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE PTSD; sleep impairment; insomnia; cognitive processing therapy; hypnosis ID POSTTRAUMATIC-STRESS-DISORDER; IMAGERY REHEARSAL THERAPY; SEXUAL-ASSAULT SURVIVORS; BEHAVIORAL THERAPY; HYPNOTIC SUGGESTION; CHRONIC NIGHTMARES; RESIDUAL INSOMNIA; QUALITY INDEX; VETERANS; DISTURBANCES AB Objective: Despite the success of empirically supported treatments for posttraumatic stress disorder (PTSD), sleep impairment frequently remains refractory after treatment. This single-site, randomized controlled trial examined the effectiveness of sleep-directed hypnosis as a complement to an empirically supported psychotherapy for PTSD (cognitive processing therapy [CPT]). Method: Participants completed either 3 weeks of hypnosis (n = 52) or a symptom monitoring control condition (n = 56) before beginning standard CPT. Multilevel modeling was used to investigate differential patterns of change to determine whether hypnosis resulted in improvements in sleep, PTSD, and depression. An intervening variable approach was then used to determine whether improvements in sleep achieved during hypnosis augmented change in PTSD and depression during CPT. Results: After the initial phase of treatment (hypnosis or symptom monitoring), the hypnosis condition showed significantly greater improvement than the control condition in sleep and depression, but not PTSD. After CPT, both conditions demonstrated significant improvement in sleep and PTSD; however, the hypnosis condition demonstrated greater improvement in depressive symptoms. As sleep improved, there were corresponding improvements in PTSD and depression, with a stronger relationship between sleep and PTSD. Conclusion: Hypnosis was effective in improving sleep impairment, but those improvements did not augment gains in PTSD recovery during the trauma-focused intervention. C1 [Galovski, Tara E.] Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. [Harik, Juliette M.] Natl Ctr PTSD, Execut Div, White River Jct, VT USA. [Blain, Leah M.] Chase Brexton Hlth Care, Behav Hlth, Columbia, MD USA. [Elwood, Lisa] Univ Indianapolis, Psychol Sci, Indianapolis, IN 46227 USA. [Gloth, Chelsea] Univ Missouri, Ctr Trauma Recovery, St Louis, MO 63121 USA. RP Galovski, TE (reprint author), Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. EM Tara.Galovski@va.gov FU National Institutes of Health, National Center for Complementary and Integrative Health [R34-MH-074-937] FX Supported in part by the National Institutes of Health, National Center for Complementary and Integrative Health (Grant R34-MH-074-937) awarded to Tara E. Galovski at the University of Missouri-St. Louis; Thomas D. Fletcher was the paid statistical consultant on the project. NR 61 TC 2 Z9 2 U1 9 U2 13 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD FEB PY 2016 VL 84 IS 2 BP 167 EP 177 DI 10.1037/ccp0000059 PG 11 WC Psychology, Clinical SC Psychology GA DT8GN UT WOS:000381728000007 PM 26689303 ER PT J AU Field, MG Alasil, T Baniasadi, N Que, C Simavli, H Sobeih, D Sola-Del Valle, D Best, MJ Chen, TC AF Field, Matthew G. Alasil, Tarek Baniasadi, Neda Que, Christian Simavli, Huseyin Sobeih, Doaa Sola-Del Valle, David Best, Matthew J. Chen, Teresa C. TI Facilitating Glaucoma Diagnosis With Intereye Retinal Nerve Fiber Layer Asymmetry Using Spectral-Domain Optical Coherence Tomography SO JOURNAL OF GLAUCOMA LA English DT Article DE glaucoma; OAG; intereye asymmetry; asymmetry; retinal nerve fiber layer; RNFL; optical coherence tomography; OCT; Spectralis; spectral-domain ID VISUAL-FIELD LOSS; OPEN-ANGLE GLAUCOMA; SCANNING LASER POLARIMETRY; THICKNESS MEASUREMENTS; MACULAR THICKNESS; CIRRUS HD; OCULAR HYPERTENSION; PREDICTIVE FACTORS; NORMAL EYES; DAMAGE AB Purpose: To test whether increased intereye retinal nerve fiber layer (RNFL) asymmetry may be indicative of glaucoma. To determine the best statistical methods and intereye RNFL cutoffs for differentiating between normal and glaucoma subjects to better alert clinicians to early glaucomatous damage. Methods: Sixty-six primary open-angle glaucoma (OAG) and 40 age-matched normal subjects had both eyes imaged at the Massachusetts Eye and Ear Infirmary with a commercially available spectral-domain optical coherence tomography (OCT) machine. Statistical methodologies were used to find cutoffs that achieved the best sensitivities and specificities for differentiating OAG from normal subjects. Results: Intereye RNFL asymmetry for global average, all quadrants, and all sectors was significantly greater in OAG than normal subjects. Intereye RNFL asymmetry for global average showed the greatest statistical difference (P < 0.001) between OAG (23.64 +/- 14.90 mu m) and normal eyes (3.58 +/- 3.96 mu m), with 6.60 times greater asymmetry in OAG eyes. The inferior quadrant showed the second greatest difference, with 3.91 times greater asymmetry in OAG eyes. Using a statistically determined cutoff of 6.0 mm as abnormal, intereye RNFL asymmetry for global average achieved a sensitivity of 74.24% and specificity of 90% in differentiating between normal and OAG subjects, achieving a better combination of sensitivity and specificity than intereye RNFL asymmetry of any quadrant or sector. Conclusions: Intereye RNFL asymmetry may be a useful clinical OCT measurement to provide quantitative assessment of early glaucomatous damage. Newly developed algorithms for intereye RNFL asymmetry may improve the ability to detect glaucoma. C1 [Field, Matthew G.; Alasil, Tarek; Baniasadi, Neda; Que, Christian; Simavli, Huseyin; Sobeih, Doaa; Sola-Del Valle, David; Chen, Teresa C.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. [Field, Matthew G.; Best, Matthew J.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. RP Chen, TC (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. EM teresa_chen@meei.harvard.edu OI Simavli, Huseyin/0000-0003-1657-9099 FU Massachusetts Eye Ear Infirmary; TUBITAK [2219] FX Supported by internal funding provided by Massachusetts Eye & Ear Infirmary. H.S.'s work was supported by TUBITAK (2219). NR 55 TC 4 Z9 4 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1057-0829 EI 1536-481X J9 J GLAUCOMA JI J. Glaucoma PD FEB PY 2016 VL 25 IS 2 BP 167 EP 176 DI 10.1097/IJG.0000000000000080 PG 10 WC Ophthalmology SC Ophthalmology GA DK3MD UT WOS:000374819800018 PM 24921896 ER PT J AU Wecht, JM Weir, JP Radulovic, M Bauman, WA AF Wecht, Jill M. Weir, Joseph P. Radulovic, Miroslav Bauman, William A. TI Effects of midodrine and L-NAME on systemic and cerebral hemodynamics during cognitive activation in spinal cord injury and intact controls SO PHYSIOLOGICAL REPORTS LA English DT Article DE Blood pressure; cerebral blood flow; cognition; L-NAME; Midodrine; NOS inhibition; spinal cord injury; tetraplegia ID BLOOD-PRESSURE ABNORMALITIES; OXIDE SYNTHASE INHIBITION; ORTHOSTATIC HYPOTENSION; HEART-RATE; SERIAL 7S; FLOW; TETRAPLEGIA; PERFORMANCE; HYDROCHLORIDE; RESPONSES AB We previously showed that increases in mean arterial pressure (MAP) following administration of midodrine hydrochloride (MH) and nitro-L-arginine methyl ester (L-NAME) resulted in increased mean cerebral blood flow velocity (MFV) during head-up tilt in hypotensive individuals with spinal cord injury (SCI) and question if this same association was evident during cognitive activation. Herein, we report MAP and MFV during two serial subtraction tasks (SSt) given before (predrug) and after (postdrug) administration of MH; (10 mg), L-NAME (1 mg/kg) or no drug (ND) in 15 subjects with SCI compared to nine able-bodied (AB) controls. Three-way factorial analysis of variance (ANOVA) models were used to determine significant main and interaction effects for group (SCI, AB), visit (MH, L-NAME, ND), and time (predrug, postdrug) for MAP and MFV during the two SSt. The three-way interaction was significant for MAP (F = 4.262; P = 0.020); both MH (30 +/- 26 mmHg; P < 0.05) and L-NAME (27 +/- 22 mmHg; P < 0.01) significantly increased MAP in the SCI group, but not in the AB group. There was a significant visit by time interaction for MFV suggesting an increase from predrug to postdrug following L-NAME (6 +/- 8 cm/sec; P < 0.05) and MH (4 +/- 7 cm/sec; P < 0.05), regardless of study group, with little change following ND (3 +/- 3 cm/sec). The relationship between change in MAP and MFV was significant in the SCI group following administration of MH (r(2) = 0.38; P < 0.05) and L-NAME (r(2) = 0.32; P < 0.05). These antihypotensive agents, at the doses tested, raised MAP, which was associated with an increase MFV during cognitive activation in hypotensive subjects with SCI. C1 [Wecht, Jill M.; Radulovic, Miroslav; Bauman, William A.] James J Peters VAMC, VA RR&D Natl Ctr Med Consequences Spinal Cord Inj, Rm 7A-13,130 West Kingsbridge Rd, Bronx, NY 10468 USA. [Wecht, Jill M.; Radulovic, Miroslav; Bauman, William A.] James J Peters VAMC, Med Serv, Bronx, NY USA. [Wecht, Jill M.; Radulovic, Miroslav; Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Wecht, Jill M.; Radulovic, Miroslav; Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Weir, Joseph P.] Univ Kansas, Dept Hlth Sport & Exercise Sci, Lawrence, KS 66045 USA. RP Wecht, JM (reprint author), James J Peters VAMC, VA RR&D Natl Ctr Med Consequences Spinal Cord Inj, Rm 7A-13,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM jm.wecht@va.gov NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2051-817X J9 PHYSIOL REP JI PHYSIOL. REP. PD FEB PY 2016 VL 4 IS 3 AR e12683 DI 10.14814/phy2.12683 PG 9 WC Physiology SC Physiology GA DR9SI UT WOS:000380236000002 ER PT J AU Singh, AK Sodickson, A Abujudeh, H AF Singh, Ajay K. Sodickson, Aaron Abujudeh, Hani TI Imaging of abdominal and pelvic injuries from the Boston Marathon bombing SO EMERGENCY RADIOLOGY LA English DT Article DE Blast; Explosion; Shrapnel; Trauma ID HYPOVOLEMIC SHOCK; EXPLOSIONS; ATTACKS; ADULTS; BLAST; SIGNS AB The aim of this study is to describe the imaging findings of abdominal and pelvic injuries in victims of the Boston Marathon bombing. A retrospective review of 87 patients following the Boston Marathon bombing was performed to evaluate for abdominal and pelvic injuries on plain radiography or CT scans of the abdomen and pelvis. Imaging exams were evaluated for shrapnel, soft tissue injury, visceral damage, vascular disruption, and fractures. The injuries were classified as primary, secondary, tertiary, and quaternary blast injuries. Eleven of the 87 patients had positive findings in the abdomen or pelvis (M:F = 7:4, average age 34.6 years). There were 22 ball bearings, two nails, one screw, and two irregular metal fragments in the 11 patients with secondary blast (shrapnel) injuries. There was no peritoneal penetration or visceral injury seen in any of the patients. One patient had multiple transverse process fractures, representing tertiary blast injury. All but one patient had superficial penetrating abdominal or pelvic injuries secondary to shrapnel. There were no cases of bowel or solid visceral organ injuries due to the lack of peritoneal violation from the relatively low-powered explosions. Absence of peritoneal penetration by shrapnel indicates no need for laparotomy following low-powered explosions. C1 [Singh, Ajay K.; Abujudeh, Hani] Massachusetts Gen Hosp, Div Emergency Radiol, Dept Radiol, Fruit St, Boston, MA 02114 USA. [Sodickson, Aaron] Brigham & Womans Hosp, Div Emergency Radiol, Dept Radiol, Boston, MA 02115 USA. RP Singh, AK (reprint author), Massachusetts Gen Hosp, Div Emergency Radiol, Dept Radiol, Fruit St, Boston, MA 02114 USA. EM mghpartners@yahoo.com NR 16 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD FEB PY 2016 VL 23 IS 1 BP 35 EP 39 DI 10.1007/s10140-015-1354-1 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR1BG UT WOS:000379640400007 PM 26445949 ER PT J AU Nguyen, KL Tian, X Alam, S Mehari, A Leung, SW Seamon, C Allen, D Minniti, CP Sachdev, V Arai, AE Kato, GJ AF Kim-Lien Nguyen Tian, Xin Alam, Shoaib Mehari, Alem Leung, Steve W. Seamon, Catherine Allen, Darlene Minniti, Caterina P. Sachdev, Vandana Arai, Andrew E. Kato, Gregory J. TI Elevated transpulmonary gradient and cardiac magnetic resonance-derived right ventricular remodeling predict poor outcomes in sickle cell disease SO HAEMATOLOGICA LA English DT Letter DE pulmonary hypertension; magnetic resonance imaging; right ventricle; cardiomyopathy; sickle cell disease ID RIGHT HEART CATHETERIZATION; PULMONARY-HYPERTENSION; MORTALITY; ANEMIA; ADULTS C1 [Alam, Shoaib; Sachdev, Vandana] Lung & Blood Inst, Cardiovasc & Pulm Branch, Bethesda, MD USA. [Mehari, Alem; Seamon, Catherine; Allen, Darlene; Minniti, Caterina P.; Kato, Gregory J.] Lung & Blood Inst, Sickle Cell Vasc Dis Sect, Hematol Branch, Bethesda, MD USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD USA. [Kim-Lien Nguyen; Mehari, Alem; Leung, Steve W.; Arai, Andrew E.] Howard Univ, Coll Med, Washington, DC USA. [Kim-Lien Nguyen] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Los Angeles, CA USA. [Kim-Lien Nguyen] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Kato, Gregory J.] Univ Pittsburgh, Div Hematol Oncol, Pittsburgh, PA USA. [Kato, Gregory J.] Univ Pittsburgh, Adult Sickle Cell Ctr Excellence, Pittsburgh, PA USA. [Minniti, Caterina P.] Montefiore Med Ctr, Sickle Cell Ctr, Div Hematol Oncol, New York, NY USA. [Leung, Steve W.] Univ Kentucky, Div Cardiovasc Med, Lexington, KY USA. RP Kato, GJ (reprint author), Lung & Blood Inst, Sickle Cell Vasc Dis Sect, Hematol Branch, Bethesda, MD USA.; Kato, GJ (reprint author), Univ Pittsburgh, Div Hematol Oncol, Pittsburgh, PA USA.; Kato, GJ (reprint author), Univ Pittsburgh, Adult Sickle Cell Ctr Excellence, Pittsburgh, PA USA. EM katogj@upmc.edu RI Kato, Gregory/I-7615-2014; Leung, Steve/E-5624-2011; OI Kato, Gregory/0000-0003-4465-3217; Leung, Steve/0000-0003-2832-2258; Nguyen, Kim-Lien/0000-0002-8854-2976 FU NHLBI NIH HHS [ZIA HL006011, ZIA HL004607, ZIA HL006012, ZIA HL006015, ZIA HL006137, ZID HL006140, ZIE HL006139]; PHS HHS [1ZIAHL004607, 1ZIAHL006011, 1ZIAHL006012, 1ZIAHL006015, 1ZIAHL006137, 1ZIDHL006140, 1ZIEHL006139] NR 15 TC 2 Z9 2 U1 1 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2016 VL 101 IS 2 BP E40 EP E43 DI 10.3324/haematol.2015.125229 PG 4 WC Hematology SC Hematology GA DQ4EI UT WOS:000379156300001 PM 26589907 ER PT J AU Erickson, ZD Mena, SJ Pierre, JM Blum, LH Martin, E Hellemann, GS Aragaki, DR Firestone, L Lee, C Lee, P Kunkel, CF Ames, D AF Erickson, Zachary D. Mena, Shirley J. Pierre, Joseph M. Blum, Lisa H. Martin, Eda Hellemann, Gerhard S. Aragaki, Dixie R. Firestone, Lisa Lee, Catherine Lee, Paul Kunkel, Charles F. Ames, Donna TI Behavioral Interventions for Antipsychotic Medication-Associated Obesity: A Randomized, Controlled Clinical Trial SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID LIFE-STYLE INTERVENTION; WEIGHT-GAIN; MENTAL-ILLNESS; PROGRAM; SCHIZOPHRENIA; PSYCHOTHERAPY; MAINTENANCE; PREDICTORS; REDUCTION; METFORMIN AB Objective: To demonstrate the effectiveness of a Diabetes Prevention Program-inspired 12-month behavioral intervention for patients with severe mental illness (SMI) and medication-associated obesity. Method: This randomized, controlled, parallel, superiority study screened 225 volunteers from November 2005 to August 2008 at the VA Greater Los Angeles Healthcare System. 122 outpatients with DSM-IV-diagnosed SMI taking antipsychotic medications who had >= 7% weight gain or body mass index (BMI) > 25 were randomized by computer-generated number to Lifestyle Balance treatment intervention (n = 60) or usual care control (n = 62) groups. Clinical raters were masked to randomization. Treatment intervention included weekly classes and individual counseling for 8 weeks, food and exercise diaries, rewards, caregiver consultations, and monthly booster classes and counseling for 1 year. Controls received self-help materials and visited at equivalent intervals without formal classes or counseling. Outcomes were changes in anthropometric measurements, psychiatric symptoms, health knowledge, and glucose, hemoglobin A1c, and lipid levels. Results: Our intention-to-treat analysis found significant differences in predicted trajectory of mean weight change between the groups over 12 months (P < .01), with treatment participants expected to lose an average 4.6 kg, while control participants would gain an average 0.6 kg. BMI and body fat percentage followed the same pattern. Both groups demonstrated statistically significant improvements in health knowledge quiz scores over time (P = .006), without significant difference between groups. Conclusions: Treatment was more effective than usual care control in treating medication-associated obesity, independent of SMI diagnosis, antipsychotic medication, and knowledge gained, suggesting that behavioral interventions are effective in SMI patients. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Erickson, Zachary D.; Mena, Shirley J.; Blum, Lisa H.; Martin, Eda] VA Greater Los Angeles Healthcare Syst, Res Dept, Los Angeles, CA USA. [Pierre, Joseph M.; Ames, Donna] VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Aragaki, Dixie R.; Firestone, Lisa; Lee, Catherine; Lee, Paul; Kunkel, Charles F.] VA Greater Los Angeles Healthcare Syst, Dept Phys Med & Rehabil, Los Angeles, CA USA. [Pierre, Joseph M.; Aragaki, Dixie R.; Firestone, Lisa; Lee, Catherine; Lee, Paul; Kunkel, Charles F.; Ames, Donna] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. [Hellemann, Gerhard S.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. RP Ames, D (reprint author), 11301 Wilshire Blvd,B151H, Los Angeles, CA 90073 USA. EM donna.ames@va.gov FU Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development; Veterans Affairs Merit Review Rehabilitation Research and Development Service (Washington, DC) [D3925-R] FX Supported by the Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development. Funded by Veterans Affairs Merit Review Rehabilitation Research and Development Service (Washington, DC; project number D3925-R). NR 28 TC 0 Z9 0 U1 9 U2 10 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2016 VL 77 IS 2 BP E183 EP E189 DI 10.4088/JCP.14m09552 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5MJ UT WOS:000379249200009 PM 26930534 ER PT J AU Cooper, SA Desjardins, PJ Turk, DC Dworkin, RH Katz, NP Kehlet, H Ballantyne, JC Burke, LB Carragee, E Cowan, P Croll, S Dionne, RA Farrar, JT Gilron, I Gordon, DB Iyengar, S Jay, GW Kalso, EA Kerns, RD McDermott, MP Raja, SN Rappaport, BA Rauschkolb, C Royal, MA Segerdahl, M Stauffer, JW Todd, KH Vanhove, GF Wallace, MS West, C White, RE Wu, C AF Cooper, Stephen A. Desjardins, Paul J. Turk, Dennis C. Dworkin, Robert H. Katz, Nathaniel P. Kehlet, Henrik Ballantyne, Jane C. Burke, Laurie B. Carragee, Eugene Cowan, Penney Croll, Scott Dionne, Raymond A. Farrar, John T. Gilron, Ian Gordon, Debra B. Iyengar, Smriti Jay, Gary W. Kalso, Eija A. Kerns, Robert D. McDermott, Michael P. Raja, Srinivasa N. Rappaport, Bob A. Rauschkolb, Christine Royal, Mike A. Segerdahl, Marta Stauffer, Joseph W. Todd, Knox H. Vanhove, Geertrui F. Wallace, Mark S. West, Christine White, Richard E. Wu, Christopher TI Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations SO PAIN LA English DT Review DE Randomized clinical trials; Acute pain; Research design; Assay sensitivity; Proof-of-concept trials; Clinical trial methods ID POSTOPERATIVE DENTAL PAIN; INDIVIDUAL PATIENT METAANALYSIS; PLACEBO-CONTROLLED TRIALS; ACTIVE-CONTROL TRIALS; MOVEMENT-EVOKED PAIN; DOUBLE-BLIND; RATING-SCALES; PARECOXIB SODIUM; MISSING DATA; EFFICACY AB This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings. C1 [Cooper, Stephen A.] Stephen A Cooper LLC, Palm Beach Gardens, FL USA. [Desjardins, Paul J.] Tufts Univ, Desjardins Associates LLC, Boston, MA 02111 USA. [Desjardins, Paul J.] Tufts Univ, Dept Oral & Maxillofacial Surg, Boston, MA 02111 USA. [Turk, Dennis C.; Ballantyne, Jane C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Dworkin, Robert H.; McDermott, Michael P.] Univ Rochester, Dept Anesthesiol, Rochester, NY USA. [Dworkin, Robert H.; McDermott, Michael P.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Dworkin, Robert H.; McDermott, Michael P.] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY USA. [Katz, Nathaniel P.] Analges Solut, Needham, MA USA. [Kehlet, Henrik] Rigshosp, Sect Surg Pathophysiol, Copenhagen, Denmark. [Burke, Laurie B.] Univ Maryland, Dept Hlth Serv Res, Baltimore, MD 21201 USA. [Burke, Laurie B.] LORA Grp LLC, Royal Oak, MD USA. [Carragee, Eugene] Stanford Univ, Dept Orthoped Surg, Palo Alto, CA 94304 USA. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA USA. [Croll, Scott] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Dionne, Raymond A.] E Carolina Univ, Dept Pharmacol, Greenville, NC USA. [Dionne, Raymond A.] E Carolina Univ, Dept Toxicol, Greenville, NC USA. [Dionne, Raymond A.] E Carolina Univ, Dept Foundat Sci, Greenville, NC USA. [Farrar, John T.] Univ Penn, Dept Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gilron, Ian] Queens Univ, Dept Anesthesiol, Kingston, ON, Canada. [Gordon, Debra B.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA USA. [Iyengar, Smriti] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Jay, Gary W.] Advise Clin, Raleigh, NC USA. [Kalso, Eija A.] Univ Helsinki, Dept Anaesthesia Intens Care & Pain Med, Helsinki, Finland. [Kalso, Eija A.] Helsinki Univ Hosp, Helsinki, Finland. [Kerns, Robert D.] US Dept Vet Affairs, New Haven, CT USA. [Raja, Srinivasa N.; Wu, Christopher] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Rappaport, Bob A.] Analges Concepts LLC, Arlington, VA USA. [Rauschkolb, Christine] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NY USA. [Royal, Mike A.] Sorrento Therapeut, San Diego, CA USA. [Segerdahl, Marta] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Stauffer, Joseph W.] Johns Hopkins Univ, Baltimore, MD USA. [Stauffer, Joseph W.] Cara Therapeut, Shelton, CT USA. [Todd, Knox H.] Univ Texas MD Anderson Canc Ctr, Dept Emergency Med, Houston, TX 77030 USA. [Vanhove, Geertrui F.] NeurogesX, San Carlos, CA USA. [Wallace, Mark S.] Univ Calif San Diego, Dept Anesthesiol, San Diego, CA 92103 USA. [West, Christine] Pfizer Inc, Groton, CT 06340 USA. [White, Richard E.] Endo Pharmaceut, Chadds Ford, PA USA. RP Cooper, SA (reprint author), 40 Durand Rd, Maplewood, NJ 07040 USA. EM paul.j.desjardins@gmail.com FU Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); FDA; US Department of Veteran Affairs; US National Institutes of Health FX Preparation of the background literature reviews and draft manuscripts was supported by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); public-private partnership with the US Food and Drug Administration (FDA) ACTTION has received research contracts, grants, and other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. No official endorsement by the FDA, US Department of Veteran Affairs, US National Institutes of Health, or the pharmaceutical and medical devices companies that have provided unrestricted grants to support the activities of IMMPACT and ACTTION should be inferred. NR 74 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 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD FEB PY 2016 VL 157 IS 2 BP 288 EP 301 DI 10.1097/j.pain.0000000000000375 PG 14 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DP1NV UT WOS:000378257600004 PM 26683233 ER PT J AU Cajanus, K Holmstrom, EJ Wessman, M Anttila, V Kaunisto, MA Kalso, E AF Cajanus, Kristiina Holmstrom, Emil J. Wessman, Maija Anttila, Verneri Kaunisto, Mari A. Kalso, Eija TI Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer SO PAIN LA English DT Article DE Analgesics; Opioid; Oxycodone; Experimental pain; Postoperative pain; FAAH enzyme; Single-nucleotide polymorphism ID ACID AMIDE HYDROLASE; MEDICATION-OVERUSE HEADACHE; PROBLEM DRUG-USE; INFLAMMATORY PAIN; MISSENSE MUTATION; NEUROPATHIC PAIN; ANANDAMIDE; SYSTEM; CANNABINOIDS; SENSITIVITY AB Fatty acid amide hydrolase (FAAH) metabolizes the endocannabinoid anandamide, which has an important role in nociception. We investigated the role of common FAAH single-nucleotide polymorphisms(SNPs) in experimentally induced and postoperative pain. One thousand women undergoing surgery for breast cancer participated in the study. They were tested for cold (n = 900) and heat pain (n = 1000) sensitivity. After surgery, their pain intensities and analgesic consumption were carefully registered. FAAH genotyping was performed using MassARRAY platform and genome-wide chip (n = 926). Association between 8 FAAH SNPs and 9 pain phenotypes was analyzed using linear regression models. The results showed that carrying 2 copies of a missense variant converting proline at position 129 to threonine (rs324420) resulted in significantly lower cold pain sensitivity and less need for postoperative analgesia. More specifically, rs324420 and another highly correlated SNP, rs1571138, associated significantly with cold pain intensity (corrected P value, 0.0014; recessive model). Patients homozygous for the minor allele (AA genotype) were less sensitive to cold pain (beta = -1.48; 95% CI, -2.14 to -0.8). Two other SNPs (rs3766246 and rs4660928) showed nominal association with cold pain, and SNPs rs4141964, rs3766246, rs324420, and rs1571138 nominal association with oxycodone consumption. In conclusion, FAAH gene variation was shown to associate with cold pain sensitivity with P129T/rs324420 being the most likely causal variant as it is known to reduce the FAAH enzyme activity. The same variant showed nominal association with postoperative oxycodone consumption. Our conclusions are, however, limited by the lack of replication and the results should be replicated in an independent cohort. C1 [Cajanus, Kristiina; Kalso, Eija] Univ Helsinki, Dept Anaesthesiol, Helsinki, Finland. [Cajanus, Kristiina; Kalso, Eija] Univ Helsinki, Dept Intens Care, Helsinki, Finland. [Cajanus, Kristiina; Kalso, Eija] Univ Helsinki, Dept Pain Med, Helsinki, Finland. [Cajanus, Kristiina; Kalso, Eija] Helsinki Univ Hosp, Helsinki, Finland. [Holmstrom, Emil J.; Wessman, Maija; Kaunisto, Mari A.] Folkhalsan Res Ctr, Folkhalsan Inst Genet, Dept Mol Genet, Helsinki, Finland. [Wessman, Maija; Kaunisto, Mari A.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Anttila, Verneri] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Anttila, Verneri] Harvard Univ, Sch Med, Boston, MA USA. [Anttila, Verneri] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Anttila, Verneri] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. RP Kalso, E (reprint author), Univ Helsinki, Cent Hosp, Dept Anaesthesiol, Pain Clin, POB 140, Helsinki 00029, Finland.; Kalso, E (reprint author), Univ Helsinki, Cent Hosp, Dept Intens Care, Pain Clin, POB 140, Helsinki 00029, Finland.; Kalso, E (reprint author), Univ Helsinki, Cent Hosp, Dept Pain Med, Pain Clin, POB 140, Helsinki 00029, Finland. EM eija.kalso@helsinki.fi RI Cajanus, Kristiina/F-9293-2016; OI Cajanus, Kristiina/0000-0001-9621-633X; Kaunisto, Mari/0000-0002-6946-9195; Kalso, Eija/0000-0002-4899-605X FU Academy of Finland [110489, 217028, 139795]; Folkhalsan Research Foundation; Medicinska Understodsforeningen Liv Halsa; Signe and Ane Gyllenberg Foundation; Helsinki University Central Hospital Research Funds [TYH2008225, TYH2010210, TYH2012212]; European Union Seventh Framework Programme [602919] FX The authors are grateful for the invaluable assistance by the research nurses Eija R. Ruoppa, RN and Minna Kaiponen, RN throughout the project. The authors are very grateful to Dr Gretchen Repasky for her valuable help in proofreading the manuscript. This study was supported by Grants from the Academy of Finland (110489, 217028, and 139795), Folkhalsan Research Foundation, Medicinska Understodsforeningen Liv & Halsa, Signe and Ane Gyllenberg Foundation, Helsinki University Central Hospital Research Funds (TYH2008225, TYH2010210, and TYH2012212), and European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement No. 602919. NR 55 TC 2 Z9 2 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD FEB PY 2016 VL 157 IS 2 BP 361 EP 369 DI 10.1097/j.pain.0000000000000398 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DP1NV UT WOS:000378257600012 PM 26808012 ER PT J AU Hu, JM Bortsov, AV Ballina, L Orrey, DC Swor, RA Peak, D Jones, J Rathlev, N Lee, DC Domeier, R Hendry, P Parry, BA McLean, SA AF Hu, JunMei Bortsov, Andrey V. Ballina, Lauren Orrey, Danielle C. Swor, Robert A. Peak, David Jones, Jeffrey Rathlev, Niels Lee, David C. Domeier, Robert Hendry, Phyllis Parry, Blair A. McLean, Samuel A. TI Chronic widespread pain after motor vehicle collision typically occurs through immediate development and nonrecovery: results of an emergency department-based cohort study SO PAIN LA English DT Article DE Motor vehicle collision; Chronic widespread pain; Pain trajectory ID WHIPLASH-ASSOCIATED DISORDERS; PERITRAUMATIC DISTRESS INVENTORY; 2000-2010 TASK-FORCE; MUSCULOSKELETAL PAIN; RISK-FACTORS; NECK PAIN; FOLLOW-UP; SEXUAL ASSAULT; NEW-ONSET; STRESS AB Motor vehicle collision (MVC) can trigger chronic widespread pain (CWP) development in vulnerable individuals. Whether such CWP typically develops through the evolution of pain from regional to widespread or through the early development of widespread pain with nonrecovery is currently unknown. We evaluated the trajectory of CWP development (American College of Rheumatology criteria) among 948 European-American individuals who presented to the emergency department (ED) for care in the early aftermath of MVC. Pain extent was assessed in the ED and 6 weeks, 6 months, and 1 year after MVC on 100%, 91%, 89%, and 91% of participants, respectively. Individuals who reported prior CWP at the time of ED evaluation (n = 53) were excluded. Trajectory modeling identified a 2-group solution as optimal, with the Bayes Factor value (138) indicating strong model selection. Linear solution plots supported a nonrecovery model. Although the number of body regions with pain in the non-CWP group steadily declined, the number of body regions with pain in the CWP trajectory group (192/895, 22%) remained relatively constant over time. These data support the hypothesis that individuals who develop CWP after MVC develop widespread pain in the early aftermath of MVC, which does not remit. C1 [Hu, JunMei; Bortsov, Andrey V.; Ballina, Lauren; Orrey, Danielle C.; McLean, Samuel A.] Univ N Carolina, TRYUMPH Res Program, Chapel Hill, NC USA. [Hu, JunMei; Bortsov, Andrey V.; Ballina, Lauren; Orrey, Danielle C.; McLean, Samuel A.] Univ N Carolina, Anesthesiol, Chapel Hill, NC USA. [Swor, Robert A.] William Beaumont Hosp, Emergency Med, Royal Oak, MI 48072 USA. [Peak, David; Parry, Blair A.] Massachusetts Gen Hosp, Emergency Med, Boston, MA 02114 USA. [Jones, Jeffrey] Spectrum Hlth Syst, Emergency Med, Grand Rapids, MI USA. [Rathlev, Niels] Baystate Med Ctr, Emergency Med, Springfield, MA USA. [Lee, David C.] N Shore Univ Hosp, Emergency Med, Manhasset, NY USA. [Domeier, Robert] St Joseph Mercy Hlth Syst, Emergency Med, Ypsilanti, MI USA. [Hendry, Phyllis] Univ Florida, Emergency Med, Jacksonville, FL USA. [McLean, Samuel A.] Univ N Carolina, Emergency Med, Chapel Hill, NC USA. RP McLean, SA (reprint author), Univ N Carolina, Sch Med, Wing C CB 7010, Chapel Hill, NC 27599 USA. EM smclean@aims.unc.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [R01AR056328] FX The authors would like to thank the participants for taking part in this study. The authors would also like to thank Dr. Bobby Jones for his advice and support on Proc Traj. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR056328. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 53 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 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD FEB PY 2016 VL 157 IS 2 BP 438 EP 444 DI 10.1097/j.pain.0000000000000388 PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DP1NV UT WOS:000378257600019 PM 26808013 ER PT J AU Wilkoff, BL Fauchier, L Stiles, MK Morillo, CA Al-Khatib, SM Almendral, J Aguinaga, L Berger, RD Cuesta, A Daubert, JP Dubner, S Ellenbogen, KA Estes, NAM Fenelon, G Garcia, FC Gasparini, M Haines, DE Healey, JS Hurtwitz, JL Keegan, R Kolb, C Kuck, KH Marinskis, G Martinelli, M McGuire, M Molina, LG Okumura, K Proclemer, A Russo, AM Singh, JP Swerdlow, CD Teo, WS Uribe, W Viskin, S Wang, CC Zhang, S AF Wilkoff, Bruce L. Fauchier, Laurent Stiles, Martin K. Morillo, Carlos A. Al-Khatib, Sana M. Almendral, Jesoes Aguinaga, Luis Berger, Ronald D. Cuesta, Alejandro Daubert, James P. Dubner, Sergio Ellenbogen, Kenneth A. Estes, N. A. Mark, III Fenelon, Guilherme Garcia, Fermin C. Gasparini, Maurizio Haines, David E. Healey, Jeff S. Hurtwitz, Jodie L. Keegan, Roberto Kolb, Christof Kuck, Karl-Heinz Marinskis, Germanas Martinelli, Martino McGuire, Mark Molina, Luisg G. Okumura, Ken Proclemer, Alessandro Russo, Andrea M. Singh, Jagmeet P. Swerdlow, Charles D. Teo, Wee Siong Uribe, William Viskin, Sami Wang, Chun-Chieh Zhang, Shu TI 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing SO JOURNAL OF ARRHYTHMIA LA English DT Article DE Implantable cardioverter-defibrillator; Bradycardia mode and rate; Tachycardia detection; Tachycardia therapy; Defibrillation testing; Programming ID CARDIAC-RESYNCHRONIZATION THERAPY; FAST VENTRICULAR-TACHYCARDIA; QUALITY-OF-LIFE; SICK-SINUS SYNDROME; DUAL-CHAMBER DEFIBRILLATORS; REDUCE INAPPROPRIATE SHOCKS; PRIMARY PREVENTION PATIENTS; RATE-RESPONSIVE PACEMAKERS; RANDOMIZED CLINICAL-TRIAL; LONG-DETECTION INTERVAL C1 [Wilkoff, Bruce L.] Cleveland Clin, Cleveland, OH 44106 USA. [Fauchier, Laurent] CHU Trousseau, Tours, France. [Stiles, Martin K.] Waikato Hosp, Hamilton, New Zealand. [Morillo, Carlos A.; Healey, Jeff S.] McMaster Univ, Dept Med, Populat Hlth Res Inst, Cardiol Div, Hamilton, ON, Canada. [Al-Khatib, Sana M.; Daubert, James P.] Duke Univ, Med Ctr, Durham, NC USA. [Almendral, Jesoes] Univ CEU San Pablo, Grp HM Hosp, Madrid, Spain. [Aguinaga, Luis] Ctr Privado Cardiol, San Miguel De Tucuman, Argentina. [Berger, Ronald D.] Johns Hopkins Univ, Baltimore, MD USA. [Cuesta, Alejandro] Inst Cardiol Infantil, Serv Arritmias, Montevideo, Uruguay. [Dubner, Sergio] Clin & Mat Suizo Argentina, Buenos Aires, DF, Argentina. [Ellenbogen, Kenneth A.] Virginia Commonwealth Univ, Med Ctr, Richmond, VA USA. [Estes, N. A. Mark, III] Tufts Univ New England Med Ctr, 750 Washington St, Boston, MA 02111 USA. [Fenelon, Guilherme] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Garcia, Fermin C.] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Gasparini, Maurizio] Humanitas Res Hosp, Milan, Italy. [Haines, David E.] William Beaumont Hosp, Div Cardiol, Royal Oak, MI 48072 USA. [Hurtwitz, Jodie L.] North Texas Heart Ctr, Dallas, TX USA. [Keegan, Roberto] Hosp Privado Sur, Bahia Blanca, Buenos Aires, Argentina. [Kolb, Christof] Deutsch Herzzentrum Munich, Munich, Germany. [Kuck, Karl-Heinz] Allgemeines Krankenhaus St Georg, Hamburg, Germany. [Marinskis, Germanas] Vilnius Univ, Clin Cardiac & Vasc Dis, Vilnius, Lithuania. [Martinelli, Martino] Univ Sao Paulo, Inst Coracao, Sao Paulo, Brazil. [McGuire, Mark] Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Molina, Luisg G.] Univ Nacl Autonoma Mexico, Mexicos Gen Hosp, Mexico City 04510, DF, Mexico. [Okumura, Ken] Hirosaki Univ, Grad Sch Med, Hirosaki, Aomori, Japan. [Proclemer, Alessandro] Azienda Osped Univ S Maria Misericordia Udine, Udine, Italy. [Russo, Andrea M.] Cooper Univ Hosp, Camden, NJ USA. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Swerdlow, Charles D.] Cedars Sinai Med Ctr, Beverly Hills, CA USA. [Teo, Wee Siong] Natl Heart Ctr Singapore, Singapore, Singapore. [Uribe, William] CES Cardiol, Medellin, Colombia. [Uribe, William] Ctr Especializados SanVicente Fdn, Medellin, Colombia. [Uribe, William] CES Cardiol, Rionegro, Colombia. [Uribe, William] Ctr Especializados SanVicente Fdn, Rionegro, Colombia. [Viskin, Sami] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Viskin, Sami] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Wang, Chun-Chieh] Chang Gung Mem Hosp, 199 Tung Hwa N Rd, Taipei 10591, Taiwan. [Zhang, Shu] Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Beijing 100021, Peoples R China. [Zhang, Shu] Peking Union Med Coll, Beijing Fu Wai Hosp, Beijing 100021, Peoples R China. [Zhang, Shu] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Dubner, Sergio] De Los Arcos Sanatorio, Buenos Aires, DF, Argentina. RP Wilkoff, BL (reprint author), Care of Senerth E, Heart Rhythm Soc, 1325G St NW,Suite 400, Washington, DC 20005 USA. EM ese-nerth@hrsonline.org RI Martinelli, Martino/D-9785-2012 OI Martinelli, Martino/0000-0003-4440-8078 NR 221 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1880-4276 EI 1883-2148 J9 J ARRYTHM JI J. Arrythm. PD FEB PY 2016 VL 32 IS 1 BP 1 EP 28 DI 10.1016/j.joa.2015.12.001 PG 28 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9XK UT WOS:000378141100001 PM 26949427 ER PT J AU Mezza, T Sorice, GP Conte, C Sun, VA Cefalo, CMA Moffa, S Pontecorvi, A Mari, A Kulkarni, RN Giaccari, A AF Mezza, Teresa Sorice, Gian P. Conte, Caterina Sun, Vinsin A. Cefalo, Chiara M. A. Moffa, Simona Pontecorvi, Alfredo Mari, Andrea Kulkarni, Rohit N. Giaccari, Andrea TI beta-Cell Glucose Sensitivity Is Linked to Insulin/Glucagon Bihormonal Cells in Nondiabetic Humans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INSULIN-SECRETION; TOLERANCE; PATHOGENESIS; RESISTANCE; MASS AB Context: Insulin resistance impacts virtually all tissues, including pancreatic beta cells. Individuals with insulin resistance, but without diabetes, exhibit an increased islet size because of an elevated number of both beta and alpha cells. Neogenesis from duct cells and transdifferentiation of alpha cells have been postulated to contribute to the beta-cell compensatory response to insulin resistance. Objective: Our objective was to explore parameters that could potentially predict altered islet morphology. Methods: We investigated 16 nondiabetic subjects by a 2-hour hyperglycemic clamp to evaluate beta-cell secretory function. We analyzed pancreas samples obtained during pancreatoduodenectomy in the same patients to examine glucagon and insulin double + cells to assess islet morphology. Results: Among all the functional in vivo parameters of insulin secretion that were explored (basal, first phase and total secretion, glucose sensitivity, arginine-stimulated insulin secretion), beta-cell glucose sensitivity was unique in exhibiting a significant correlation with both islet size and alpha-beta double + islet cells. Conclusions: Our data suggest that poor beta-cell glucose sensitivity is linked to islet transdifferentiation, possibly from alpha cells to beta cells, in an attempt to cope with higher demands for insulin secretion. Understanding the mechanism(s) that underlies the adaptive response of the islet cells to insulin resistance is a potential approach to design tools to enhance functional beta-cell mass for diabetes therapy. C1 [Mezza, Teresa; Sorice, Gian P.; Conte, Caterina; Sun, Vinsin A.; Cefalo, Chiara M. A.; Moffa, Simona; Pontecorvi, Alfredo; Giaccari, Andrea] Univ Cattolica Sacro Cuore, Endometab Dis Unit, I-00168 Rome, Italy. [Mezza, Teresa; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Islet Cell & Regenerat Biol,Joslin Diabet Ctr,Dep, Boston, MA 02215 USA. [Mari, Andrea] CNR, Inst Neurosci, Padua, Italy. RP Giaccari, A (reprint author), Univ Cattolica Sacro Cuore, Policlin Gemelli, Unit Endometab Dis, Largo Agostino Gemelli 8, I-00168 Rome, Italy. EM giaccari@rm.unicatt.it OI Mezza, Teresa/0000-0001-5407-9576 FU Universita Cattolica del Sacro Cuore (Fondi AteneoLinea D.3.2); Italian Ministry of Education, University and Research [PRIN 2010JS3PMZ 011]; European Foundation for the Study of Diabetes award - AstraZeneca; Diabete Ricerca; National Institutes of Health [RO1DK67536, NIH R01DK103215, P30 DK36386] FX This study was supported by grants from the Universita Cattolica del Sacro Cuore (Fondi AteneoLinea D.3.2); the Italian Ministry of Education, University and Research (PRIN 2010JS3PMZ 011); and by an European Foundation for the Study of Diabetes award supported by AstraZeneca (to A.G.). T.M., G.P.S., and C.M.A. are the recipients of a fellowship prize from Diabete Ricerca. Some of the reagents used in the study were supported by National Institutes of Health Grants RO1DK67536 and NIH R01DK103215 (to R.N.K.) and Grant P30 DK36386 (Joslin Diabetes Research Center). NR 12 TC 1 Z9 1 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 470 EP 475 DI 10.1210/jc.2015-2802 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700015 PM 26649619 ER PT J AU Roussel-Gervais, A Couture, C Langlais, D Takayasu, S Balsalobre, A Rueda, BR Zukerberg, LR Figarella-Branger, D Brue, T Drouin, J AF Roussel-Gervais, Audrey Couture, Catherine Langlais, David Takayasu, Shinobu Balsalobre, Aurelio Rueda, Bo R. Zukerberg, Lawrence R. Figarella-Branger, Dominique Brue, Thierry Drouin, Jacques TI The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FACTOR-KAPPA-B; MOLECULAR-MECHANISMS; TUMOR-SUPPRESSOR; CHROMOSOME 18Q; CYCLIN-E; C-JUN; RECEPTOR; TRANSCRIPTION; TUMORIGENESIS; EXPRESSION AB Context: Cushing disease (CD) is due to pituitary corticotrope adenomas that produce unrestrained ACTH secretion and have lost the negative feedback exerted by glucocorticoids (GCs). GCs also restrain corticotrope proliferation, and the mechanisms of this inhibition are poorly understood. Objective: The aim of the study was to identify cell cycle regulatory genes that are regulated by GCs and the glucocorticoid receptor and to assess regulatory genes that have a rate-limiting action on corticotrope proliferation and may be disregulated in CD. Design: The mouse corticotrope tumor cells AtT-20 were used to identify GC-regulated genes that contribute to control of cell cycle progression. Surgery sections from patients with CD were used to assess expression of CABLES1 in corticotrope adenomas. Methods: Gene expression profiling, small interfering RNA knockdowns, cell cycle analyses, and genetic manipulations were performed in AtT-20 cells. Sequencing of chromatin immunoprecipitation for pituitary-restricted transcription factors and RNA polymerase II were used to identify regulatory elements and genes that bind GR and are direct transcriptional targets. A panel of previously well-characterized corticotrope adenomas was used to correlate expression of CABLES1 with that of other markers. Results: GCs altered expression of 3 positive and 3 negative regulators of cell cycle progression. Two Myc genes (L-Myc and N-Myc) and E2F2 are repressed by GCs, whereas genes for the negative regulators of the cell cycle, Gadd45 beta, Gadd45 gamma, and Cables1 are activated by GCs. Cables1 small interfering RNA knockdown strongly stimulates AtT-20 cell proliferation and antagonizes the growth inhibition produced by GCs. The Gadd45 and Cables1 genes have the hallmarks of direct GC targets. CABLES1 is expressed in normal human pituitary cells, but expression is lost in similar to 55% of corticotrope adenomas, and this is strongly correlated with the loss of p27(Kip1) expression. Conclusions: CABLES1 is a critical regulator of corticotrope proliferation that defines a pathway often inactivated in CD and links proliferation to GC resistance. C1 [Roussel-Gervais, Audrey; Couture, Catherine; Langlais, David; Takayasu, Shinobu; Balsalobre, Aurelio; Drouin, Jacques] Inst Rech Clin Montreal, Mol Genet Lab, 110 Ave Pins Ouest, Montreal, PQ H2W 1R7, Canada. [Rueda, Bo R.; Zukerberg, Lawrence R.; Drouin, Jacques] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Figarella-Branger, Dominique; Brue, Thierry] Aix Marseille Univ, CNRS, Ctr Res Neurobiol & Neurophysiol Marseille, Unite Mixte Rech 7286, F-13344 Marseille, France. [Figarella-Branger, Dominique; Brue, Thierry] Hop Conception, Assistance Publ Hop Marseille, Serv Endocrinol Diabete & Malad Metab, Ctr Reference Malad Rares Origine Hypophysaire, F-13285 Marseille, France. RP Drouin, J (reprint author), Inst Rech Clin Montreal, Mol Genet Lab, 110 Ave Pins Ouest, Montreal, PQ H2W 1R7, Canada. EM jacques.drouin@ircm.qc.ca OI Brue, Thierry/0000-0001-8482-6691 FU Canadian Institutes for Health Research; Canadian Cancer Society; Universite de Montreal; Fonds de recherche du Quebec-Sante scholarship FX This work was supported by grants from the Canadian Institutes for Health Research and the Canadian Cancer Society (to J.D.). D.L. was supported by a scholarship from Universite de Montreal. A.R.-G. was supported by a Fonds de recherche du Quebec-Sante scholarship. NR 38 TC 3 Z9 3 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 513 EP 522 DI 10.1210/jc.2015-3324 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700020 PM 26695862 ER PT J AU Konijeti, GG Arora, P Boylan, MR Song, Y Huang, S Harrell, F Newton-Cheh, C O'Neill, D Korzenik, J Wang, TJ Chan, AT AF Konijeti, Gauree Gupta Arora, Pankaj Boylan, Matthew R. Song, Yanna Huang, Shi Harrell, Frank Newton-Cheh, Christopher O'Neill, Dillon Korzenik, Joshua Wang, Thomas J. Chan, Andrew T. TI Vitamin D Supplementation Modulates T Cell-Mediated Immunity in Humans: Results from a Randomized Control Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INFLAMMATORY BOWEL DISEASES; CROHNS-DISEASE; MULTIPLE-SCLEROSIS; REDUCED RISK; DOUBLE-BLIND; CHOLECALCIFEROL; INFECTION; OUTCOMES; THERAPY AB Context: Although studies have linked vitamin D deficiency with immune-mediated diseases, data demonstrating a direct effect on T-cell function are sparse. Objective: Our objective was to determine whether oral vitamin D3 influences T-cell activation in humans with vitamin D deficiency. Design: This was a single-center ancillary study within Vitamin D Therapy in Individuals at High Risk of Hypertension, a double-blind, multicenter, randomized controlled trial. Setting: This study was undertaken in a single academic medical center. Participants: Adults with vitamin D deficiency and untreated pre-or early stage I hypertension were included. Intervention: In Vitamin D Therapy in Individuals at High Risk of Hypertension, participants were randomized to either low-(400 IU daily) or high-(4000 IU daily) dose oral vitamin D3 for 6 months. In this ancillary study of 38 patients, we measured CD4+ T-cell activation estimated by intracellular ATP release after stimulation of whole blood with plant lectin phytohemagglutinin collected at baseline (pretreatment) and 2-month follow-up. Main Outcome Measure: Determining whether ATP level changes were significantly different between treatment groups was the main outcome measure. Results: Treatment with 4000 IU of vitamin D3 decreased intracellular CD4+ ATP release by 95.5 ng/ml (interquartile range, -219.5 to 105.8). In contrast, 400 IU of vitamin D3 decreased intracellular CD4+ ATP release by 0.5 ng/ml (interquartile range, -69.2 to 148.5). In a proportional odds model, high-dose vitamin D3 was more likely than low-dose vitamin D3 to decrease CD4+ ATP release (odds ratio, 3.43; 95% confidence interval, 1.06-1.11). Conclusions: In this ancillary study of a randomized controlled trial, we found that high-dose vitamin D3 significantly reduced CD4+ T-cell activation compared to low-dose vitamin D3, providing human evidence that vitamin D can influence cell-mediated immunity. C1 [Konijeti, Gauree Gupta] Scripps Clin, Div Gastroenterol, La Jolla, CA 92037 USA. [Konijeti, Gauree Gupta] Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Konijeti, Gauree Gupta; Boylan, Matthew R.; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St,GRJ 825C, Boston, MA 02114 USA. [Arora, Pankaj] Univ Alabama Birmingham, Div Cardiol, Birmingham, AL 35210 USA. [Song, Yanna; Huang, Shi; Harrell, Frank; O'Neill, Dillon; Wang, Thomas J.] Vanderbilt Univ, Dept Biostat, Nashville, TN 37232 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiol, Nashville, TN 37232 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Korzenik, Joshua] Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St,GRJ 825C, Boston, MA 02114 USA. EM achan@mgh.harvard.edu FU Diasorin; National Center for Advancing Translational Sciences (NCATS)/National Institutes of Health (NIH) [KL2TR001112-03]; [K24 DK098311]; [T32 DK 007191] FX The Vitamin D Therapy in Individuals at High Risk of Hypertension study was supported by a research grant from Diasorin. Assay support was provided by LabCorp. The ancillary study on T-cell activation was funded by K24 DK098311 (to A.T.C.). Supported was provided by T32 DK 007191 and National Center for Advancing Translational Sciences (NCATS)/National Institutes of Health (NIH) grant KL2TR001112-03 (to G.G.K.). ImmuKnow kits were provided by Cylex, now part of Viracor-IBT Laboratories. NR 24 TC 3 Z9 3 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 533 EP 538 DI 10.1210/jc.2015-3599 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700022 PM 26653112 ER PT J AU Leong, A Berkowitz, SA Triant, VA Porneala, B He, W Atlas, SJ Wexler, DJ Meigs, JB AF Leong, Aaron Berkowitz, Seth A. Triant, Virginia A. Porneala, Bianca He, Wei Atlas, Steven J. Wexler, Deborah J. Meigs, James B. TI Hypoglycemia in Diabetes Mellitus as a Coronary Artery Disease Risk Factor in Patients at Elevated Vascular Risk SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INTENSIVE GLUCOSE CONTROL; CARDIOVASCULAR-DISEASE; GLYCEMIC CONTROL; ACCORD TRIAL; OLDER-ADULTS; PRIMARY-CARE; FOLLOW-UP; MORTALITY; EVENTS; INSULIN AB Context: Although clinical trials have shown that hypoglycemia is associated with coronary artery disease (CAD), little is known whether hypoglycemia is a CAD risk factor in primary care. Objective: We sought to determine whether previous hypoglycemia was associated with incident CAD, and whether this association differed in patients of different underlying vascular risk. Design, setting and participants: This is a longitudinal cohort study of diabetes patients without CAD before January 1, 2006 (n = 9173) followed at an academic network of 13 primary care practices from January 1, 2006 to June 30, 2012. Hypoglycemic events before January 1, 2006 were identified via International Classification of Diseases Ninth Revision codes from emergency department, inpatient and outpatient visits. Main Outcome Measure: Patients were followed until incident CAD or June 30, 2012. Cox regression with time interaction was used to determine the association between hypoglycemia and CAD (significance set at P <= .05). We then tested the association among high vascular risk patients (age >= 55 y, hemoglobin A1c >= 7.5%, >= 2 risk factors [dyslipidemia, hypertension or obesity]), a subset of high vascular risk patients aged 65 years or older, and the remaining patients with lower vascular risk. Results: Three percent of patients (n = 285) had previous hypoglycemia. Hypoglycemia was associated with a 2-fold CAD risk (hazard ratio [HR] 2.15; 95% confidence interval [95% CI] 1.24-3.74), adjusting for time interaction and vascular risk factors. Among high vascular risk patients, the risk was 3-fold (HR 3.01 [95% CI 1.15-7.91], n = 1823 [20% of cohort]), and over 4-fold (HR 4.62 [95% CI 1.65-12.9], n = 996) in the subset aged more than or equal to 65 years. No association was found in the remaining 80% of the cohort with lower vascular risk. Conclusions: Previous hypoglycemia was associated with CAD among high vascular risk patients. Hypoglycemia may not be a CAD risk factor for the majority of primary care patients with lower underlying vascular risk. C1 [Leong, Aaron; Berkowitz, Seth A.; Triant, Virginia A.; Porneala, Bianca; He, Wei; Atlas, Steven J.; Wexler, Deborah J.; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Leong, Aaron; Berkowitz, Seth A.; Triant, Virginia A.; Atlas, Steven J.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Berkowitz, Seth A.; Wexler, Deborah J.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@mgh.harvard.edu OI Berkowitz, Seth/0000-0003-1030-4297 FU National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140] FX A.L. is a Canadian Diabetes Association Postdoctoral Research fellow. J.B.M. is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases Grant K24 DK080140. NR 41 TC 3 Z9 3 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 659 EP 668 DI 10.1210/jc.2015-3169 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700036 PM 26672635 ER PT J AU Hwang, YC Fujimoto, WY Hayashi, T Kahn, SE Leonetti, DL Boyko, EJ AF Hwang, You-Cheol Fujimoto, Wilfred Y. Hayashi, Tomoshige Kahn, Steven E. Leonetti, Donna L. Boyko, Edward J. TI Increased Visceral Adipose Tissue Is an Independent Predictor for Future Development of Atherogenic Dyslipidemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; METABOLIC RISK-FACTORS; JAPANESE-AMERICAN MEN; INCIDENT HYPERTENSION; INSULIN SENSITIVITY; FAT DISTRIBUTION; OBESE ADULTS; BODY-FAT; PLASMA; PREVALENCE AB Context: Atherogenic dyslipidemia is frequently observed in persons with a greater amount of visceral adipose tissue (VAT). However, it is still uncertain whether VAT is independently associated with the future development of atherogenic dyslipidemia. Objectives: The aim of this study was to determine whether baseline and changes in VAT and subcutaneous adipose tissue (SAT) are associated with future development of atherogenic dyslipidemia independent of baseline lipid levels and standard anthropometric indices. Design and Setting: Community-based prospective cohort study with 5 years of follow-up. Participants: A total of 452 Japanese Americans (240 men, 212 women), aged 34-75 years were assessed at baseline and after 5 years of follow-up. Main Outcome Measures: Abdominal fat areas were measured by computed tomography. Atherogenic dyslipidemia was defined as one or more abnormalities in high-density lipoprotein (HDL) cholesterol, triglycerides, or non-HDL cholesterol levels. Results: Baseline VAT and change in VAT over 5 years were independently associated with log-transformed HDL cholesterol, log-transformed triglyceride, and non-HDL cholesterol after 5 years (standardized beta = -0.126, 0.277, and 0.066 for baseline VAT, respectively, and -0.095, 0.223, and 0.090 for change in VAT, respectively). However, baseline and change in SAT were not associated with any future atherogenic lipid level. In multivariate logistic regression analysis, incremental change in VAT (odds ratio [95% confidence interval], 1.73 [1.20-2.48]; P = .003), triglycerides (4.01 [1.72-9.33]; P < .001), HDL cholesterol (0.32 [0.18-0.58]; P < .001), and non-HDL cholesterol (7.58 [4.43-12.95]; P < .001) were significantly associated with the future development of atherogenic dyslipidemia independent of age, sex, diastolic blood pressure, homeostasis model assessment insulin resistance, body mass index (BMI), change in BMI, SAT, and baseline atherogenic lipid levels. Conclusion: Baseline and change in VAT were independent predictors for future development of atherogenic dyslipidemia. However, BMI, waist circumference, and SAT were not associated with future development of atherogenic dyslipidemia. C1 [Hwang, You-Cheol; Boyko, Edward J.] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA. [Hwang, You-Cheol] Kyung Hee Univ, Sch Med, Kyung Hee Univ Hosp Gangdong, Div Endocrinol & Metab,Dept Med, Seoul 134727, South Korea. [Fujimoto, Wilfred Y.; Kahn, Steven E.] Univ Washington, Sch Med, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98105 USA. [Hayashi, Tomoshige] Osaka City Univ, Grad Sch Med, Dept Prevent Med & Environm Hlth, Osaka 3-3-138, Osaka, Japan. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Hosp & Specialty Med Serv, Seattle, WA 98108 USA. [Leonetti, Donna L.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. RP Boyko, EJ (reprint author), VA Puget Sound, S-123-PCC,1660 South Columbian Way, Seattle, WA 98108 USA. EM eboyko@uw.edu OI Kahn, Steven/0000-0001-7307-9002 FU King County Japanese American community FX We dedicate this manuscript to the memory of Marguerite J. McNeely who for many years played an important role as investigator in the Japanese American Community Diabetes Study. Her critical contributions will be missed. We are grateful to the King County Japanese American community for support and cooperation. NR 35 TC 3 Z9 3 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 678 EP 685 DI 10.1210/jc.2015-3246 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700038 PM 26636177 ER PT J AU Duca, LM Maahs, DM Schauer, IE Bergman, BC Nadeau, KJ Bjornstad, P Rewers, M Snell-Bergeon, JK AF Duca, Lindsey M. Maahs, David M. Schauer, Irene E. Bergman, Bryan C. Nadeau, Kristen J. Bjornstad, Petter Rewers, Marian Snell-Bergeon, Janet K. TI Development and Validation of a Method to Estimate Insulin Sensitivity in Patients With and Without Type 1 Diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORONARY-ARTERY CALCIFICATION; CARDIOVASCULAR-DISEASE; PITTSBURGH EPIDEMIOLOGY; GLUCOSE CLAMP; RESISTANCE; HYPERTENSION; COMPLICATION; NEPHROPATHY; ADOLESCENTS; OBESITY AB Context: People with type 1 diabetes (T1D) have markedly reduced insulin sensitivity (IS) compared to their nondiabetic counterparts, and reduced IS is linked to higher cardiovascular risk. Objective: This study aimed to develop and validate an improved method for estimating IS in people with T1D. Design: Prospective cohort. Setting: Adults (36 with T1D, 41 nondiabetic) were recruited from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study for measurement of IS by hyperinsulinemic-euglycemic clamp to develop a clinically useful IS prediction equation (eIS) for T1D and nondiabetic individuals. These equations were then compared with previously published equations from the SEARCH and Pittsburgh Epidemiology of Diabetes Complications studies for the ability to predict measured IS in test sets of adults and adolescents from independent clamp studies. Intervention: None. Main Outcome Measure: Comparison of clamp-measured IS to estimated IS. Results: The best-fit prediction model (eIS) differed by diabetes status and included waist circumference, triglycerides, adiponectin, and diastolic blood pressure in all CACTI adults and insulin dose in adults with T1D (adjusted R-2 = 0.64) or fasting glucose and hemoglobin A1c (HbA1c) in nondiabetic adults (adjusted R-2 = 0.63). The eIS highly correlated with clamp-measured IS in all of the non-CACTI comparison populations (r = 0.83, P = .0002 in T1D adults; r = 0.71, P = .01 in nondiabetic adults; r = 0.44, P = .008 in T1D adolescents; r = 0.44, P = .006 in nondiabetic adolescents). Conclusions: eIS performed better than previous equations for estimating IS in individuals with and without T1D. These equations could simplify point-of-care assessment of IS to identify patients who could benefit from targeted intervention. C1 [Duca, Lindsey M.; Maahs, David M.; Bjornstad, Petter; Rewers, Marian; Snell-Bergeon, Janet K.] Univ Colorado, Sch Med, Barbara Davis Ctr Diabet, Aurora, CO 80045 USA. [Duca, Lindsey M.; Maahs, David M.; Snell-Bergeon, Janet K.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO 80045 USA. [Schauer, Irene E.; Bergman, Bryan C.] Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Sch Med, Aurora, CO 80045 USA. [Nadeau, Kristen J.] Univ Colorado, Sch Med, Div Pediat Endocrinol, Dept Pediat, Aurora, CO 80045 USA. [Schauer, Irene E.] Denver VA Med Ctr, Denver, CO 80220 USA. RP Duca, LM (reprint author), Univ Colorado Denver, Barbara Davis Ctr Childhood Diabet, Sch Med, Box A-140,1775 Aurora Court, Aurora, CO 80045 USA. EM Lindsey.Duca@ucdenver.edu OI Bergman, Bryan/0000-0002-9561-1052; Bjornstad, Petter/0000-0002-5160-2947 FU National Institutes of Health (NIH) [M01 RR000051]; Colorado Clinical and Translational Sciences Institute (CCTSI) [UL1 TR000154]; NIH National Heart, Lung and Blood Institute [R01 HL61753, R01 HL079611, R01 HL11309]; American Diabetes Association [1-10-JF-50, 7-13-CD-10, 7-11-CD-08]; Juvenile Diabetes Research Foundation [11-2010-343, 17-2013-313]; NIH Building Interdisciplinary Research Careers in Women's Health (BIRCWH) [K12 5K12HD057022-04]; National Center for Research Resources [K23 RR020038-01]; NIH [R56 DK088971]; Office of Research in Women's Health BIRCWH K12 Program; Diabetes Endocrinology Research Center Clinical Investigation Core Grant [P30 DK57516] FX The study was performed at the Barbara Davis Center for Childhood Diabetes in Denver, Colorado, and at the Clinical Translational Research Centers (CTRC) at the University of Colorado and Children's Hospital Colorado and was supported by the National Institutes of Health (NIH) Grant M01 RR000051 and Colorado Clinical and Translational Sciences Institute (CCTSI) Grant UL1 TR000154. Support was provided by the NIH National Heart, Lung and Blood Institute Grants R01 HL61753, R01 HL079611, and R01 HL11309; the American Diabetes Association Junior Faculty Award 1-10-JF-50 and 7-13-CD-10 (to J.K.S.-B.), American Diabetes Association Grant 7-11-CD-08, the Juvenile Diabetes Research Foundation Grant 11-2010-343 and 17-2013-313, NIH Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Grant K12 5K12HD057022-04, the National Center for Research Resources Grant K23 RR020038-01, NIH Grant R56 DK088971 (to K.J.N.), Office of Research in Women's Health BIRCWH K12 Program (to I.E.S.), and Diabetes Endocrinology Research Center Clinical Investigation Core Grant P30 DK57516. NR 28 TC 1 Z9 1 U1 1 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 686 EP 695 DI 10.1210/jc.2015-3272 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700039 PM 26672636 ER PT J AU Yu, EW Wewalka, M Ding, SA Simonson, DC Foster, K Holst, JJ Vernon, A Goldfine, AB Halperin, F AF Yu, Elaine W. Wewalka, Marlene Ding, Su-Ann Simonson, Donald C. Foster, Kathleen Holst, Jens J. Vernon, Ashley Goldfine, Allison B. Halperin, Florencia TI Effects of Gastric Bypass and Gastric Banding on Bone Remodeling in Obese Patients With Type 2 Diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; PEPTIDE-YY LEVELS; BARIATRIC SURGERY; MINERAL DENSITY; BODY-COMPOSITION; WEIGHT-LOSS; CIRCADIAN VARIATION; CALCIUM-ABSORPTION; SLEEVE GASTRECTOMY; MEDICAL-MANAGEMENT AB Context: Roux-en-Y gastric bypass (RYGB) leads to high-turnover bone loss, but little is known about skeletal effects of laparoscopic adjustable gastric banding (LAGB) or mechanisms underlying bone loss after bariatric surgery. Objective: To evaluate effects of RYGB and LAGB on fasting and postprandial indices of bone remodeling. Design and Setting: Ancillary investigation of a prospective study at 2 academic institutions. Participants: Obese adults aged 21-65 years with type 2 diabetes who underwent RYGB (n = 11) or LAGB (n = 8). Outcomes: Serum C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and PTH were measured during a mixed meal tolerance test at baseline, 10 days and 1 year after surgery. Changes in 25-hydroxyvitamin D, polypeptide YY (PYY), glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and insulin were also assessed. Results: Fasting CTX increased 10 days after RYGB but not LAGB (+69 +/- 23% vs +12 +/- 12%, P < .001), despite comparable weight loss at that time. By 1 year, fasting CTX and P1NP increased more after RYGB than LAGB (CTX +221 +/- 60% vs +15 +/- 6%, P < 0.001; P1NP +93 +/- 25% vs -9 +/- 10%, P < .001) and weight loss was greater with RYGB. Changes in CTX were independent of PTH and 25-hydroxyvitamin D but were associated with increases in fasting PYY. Postprandial suppression of CTX was more pronounced after RYGB than LAGB at 10 days and 1 year postoperatively. Conclusions: RYGB is accompanied by early increases in fasting indices of bone remodeling, independent of weight loss or changes in PTH or 25-hydroxyvitamin D. LAGB did not affect bone markers. PYY and other enterohormonal signals may play a role in RYGB-specific skeletal changes. C1 [Yu, Elaine W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Wewalka, Marlene; Ding, Su-Ann; Foster, Kathleen; Goldfine, Allison B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Simonson, Donald C.; Goldfine, Allison B.; Halperin, Florencia] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Holst, Jens J.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, DK-1168 Copenhagen, Denmark. [Holst, Jens J.] Univ Copenhagen, Dept Biomed Sci, DK-1168 Copenhagen, Denmark. [Vernon, Ashley] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Metab & Bariatr Surg, Boston, MA 02115 USA. RP Yu, EW (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1051, Boston, MA 02114 USA. EM ewyu@mgh.harvard.edu FU National Institutes of Health [K23-DK093713, RC1-DK086918, R56-DK095451, P30-DK036836]; Harvard Catalyst and The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst and The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences) [8UL1TR000170-05]; Harvard Catalyst and The Harvard Clinical and Translational Science Center (KL2/MeRIT Program Award) [UL1 RR 025758]; Harvard Catalyst and The Harvard Clinical and Translational Science Center (Harvard University and its affiliated academic healthcare centers); Joslin Clinical Research Center; Marietta Blau Grant from the Osterreichischer Austausdienst [ICM-2010-02797]; Herbert Graetz Fund; Covidien; Lifescan, a division of Johnson and Johnson; Nestle; NovoNordisk FX This work was supported by National Institutes of Health Grants K23-DK093713, RC1-DK086918, R56-DK095451, and P30-DK036836; Harvard Catalyst and The Harvard Clinical and Translational Science Center (National Center for Research Resources and National Center for Advancing Translational Sciences, Award 8UL1TR000170-05; KL2/MeRIT Program Award UL1 RR 025758; and financial contributions from Harvard University and its affiliated academic healthcare centers); the Joslin Clinical Research Center and its philanthropic donors; the Marietta Blau Grant ICM-2010-02797 from the Osterreichischer Austausdienst; the Herbert Graetz Fund; Covidien; Lifescan, a division of Johnson and Johnson; Nestle; and NovoNordisk. NR 43 TC 3 Z9 3 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2016 VL 101 IS 2 BP 714 EP 722 DI 10.1210/jc.2015-3437 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP6XI UT WOS:000378642700042 PM 26600045 ER PT J AU Hoffmann, U Massaro, JM D'Agostino, RB Kathiresan, S Fox, CS O'Donnell, CJ AF Hoffmann, Udo Massaro, Joseph M. D'Agostino, Ralph B., Sr. Kathiresan, Sekar Fox, Caroline S. O'Donnell, Christopher J. TI Cardiovascular Event Prediction and Risk Reclassification by Coronary, Aortic, and Valvular Calcification in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE coronary disease; prognosis; risk factors ID ARTERY CALCIUM; COMPUTED-TOMOGRAPHY; DISEASE; ASSOCIATION; MORTALITY; ATHEROSCLEROSIS; STROKE; DISCRIMINATION; POPULATION; MORBIDITY AB Background-We determined whether vascular and valvular calcification predicted incident major coronary heart disease, cardiovascular disease (CVD), and all-cause mortality independent of Framingham risk factors in the community-based Framingham Heart Study. Methods and Results-Coronary artery calcium (CAC), thoracic and abdominal aortic calcium, and mitral or aortic valve calcium were measured by cardiac computed tomography in participants free of CVD. Participants were followed for a median of 8 years. Multivariate Cox proportional hazards models were used to determine association of CAC, thoracic and abdominal aortic calcium, and mitral and aortic valve calcium with end points. Improvement in discrimination beyond risk factors was tested via the C-statistic and net reclassification index. In this cohort of 3486 participants (mean age 50 +/- 10 years; 51% female), CAC was most strongly associated with major coronary heart disease, followed by major CVD, and all-cause mortality independent of Framingham risk factors. Among noncoronary calcifications, mitral valve calcium was associated with major CVD and all-cause mortality independent of Framingham risk factors and CAC. CAC significantly improved discriminatory value beyond risk factors for coronary heart disease (area under the curve 0.78-0.82; net reclassification index 32%, 95% CI 11-53) but not for CVD. CAC accurately reclassified 85% of the 261 patients who were at intermediate (5-10%) 10-year risk for coronary heart disease based on Framingham risk factors to either low risk (n=172; no events observed) or high risk (n=53; observed event rate 8%). Conclusions-CAC improves discrimination and risk reclassification for major coronary heart disease and CVD beyond risk factors in asymptomatic community-dwelling persons and accurately reclassifies two-thirds of the intermediate-risk population. C1 [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02115 USA. [Hoffmann, Udo; Kathiresan, Sekar; O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Metab & Diabet,Dept Med, Boston, MA 02115 USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; Fox, Caroline S.; O'Donnell, Christopher J.] Boston Univ, Framingham, MA USA. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 100 Charles River Plaza Suite 400, Boston, MA 02114 USA.; Hoffmann, U (reprint author), Harvard Univ, Sch Med, 100 Charles River Plaza Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org FU NIH Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385] FX This work was supported by the NIH Heart, Lung, and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, and HL107385). The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation o the data; and preparation, review, or approval of the manuscript. NR 30 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2016 VL 5 IS 2 AR e003144 DI 10.1161/JAHA.115.003144 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9TW UT WOS:000378131100023 ER PT J AU Therkelsen, KE Abraham, TM Pedley, A Massaro, JM Sutherland, P Hoffmann, U Fox, CS AF Therkelsen, Kate E. Abraham, Tobin M. Pedley, Alison Massaro, Joseph M. Sutherland, Patrice Hoffmann, Udo Fox, Caroline S. TI Association Between Prolactin and Incidence of Cardiovascular Risk Factors in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE epidemiology; hormones; obesity; population ID HORMONE-BINDING GLOBULIN; SIGNAL-TRANSDUCTION; PLASMA PROLACTIN; BODY-WEIGHT; WOMEN; MEN; BROMOCRIPTINE; HYPERTENSION; FAT; TESTOSTERONE AB Background-Prolactin is an anterior pituitary hormone that may modulate the adverse effects of obesity. Prolactin has been associated with cardiovascular disease mortality, but less is known about whether prolactin predicts incidence of cardiovascular disease risk factors. Methods and Results-Our sample (n=3232, mean age 40.4 years, 52.1% women) was drawn from Framingham Heart Study participants who attended 2 examinations an average of 6.1 years apart. After excluding those with elevated prolactin (>30 mg/dL for women, >20 mg/dL for men), multivariable-adjusted regressions modeled the associations between baseline prolactin and changes in cardiovascular disease risk factors. Models were adjusted for age, sex, baseline value of the risk factor, smoking status, hormone replacement therapy, and menopausal status and additionally for body mass index. Mean prolactin levels were 11.9 mg/dL (SD 5.2) in women and 8.0 mg/dL (SD 2.9) in men. No associations were observed for change in weight, body composition, total cholesterol, triglycerides, or fasting glucose. In women, for example, for each 5-mg/dL increment in prolactin, odds of incident hypercholesterolemia were 1.06, which was not significant (95% CI 0.91-1.23, P=0.46). Some exceptions were of note. In women, for each 5-mg/dL increment in prolactin, we observed increased odds of low high-density lipoprotein cholesterol at follow-up (odds ratio 1.50, 95% CI 1.18-1.91, P=0.001) that persisted after adjustment for body mass index (P=0.001). In men, a 5-mg/dL increment in prolactin was associated with increased odds of incident hypertension (odds ratio 1.61, 95% CI 1.18-2.20 P=0.002) and incident diabetes (odds ratio 1.70, 95% CI 1.04-2.78, P=0.03). Conclusions-Prolactin is not associated with a comprehensive panel of incident cardiovascular disease risk factors. Measurement of circulating prolactin levels in the community likely does not provide substantial insight into cardiometabolic risk. C1 [Therkelsen, Kate E.; Pedley, Alison; Sutherland, Patrice; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Abraham, Tobin M.; Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, 75 Francis St, Boston, MA 02115 USA. [Abraham, Tobin M.; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Fox, Caroline S.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU NIH; [N01-HC-25195] FX The Framingham Heart Study of the National Heart, Lung and Blood Institute is supported by contract N01-HC-25195. Abraham is supported by an NIH-sponsored T32 training grant. NR 39 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2016 VL 5 IS 2 AR e002640 DI 10.1161/JAHA.115.002640 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9TW UT WOS:000378131100051 ER PT J AU Xu, HY Ruff, CT Giugliano, RP Murphy, SA Nordio, F Patel, I Shi, MG Mercuri, M Antman, EM Braunwald, E AF Xu, Haiyan Ruff, Christian T. Giugliano, Robert P. Murphy, Sabina A. Nordio, Francesco Patel, Indravadan Shi, Minggao Mercuri, Michele Antman, Elliott M. Braunwald, Eugene TI Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF-TIMI48 Trial SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE anticoagulant; antiplatelet; atrial fibrillation; edoxaban ID ORAL ANTICOAGULANT-THERAPY; ACUTE CORONARY SYNDROME; MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY; RANDOMIZED-TRIALS; ASPIRIN; ASSOCIATION; CLOPIDOGREL; MANAGEMENT; RISK AB Background-We studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti-Xa agent edoxaban in patients with atrial fibrillation (AF). Methods and Results-ENGAGE AF-TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved high-dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower-dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS(2)Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HRadj]=1.46; 95% CI, 1.27-1.67, P< 0.001). SAPT did not alter the relative efficacy of edoxaban compared to warfarin in preventing stroke or systemic embolic events (SEEs): edoxaban versus warfarin without SAPT, hazard ratio (HRadj for HDER)=0.94; (95% CI: 0.77-1.15) with SAPT, HRadj=0.70 (95% CI: 0.50-0.98), P interaction (P-int)=0.14. (HRadj for LDER versus warfarin without SAPT=1.19 (95% CI 0.99-1.43) With SAPT, 1.03 (95% CI, 0.76-1.39) P-int=0.42. Major bleeding was lower with edoxaban than warfarin both without SAPT, HRadj for HDER=0.80 (95% CI, 0.68-0.95), and with SAPT, HRadj=0.82 (95% CI, 0.65-1.03; P-int=0.91). For LDER without SAPT (HRadj=0.56 [95% CI 0.46-0.67]) and with SAPT (HRadj=0.51 [95% CI 0.39-0.66]). Conclusions-Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT. Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT. C1 [Xu, Haiyan; Ruff, Christian T.; Giugliano, Robert P.; Murphy, Sabina A.; Nordio, Francesco; Antman, Elliott M.; Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp,Med Sch, Boston, MA 02115 USA. [Patel, Indravadan; Shi, Minggao; Mercuri, Michele] Daiichi Sankyo Pharma Dev, Edison, NJ USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,1st Off Floor, Boston, MA 02115 USA. EM ebraunwald@partners.org FU Daiichi Sankyo Pharma Development, Edison, NJ FX The ENGAGE AF TIMI 48 trial was funded by Daiichi Sankyo Pharma Development, Edison, NJ). NR 24 TC 6 Z9 6 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2016 VL 5 IS 2 AR e002587 DI 10.1161/JAHA.115.002587 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO9TW UT WOS:000378131100054 ER PT J AU Mroczkowski, MM Goes, FS Riddle, MA Grados, MA Bienvenu, OJ Greenberg, BD Fyer, AJ Mccracken, JT Rauch, SL Murphy, DL Knowles, JA Piacentini, J Cullen, B Rasmussen, SA Pauls, DL Nestadt, G Samuels, J AF Mroczkowski, M. M. Goes, F. S. Riddle, M. A. Grados, M. A. Bienvenu, O. J. Greenberg, B. D. Fyer, A. J. Mccracken, J. T. Rauch, S. L. Murphy, D. L. Knowles, J. A. Piacentini, J. Cullen, B. Rasmussen, S. A. Pauls, D. L. Nestadt, G. Samuels, J. TI Dependent personality, separation anxiety disorder and other anxiety disorders in OCD SO PERSONALITY AND MENTAL HEALTH LA English DT Article ID SCHIZOPHRENIA; RELIABILITY; PREDICTORS; RATIONALE; INTERVIEW; SCHEDULE; 12-MONTH; CHILDREN; VERSION; SAMPLE AB Background - The purpose of this study was to investigate whether dependent personality and/or general personality dimensions might explain the strong relationships between separation anxiety disorder (Sep-AD) and three other anxiety disorders (agoraphobia, panic disorder and social anxiety disorder) in individuals with obsessive compulsive disorder (OCD). Methods - Using data from 509 adult participants collected during the OCD Collaborative Genetic Study, we used logistic regression models to evaluate the relationships between Sep-AD, dependent personality score, general personality dimensions and three additional anxiety disorders. Results - The dependent personality score was strongly associated with Sep-AD and the other anxiety disorders in models adjusted for age at interview, age at onset of OC symptoms and worst ever OCD severity score. Several general personality dimensions, especially neuroticism, extraversion and conscientiousness, were also related to Sep-AD and the other anxiety disorders. Sep-AD was not independently related to these anxiety disorders, in multivariate models including general personality and dependent personality disorder scores. Conclusions - The results suggest that Sep-AD in childhood and these other anxiety disorders in adulthood are consequences of dependent personality disorder (for agoraphobia and panic disorder) or introversion (for social phobia). It is unknown whether these results would be similar in a non-OCD sample. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Mroczkowski, M. M.; Fyer, A. J.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA. [Goes, F. S.; Riddle, M. A.; Grados, M. A.; Bienvenu, O. J.; Cullen, B.; Nestadt, G.; Samuels, J.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Greenberg, B. D.; Rasmussen, S. A.] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Providence, RI 02912 USA. [Fyer, A. J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Mccracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Rauch, S. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.; Pauls, D. L.] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Knowles, J. A.] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Pauls, D. L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Samuels, J (reprint author), Dept Psychiat & Behav Sci, 550 N Broadway 902, Baltimore, MD 21205 USA. EM jsamuel1@jhmi.edu OI Samuels, Jack/0000-0002-6715-7905 NR 27 TC 1 Z9 1 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8621 EI 1932-863X J9 PERSONAL MENT HEALTH JI Personal. Ment. Health PD FEB PY 2016 VL 10 IS 1 BP 22 EP 28 DI 10.1002/pmh.1321 PG 7 WC Psychiatry; Psychology, Social SC Psychiatry; Psychology GA DO9VL UT WOS:000378136000003 PM 26542617 ER PT J AU Abe, J Alop-Mabuti, A Burger, P Button, J Ellsberry, M Hitzeman, J Morgenstern, D Nunies, K Strother, M Darling-Munson, J Chan, YL Cassady, R Vasconcellos, SMK Iseman, MD Chan, ED Honda, JR AF Abe, Jonathan Alop-Mabuti, Aleena Burger, Peyton Button, Jackson Ellsberry, Madeline Hitzeman, Jaycinth Morgenstern, David Nunies, Kasey Strother, Mara Darling-Munson, Jared Chan, Yvonne L. Cassady, Robert Vasconcellos, Sarah Maile K. Iseman, Michael D. Chan, Edward D. Honda, Jennifer R. TI Comparing the temporal colonization and microbial diversity of showerhead biofilms in Hawai'i and Colorado SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE microbial biofilms; environmental health; water quality; citizen science; microbiology education ID MYCOBACTERIAL LUNG-DISEASE; WATER DISTRIBUTION-SYSTEMS; NONTUBERCULOUS MYCOBACTERIA; PULMONARY-DISEASE; HOUSEHOLD; INFECTION; AVIUM; INTRACELLULARE; EPIDEMIOLOGY; PATHOGENS AB The household is a potential source of opportunistic pathogens to humans, a particularly critical issue for immunodeficient individuals. An important human-microbe interface is the biofilm that develops on showerhead surfaces. Once microbe-laden biofilms become aerosolized, they can potentially be inhaled into the lungs. Understanding how quickly a new showerhead becomes colonized would provide useful information to minimize exposure to potentially pathogenic environmental microbes. High school scientists sampled the inner surfaces of pre-existing and newly fitted showerheads monthly over a nine-month period and applied standard microbiologic culture techniques to qualitatively assess microbial growth. Water chemistry was also monitored using commercial test strips. Sampling was performed in households on Oahu, Hawai'i and Denver, Colorado, representing warm/humid and cold/arid environments, respectively. Pre-existing showerheads in Hawai'i showed more diverse microbial growth and significantly greater microbial numbers than a comparable showerhead from Colorado. New, chrome-plated or plastic showerheads in Hawai'i showed diverse and abundant growth one month after installment compared to new showerheads from Colorado. The pH, total chlorine and water hardness levels varied significantly between the Hawai'i and Colorado samples. Enthusiastic student and teacher participation allowed us to answer long-standing questions regarding the temporal colonization of microbial biofilms on pre-existing and new showerhead surfaces. C1 [Abe, Jonathan; Chan, Yvonne L.] Iolani Sch, Honolulu, HI 96826 USA. [Alop-Mabuti, Aleena; Button, Jackson; Hitzeman, Jaycinth; Nunies, Kasey; Vasconcellos, Sarah Maile K.] Isl Pacific Acad, Kapolei, HI 96707 USA. [Burger, Peyton; Ellsberry, Madeline; Morgenstern, David; Strother, Mara; Cassady, Robert] Standley Lake High Sch, Denver, CO 80021 USA. [Darling-Munson, Jared; Iseman, Michael D.; Chan, Edward D.; Honda, Jennifer R.] Natl Jewish Hlth, 1400 Jackson St,Neustadt Bldg,Room D509, Denver, CO 80206 USA. [Chan, Edward D.; Honda, Jennifer R.] Univ Colorado, Dept Med, Pulm & Crit Care Med Div, Anschutz Med Campus, Aurora, CO 80045 USA. [Chan, Edward D.; Honda, Jennifer R.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Honda, JR (reprint author), Univ Colorado, Div Pulm Sci & Crit Care Med, Anschutz Med Campus,RC2,Box C272, Aurora, CO 80045 USA. EM Jennifer.Honda@ucdenver.edu FU Randall/Maciver Trust; University of Colorado Anschutz Medical Campus Pulmonary and Critical Care Medicine Division; Shoot for the Cure Foundation FX Dr Jennifer R. Honda is supported by the Randall/Maciver Trust, The University of Colorado Anschutz Medical Campus Pulmonary and Critical Care Medicine Division, and The Shoot for the Cure Foundation. NR 29 TC 1 Z9 1 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0378-1097 EI 1574-6968 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD FEB PY 2016 VL 363 IS 4 AR fnw005 DI 10.1093/femsle/fnw005 PG 8 WC Microbiology SC Microbiology GA DO7MI UT WOS:000377966300010 ER PT J AU Bekaii-Saab, TS Mikhail, S Langleben, A Becerra, C Jonker, DJ Asmis, TR Cote, GM Wu, CSY Kwak, EL Spira, AI Braiteh, FS Richey, SL Hume, S Hitron, M Li, C AF Bekaii-Saab, Tanios S. Mikhail, Sameh Langleben, Adrian Becerra, Carlos Jonker, Derek J. Asmis, Timothy R. Cote, Gregory Michael Wu, Christina Sing-Ying Kwak, Eunice Lee Spira, Alexander I. Braiteh, Fadi S. Richey, Stephen Lane Hume, Stephanie Hitron, Matthew Li, Chiang TI A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Solove Res Inst, Columbus, OH 43210 USA. St Marys Hosp, Westmount, PQ, Canada. Texas Oncol, Baylor Sammons Canc Ctr, Dallas, TX USA. Ottawa Hosp, Ctr Canc, Ottawa, ON, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. Ohio State Univ, Ctr Comprehens Canc, Arthur G James Canc Hosp, Richard J Solove Res Inst, Columbus, OH 43210 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Virginia Canc Specialists Res Inst, US Oncol Res, Fairfax, VA USA. McKesson Specialty Hlth, US Oncol Network, The Woodlands, TX USA. Texas Oncol, US Oncol Network, McKesson Specialty Hlth, Ft Worth, TX USA. Boston Biomed Inc, Cambridge, MA USA. NR 0 TC 0 Z9 0 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 196 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600190 ER PT J AU Bendell, JC Murphy, JE Mahalingam, D Halmos, B Sirard, CA Landau, SB Ryan, DP AF Bendell, Johanna C. Murphy, Janet E. Mahalingam, Devalingam Halmos, Balazs Sirard, Cynthia A. Landau, Steven B. Ryan, David P. TI Phase I study of DKN-01, an anti-DKK1 antibody, in combination with paclitaxel (pac) in patients (pts) with DKK1+relapsed or refractory esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. Columbia Univ, Med Ctr, New York, NY USA. HeathCare Pharmaceut Inc, Cambridge, MA USA. Healthcare Ventures, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 111 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600109 ER PT J AU Chan, EM Hong, TS Clark, JW Blaszkowsky, LS Allen, JN Zhu, A Goyal, L Murphy, JE Kwak, EL Wo, JY Ryan, DP Faris, JE AF Chan, Edmond Mankee Hong, Theodore S. Clark, Jeffrey William Blaszkowsky, Lawrence Scott Allen, Jill N. Zhu, Andrew Goyal, Lipika Murphy, Janet E. Kwak, Eunice L. Wo, Jennifer Y. Ryan, David P. Faris, Jason Edward TI Gemcitabine (G) plus nab-paclitaxel (nab-P) versus G in patients (pts) with advanced pancreatic cancer (PDAC) after FOLFIRINOX: A single center, retrospective review. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 348 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600337 ER PT J AU Crane, CH Tao, R Bhosale, P Javle, MM Shroff, RT Aloia, TA Kaseb, AO Koay, EJ Bishop, AJ Swanick, CW Hong, TS Das, P Krishnan, S AF Crane, Christopher H. Tao, Randa Bhosale, Priya Javle, Milind M. Shroff, Rachna T. Aloia, Thomas A. Kaseb, Ahmed Omar Koay, Eugene Jon Bishop, Andrew Justin Swanick, Cameron Williams Hong, Theodore S. Das, Prajnan Krishnan, Sunil TI Effect of ablative radiotherapy on survival in patients with inoperable intrahepatic cholangiocarcinoma: A dose response analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 294 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600287 ER PT J AU Demetri, GD Reichardt, P Kang, YK Blay, JY Joensuu, H Schaefer, K Wagner, A Casali, PG Kappeler, C AF Demetri, George D. Reichardt, Peter Kang, Yoon-Koo Blay, Jean-Yves Joensuu, Heikki Schaefer, Klaus Wagner, Andrea Casali, Paolo Giovanni Kappeler, Christian TI Final overall survival (OS) analysis with modeling of crossover impact in the phase III GRID trial of regorafenib vs placebo in advanced gastrointestinal stromal tumors (GIST). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ludwig Ctr, Boston, MA USA. HELIOS Klinikum Berlin Buch, Berlin, Germany. Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. Ctr Leon Berard, F-69373 Lyon, France. Univ Lyon 1, F-69365 Lyon, France. Univ Helsinki, Cent Hosp, Helsinki, Finland. Bayer Pharma AG, Berlin, Germany. Ist Nazl Tumori, Via Venezian 1, I-20133 Milan, Italy. RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X NR 0 TC 1 Z9 1 U1 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 156 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600151 ER PT J AU Enzinger, PC McCleary, NJ Zheng, H Abrams, TA Yurgelun, MB Azzoli, CG Cleary, JM Rubinson, DA Brooks, G Chan, JA Goyal, L Meyerhardt, JA Ng, K Schrag, D Savarese, DMF Graham, C Carey, MM Fuchs, CS AF Enzinger, Peter C. McCleary, Nadine Jackson Zheng, Hui Abrams, Thomas Adam Yurgelun, Matthew B. Azzoli, Christopher G. Cleary, James M. Rubinson, Douglas Adam Brooks, Gabriel Chan, Jennifer A. Goyal, Lipika Meyerhardt, Jeffrey A. Ng, Kimmie Schrag, Deborah Savarese, Diane M. F. Graham, Christopher Carey, Margaret M. Fuchs, Charles S. TI Multicenter double-blind randomized phase II: FOLFOX plus ziv-aflibercept/placebo for patients (pts) with chemo-naive metastatic esophagogastric adenocarcinoma (MEGA) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. MGH Canc Ctr, Brookline, MA USA. Div Hematol Oncol, Waltham, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 4 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600005 ER PT J AU Frampton, GM Schrock, AB Chalmers, ZR Sun, J Ennis, R Gowen, K Beg, MS Rubinson, DA Yelensky, R Stephens, PJ Miller, VA Ross, JS Ali, SM Klempner, SJ AF Frampton, Garrett Michael Schrock, Alexa Betzig Chalmers, Zachary Rockow Sun, James Ennis, Riley Gowen, Kyle Beg, Muhammad Shaalan Rubinson, Douglas Adam Yelensky, Roman Stephens, Philip J. Miller, Vincent A. Ross, Jeffrey S. Ali, Siraj Mahamed Klempner, Samuel Jacob TI Comprehensive genomic profiling (CGP) to assess mutational load in gastric and esophageal adenocarcinomas: Implications for immunotherapies. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Fdn Med Inc, Cambridge, MA USA. Univ Texas SW Med Ctr Dallas, Div Hematol Oncol, Dallas, TX 75390 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif Irvine, Fullerton, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 66 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600065 ER PT J AU Fuchs, CS Ohtsu, A Tabernero, J Van Cutsem, E Wang, JD Lam, B Koshiji, M Bang, YJ AF Fuchs, Charles S. Ohtsu, Atsushi Tabernero, Josep Van Cutsem, Eric Wang, Jiang Dian Lam, Baohoang Koshiji, Minori Bang, Yung-Jue TI Pembrolizumab (MK-3475) plus 5-fluorouracil (5-FU) and cisplatin for first-line treatment of advanced gastric cancer: Preliminary safety data from KEYNOTE-059. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. Vall dHebron Univ Hosp, Barcelona, Spain. Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. Merck & Co Inc, Kenilworth, NJ USA. Seoul Natl Univ Hosp, Seoul 110744, South Korea. NR 0 TC 0 Z9 0 U1 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 161 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600156 ER PT J AU Fuchs, CS Tabernero, J Al-Batran, SE Chau, I Ilson, DH Van Cutsem, E Shitara, K Ferry, D Emig, M Vanvoorden, V Hsu, YZ Xu, YH Sashegyi, A Das, M Shah, MA AF Fuchs, Charles S. Tabernero, Josep Al-Batran, Salah-Eddin Chau, Ian Ilson, David H. Van Cutsem, Eric Shitara, Kohei Ferry, David Emig, Michael Vanvoorden, Veerle Hsu, Yanzhi Xu, Yihuan Sashegyi, Andreas Das, Mayukh Shah, Manish A. TI A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. Vall dHebron Univ Hosp, Barcelona, Spain. UCT Univ Canc Ctr Frankfurt, Inst Clin Canc Res, Frankfurt, Germany. Royal Marsden Hosp, London SW3 6JJ, England. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Univ Hosp Gasthuisberg, Leuven, Belgium. Natl Canc Ctr Hosp East, Dept Gastrointestinal Oncol, Kashiwa, Chiba, Japan. Eli Lilly & Co, Bridgewater, NJ USA. Lilly Deutschland GmbH, Bad Homburg, Germany. Eli Lilly & Co, Brussels, Belgium. Eli Lilly & Co, Indianapolis, IN 46285 USA. Weill Cornell Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA TPS178 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600173 ER PT J AU Fuchs, CS Denker, AE Tabernero, J Van Cutsem, E Ohtsu, A Lam, B Koshiji, M Bang, YJ AF Fuchs, Charles S. Denker, Andrew E. Tabernero, Josep Van Cutsem, Eric Ohtsu, Atsushi Lam, Baohoang Koshiji, Minori Bang, Yung-Jue TI Pembrolizumab (MK-3475) for recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma: Multicohort phase II KEYNOTE-059 study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Merck & Co Inc, Kenilworth, NJ USA. Vall dHebron Univ Hosp, Barcelona, Spain. Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. Seoul Natl Univ Hosp, Seoul 110744, South Korea. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA TPS184 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600178 ER PT J AU Giannakis, M Mu, JX Shukla, S Qian, ZR Cohen, O Nishihara, R Cao, Y Yamauchi, M Sukawa, Y Nosho, K Ng, K Meyerhardt, JA Lawrence, M Gabriel, SB Lander, E Getz, G Wu, C Fuchs, CS Ogino, S Garraway, LA AF Giannakis, Marios Mu, Jasmine Xinmeng Shukla, Sachet Qian, Zhi Rong Cohen, Ofir Nishihara, Reiko Cao, Yin Yamauchi, Mai Sukawa, Yasutaka Nosho, Katsuhiko Ng, Kimmie Meyerhardt, Jeffrey A. Lawrence, Michael Gabriel, Stacey B. Lander, Eric Getz, Gad Wu, Catherine Fuchs, Charles S. Ogino, Shuji Garraway, Levi A. TI Novel driver genes and genomic predictors of immune infiltrates in colorectal cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Broad Inst, Cambridge, MA USA. Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. Sapporo Med Univ, Sch Med, Sapporo, Hokkaido, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 557 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600537 ER PT J AU Goel, G Ramanan, K Kaltenmeier, C Zhang, L Freeman, GJ Normolle, DP Tang, DL Lotze, MT AF Goel, Gaurav Ramanan, Krishnaveni Kaltenmeier, Christof Zhang, Lin Freeman, Gordon J. Normolle, Daniel Paul Tang, Daolin Lotze, Michael T. TI Effect of 5-fluorouracil on membranous PD-L1 expression in colon cancer cells. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Hillman Canc Ctr, Pittsburgh, PA USA. OI GOEL, GAURAV/0000-0002-1688-8644 NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 592 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600570 ER PT J AU Harding, JJ Bendell, JC Fuchs, CS Wang, XJ Wacheck, V Zhu, AX AF Harding, James J. Bendell, Johanna C. Fuchs, Charles S. Wang, Xuejing Wacheck, Volker Zhu, Andrew X. TI Emibetuzumab plus ramucirumab: Simultaneous targeting of MET and VEGFR-2 in patients with advanced hepatocellular cancer in a phase 1b/2 study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 300 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600293 ER PT J AU Hong, TS Wo, JYL Ben-Josef, E McDonnell, E Drapek, LC Blaszkowsky, LS Kwak, EL Clark, JW Goyal, L Ryan, DP Javle, MM Arellano, R Wolfgang, JA Mullen, JT Ferrone, C Tanabe, K DeLaney, TF Crane, CH Zhu, AX AF Hong, Theodore S. Wo, Jennifer Yon-Li Ben-Josef, Edgar McDonnell, Erin Drapek, Lorraine C. Blaszkowsky, Lawrence Scott Kwak, Eunice Lee Clark, Jeffrey W. Goyal, Lipika Ryan, David P. Javle, Milind M. Arellano, Ronald Wolfgang, John A. Mullen, John Thomas Ferrone, Cristina Tanabe, Kenneth DeLaney, Thomas F. Crane, Christopher H. Zhu, Andrew X. TI A multi-institutional phase II study of high-dose hypofractionated proton beam therapy (HF-PBT) for unresectable primary liver cancers: Long-term outcomes in patients (pts) with hepatocellular carcinoma (HCC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Waban, MA USA. Univ Penn, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. MGH Canc Ctr, Brookline, MA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 376 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600363 ER PT J AU Hurwitz, H Hainsworth, JD Swanton, C Perez, EA Sweeney, C Burris, HA Spigel, D Meric-Bernstam, F Strickland, DK Leon, L Brammer, M Beattie, MS Bose, R AF Hurwitz, Herbert Hainsworth, John D. Swanton, Charles Perez, Edith A. Sweeney, Christopher Burris, Howard A. Spigel, David Meric-Bernstam, Funda Strickland, Donald K. Leon, Larry Brammer, Melissa Beattie, Mary Stanley Bose, Ron TI Targeted therapy for gastrointestinaI (GI) tumors based on molecular profiles: Early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Duke Univ, Med Ctr, Durham, NC USA. Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. UCL, Inst Canc, Sarah Cannon Res Inst, London, England. Mayo Clin, Jacksonville, FL 32224 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Sarah Cannon Res Inst, Nashville, TN USA. Genentech Inc, San Francisco, CA 94080 USA. Washington Univ, Sch Med, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 653 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600629 ER PT J AU Javle, MM Shroff, RT Zhu, A Sadeghi, S Choo, S Borad, MJ Lowery, MA El-Khoueiry, A Macarulla, T Philip, PA Oh, DY Van Cutsem, E Yeh, KH Isaacs, R McGarry, C Sen, S Bekaii-Saab, TS AF Javle, Milind M. Shroff, Rachna T. Zhu, Andrew Sadeghi, Saeed Choo, Supin Borad, Mitesh J. Lowery, Maeve Aine El-Khoueiry, Anthony Macarulla, Teresa Philip, Agop Philip Oh, Do-Youn Van Cutsem, Eric Yeh, Kun-Huei Isaacs, Randi McGarry, Carolyn Sen, Suman Bekaii-Saab, Tanios S. TI A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif Los Angeles, Sch Med, Santa Monica, CA USA. Natl Canc Ctr, Div Med Oncol, Singapore, Singapore. Mayo Clin, Scottsdale, AZ USA. Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Vall dHebron Inst Oncol, Vall dHebron Univ Hosp, Barcelona, Spain. Karmanos Canc Inst, Detroit, MI USA. Seoul Natl Univ, Seoul Natl Univ Hosp, Canc Res Inst, Coll Med, Seoul, South Korea. Univ Hosp Gasthuisberg, Leuven, Belgium. Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan. Novartis Pharmaceut, E Hanover, NJ USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. NR 0 TC 3 Z9 3 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 335 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600325 ER PT J AU Keane, FK Wo, JYL Ferrone, C Clark, JW Blaszkowsky, LS Allen, JN Kwak, EL Ryan, DP Lillemoe, KD Fernandez-del Castillo, C Hong, TS AF Keane, Florence K. Wo, Jennifer Yon-Li Ferrone, Cristina Clark, Jeffrey W. Blaszkowsky, Lawrence Scott Allen, Jill N. Kwak, Eunice Lee Ryan, David P. Lillemoe, Keith D. Fernandez-del Castillo, Carlos Hong, Theodore S. TI Intraoperative radiotherapy (IORT) in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for locally advanced and borderline resectable adenocarcinoma of the pancreas (PDAC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Massachusetts Gen Hosp, Harvard Radiat Oncol Program, Boston, MA 02114 USA. Massachusetts Gen Hosp, Waban, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 393 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600379 ER PT J AU Le, DT Bendell, JC Calvo, E Kim, JW Ascierto, PA Sharma, P Ott, PA Bono, P Jaeger, D Evans, TRJ De Braud, FG Chau, I Christensen, O Harbison, C Lin, CS Janjigian, YY AF Le, Dung T. Bendell, Johanna C. Calvo, Emiliano Kim, Joseph W. Ascierto, Paolo Antonio Sharma, Padmanee Ott, Patrick Alexander Bono, Petri Jaeger, Dirk Evans, T. R. Jeffry De Braud, Filippo G. Chau, Ian Christensen, Olaf Harbison, Christopher Lin, Chen-Sheng Janjigian, Yelena Yuriy TI Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): Results from the CheckMate-032 study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. START Madrid, Ctr Integral Oncol Clara Campal, Madrid, Spain. Yale Univ, Med Ctr, Yale Canc Ctr, New Haven, CT USA. IRCCS, Ist Nazl Tumori, Naples, Italy. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Helsinki, Cent Hosp, Helsinki, Finland. Univ Heidelberg Hosp, Natl Ctr Tumor Dis, Heidelberg, Germany. Univ Glasgow, Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. Fdn IRCCS Ist Nazl Tumori, Milan, Italy. Royal Marsden Hosp, London SW3 6JJ, England. Bristol Myers Squibb Co, Princeton, NJ USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 0 TC 1 Z9 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 6 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600007 ER PT J AU Macarulla, T Tabernero, J Palmer, DH Sharma, S Yu, KH Sellami, DB Zhou, J Yi, W Boss, H Kwak, EL AF Macarulla, Teresa Tabernero, Josep Palmer, Daniel H. Sharma, Sunil Yu, Kenneth H. Sellami, Dalila B. Zhou, Jocelyn Yi, Wu Boss, Hildegard Kwak, Eunice L. TI A phase Ib dose escalation, safety, and tolerability study of sonidegib in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Barcelona, Spain. Univ Liverpool, Canc Res UK Ctr, Liverpool L69 3BX, Merseyside, England. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USA. Novartis Pharmaceut, E Hanover, NJ USA. Novartis Pharma AG, Basel, Switzerland. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 371 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600359 ER PT J AU Mayer, RJ Ohtsu, A Yoshino, T Falcone, A Garcia-Carbonero, R Tabernero, J Sobrero, AF Peeters, M Benedetti, F Makris, L Ambe, H Zaniboni, A Shimada, Y Yamazaki, K Komatsu, Y Hochster, HS Lenz, HJ Tran, B Van Cutsem, E AF Mayer, Robert J. Ohtsu, Atsushi Yoshino, Takayuki Falcone, Alfredo Garcia-Carbonero, Rocio Tabernero, Josep Sobrero, Alberto F. Peeters, Marc Benedetti, Fabio Makris, Lukas Ambe, Hiroshi Zaniboni, Alberto Shimada, Yasuhiro Yamazaki, Kentaro Komatsu, Yoshito Hochster, Howard S. Lenz, Heinz-Josef Ben Tran Van Cutsem, Eric CA RECOURSE Study Grp TI TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. Azienda Osped Univ Pisana, Pisa, Italy. Hosp Univ Virgen del Rocio, Seville, Spain. Vall dHebron Univ Hosp, Barcelona, Spain. IRCCS AOU San Martino IST, Genoa, Italy. Univ Antwerp Hosp, Edegem, Belgium. Taiho Oncol Inc, Princeton, NJ USA. Stathmi Inc, New Hope, PA USA. Taiho Pharmaceut Co LTD, Tokyo, Japan. Fdn Poliambulanza, Brescia, Italy. Natl Canc Ctr, Chuo Ku, 1-1 Tsukiji 5 Chome, Tokyo, Japan. Shizuoka Canc Ctr, Shizuoka, Japan. Hokkaido Univ Hosp, Sapporo, Hokkaido 060, Japan. Yale Canc Ctr, New Haven, CT USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Royal Melbourne Hosp, Melbourne, Vic, Australia. Univ Hosp Leuven, Leuven, Belgium. RI Peeters, Marc/C-5525-2013 OI Peeters, Marc/0000-0003-4969-2303 NR 0 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 634 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600610 ER PT J AU Ohtsu, A Yoshino, T Wahba, MM Benedetti, FM Falcone, A Garcia-Carbonero, R Tabernero, J Sobrero, AF Peeters, M Zaniboni, A Shimada, Y Yamazaki, K Komatsu, Y Hochster, HS Lenz, HJ Tran, B Mayer, RJ Van Cutsem, E AF Ohtsu, Atsushi Yoshino, Takayuki Wahba, Mona M. Benedetti, Fabio M. Falcone, Alfredo Garcia-Carbonero, Rocio Tabernero, Josep Sobrero, Alberto F. Peeters, Marc Zaniboni, Alberto Shimada, Yasuhiro Yamazaki, Kentaro Komatsu, Yoshito Hochster, Howard S. Lenz, Heinz-Josef Ben Tran Mayer, Robert J. Van Cutsem, Eric CA RECOURSE Study Grp TI Phase III RECOURSE trial of TAS-102 versus placebo with best supportive care in patients with metastatic colorectal cancer: Geographic subgroups. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. Taiho Oncol Inc, Princeton, NJ USA. Azienda Osped Univ Pisana, Pisa, Italy. Hosp Univ Virgen del Rocio, Seville, Spain. Vall dHebron Univ Hosp, Barcelona, Spain. IRCCS AOU San Martino IST, Genoa, Italy. Univ Antwerp Hosp, Edegem, Belgium. Fdn Poliambulanza, Brescia, Italy. Natl Canc Ctr, Chuo Ku, 1-1 Tsukiji 5 Chome, Tokyo, Japan. Saitama Canc Ctr, Saitama, Japan. Hokkaido Univ Hosp, Sapporo, Hokkaido 060, Japan. Yale Canc Ctr, New Haven, CT USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Royal Melbourne Hosp, Melbourne, Vic, Australia. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Hosp Leuven, Leuven, Belgium. RI Peeters, Marc/C-5525-2013 OI Peeters, Marc/0000-0003-4969-2303 NR 0 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 646 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600622 ER PT J AU Ohtsu, A Tabernero, J Bang, YJ Fuchs, CS Sun, LD Wang, Z Csiki, I Koshiji, M Van Cutsem, E AF Ohtsu, Atsushi Tabernero, Josep Bang, Yung-Jue Fuchs, Charles S. Sun, Linda Wang, Zhen Csiki, Ildiko Koshiji, Minori Van Cutsem, Eric TI Pembrolizumab (MK-3475) versus paclitaxel as second-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Phase 3 KEYNOTE-061 study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. Vall dHebron Univ Hosp, Barcelona, Spain. Seoul Natl Univ Hosp, Seoul 110744, South Korea. Dana Farber Canc Inst, Boston, MA 02115 USA. Merck & Co Inc, Kenilworth, NJ USA. MSD China, Beijing, Peoples R China. Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA TPS183 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600177 ER PT J AU Pike, JW Mouw, KW Braunstein, LZ Martin, NE Mamon, HJ Hornick, JL Van Allen, EM D'Andrea, AD AF Pike, Jonathan W. Mouw, Kent William Braunstein, Lior Zvi Martin, Neil E. Mamon, Harvey J. Hornick, Jason L. Van Allen, Eliezer Mendel D'Andrea, Alan D. TI Genomic features of primary and recurrent anal squamous cell carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Dana Farber Canc Inst, Brookline, MA USA. Harvard Radiat Oncol Program, Boston, MA USA. Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 556 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600536 ER PT J AU Shah, MA Bennouna, J Shen, L Enzinger, PC Li, Q Csiki, I Koshiji, M Doi, T AF Shah, Manish A. Bennouna, Jaafar Shen, Lin Enzinger, Peter C. Li, Qiao Csiki, Ildiko Koshiji, Minori Doi, Toshihiko TI Pembrolizumab (MK-3475) for previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: Phase II KEYNOTE-180 study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. Inst Cancerol Ouest, Nantes, France. Peking Univ, Canc Hosp & Inst, Beijing 100871, Peoples R China. Dana Farber Canc Inst, Boston, MA 02115 USA. MSD China, Beijing, Peoples R China. Merck & Co Inc, Kenilworth, NJ USA. Natl Canc Ctr Hosp East, Chiba, Japan. NR 0 TC 0 Z9 0 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA TPS189 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600183 ER PT J AU Singh, S Carnaghi, C Buzzoni, R Pommier, RF Raderer, M Tomasek, J Lahner, H Valle, JW Voi, M Bubuteishvili-Pacaud, L Lincy, J Sachs, C Okita, N Libutti, SK Oh, DY Kulke, MH Strosberg, JR Yao, JC Pavel, ME Fazio, N AF Singh, Simron Carnaghi, Carlo Buzzoni, Roberto Pommier, Rodney F. Raderer, Markus Tomasek, Jiri Lahner, Harald Valle, Juan W. Voi, Maurizio Bubuteishvili-Pacaud, Lida Lincy, Jeremie Sachs, Carolin Okita, Natsuko Libutti, Steven K. Oh, Do-Youn Kulke, Matthew H. Strosberg, Jonathan R. Yao, James C. Pavel, Marianne E. Fazio, Nicola CA RAD001 Adv Neuroendocrine Tumors Fourth Trial RADIANT-4 Study Grp TI Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. IRCCS Ist Clin Humanitas, Rozzano, Italy. Fdn IRCCS Ist Nazl Tumori, Milan, Italy. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Klin Innere Med I, Vienna, Austria. Masaryk Mem Canc Inst, Brno, Czech Republic. Univ Klinikum Essen, Zentrum Innere Med, Essen, Germany. Univ Manchester, Christie Hosp, Inst Canc Studies, Manchester, Lancs, England. Novartis Pharmaceut, E Hanover, NJ USA. Novartis Pharma AG, Basel, Switzerland. Natl Canc Ctr, Chuo Ku, 1-1 Tsukiji 5 chome, Tokyo, Japan. Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul Natl Univ Hosp, Seoul, South Korea. Dana Farber Canc Inst, Boston, MA 02115 USA. H Lee Moffitt Canc Ctr & Res Inst, Dept Med, Tampa, FL USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Charite, Campus Virchow Klinikum, D-13353 Berlin, Germany. IRCCS, Ist Europeo Oncol, Milan, Italy. NR 0 TC 1 Z9 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 315 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600308 ER PT J AU Strosberg, JR Wolin, EM Chasen, B Kulke, MH Bushnell, DL Caplin, ME Baum, RP Kunz, PL Hobday, TJ Hendifar, AE Oberg, KE Sierra, ML Kwekkeboom, DJ Ruszniewski, PB Krenning, E AF Strosberg, Jonathan R. Wolin, Edward M. Chasen, Beth Kulke, Matthew H. Bushnell, David L. Caplin, Martyn E. Baum, Richard P. Kunz, Pamela L. Hobday, Timothy J. Hendifar, Andrew Eugene Oberg, Kjell E. Sierra, Maribel Lopera Kwekkeboom, Dik J. Ruszniewski, Philippe B. Krenning, Eric TI NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Univ Kentucky, Lexington, KY USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Vet Adm Med Ctr, Iowa City, IA USA. Royal Free Hosp, Pond St, London NW3 2QG, England. Zent Klin Bad Berka, Bad Berka, Germany. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Mayo Clin, Coll Med, Dept Oncol, Rochester, MN USA. Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. Univ Uppsala Hosp, Uppsala, Sweden. Adv Accelerator Applicat, New York, NY USA. Erasmus Univ, Med Ctr, Rotterdam, Netherlands. Beaujon Hosp, Clichy, France. Erasmus MC, Rotterdam, Netherlands. NR 0 TC 12 Z9 12 U1 2 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 194 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600188 ER PT J AU Sun, WJ Rosen, LS Rasco, DW Yoshida, K Seraj, J Shapiro, G Cleary, JM AF Sun, Weijing Rosen, Lee S. Rasco, Drew W. Yoshida, Kenichiro Seraj, Jabed Shapiro, Geoffrey Cleary, James M. TI An open-label, randomized, parallel-group study of the pharmacokinetics of trifluridine as a component of TAS-102 versus FTD alone. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif Los Angeles, Div Hemato Oncol, Santa Monica, CA USA. South Texas Accelerated Res Therapeut, San Antonio, TX USA. Taiho Oncol Inc, Princeton, NJ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 751 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600727 ER PT J AU Tabernero, J Bang, YJ Fuchs, CS Ohtsu, A Kher, U Lam, B Koshiji, M Van Cutsem, E AF Tabernero, Josep Bang, Yung-Jue Fuchs, Charles S. Ohtsu, Atsushi Kher, Uma Lam, Baohoang Koshiji, Minori Van Cutsem, Eric TI KEYNOTE-062: Phase III study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Vall dHebron Univ Hosp, Barcelona, Spain. Seoul Natl Univ Hosp, Seoul 110744, South Korea. Dana Farber Canc Inst, Boston, MA 02115 USA. Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. Merck & Co Inc, Kenilworth, NJ USA. Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA TPS185 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600179 ER PT J AU Tsai, FC Ghorbani, S Greenwald, BD Jang, S Dumot, JA McKinley, MJ Shaheen, NJ Habr, F Wolfsen, HC Abrams, JA Lightdale, C Nishioka, NS Johnston, MH Zfass, A Coyle, W AF Tsai, Franklin C. Ghorbani, Shireen Greenwald, Bruce D. Jang, Sunguk Dumot, John A. McKinley, Matthew J. Shaheen, Nicholas J. Habr, Fadlallah Wolfsen, Herbert C. Abrams, Julian A. Lightdale, Charles Nishioka, Norman S. Johnston, Mark H. Zfass, Alvin Coyle, Walter TI Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Scripps Clin, La Jolla, CA 92037 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Cleveland Clin, Cleveland, OH 44106 USA. ProHEALTHcare Associates, North Shore LIJ Hlth Syst, Lake Success, NY USA. UNC Sch Med, Chapel Hill, NC USA. Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. Mayo Clin, Jacksonville, FL 32224 USA. Columbia Univ, Med Ctr, New York, NY USA. Columbia Univ, New York, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Lancaster Gastroenterol Inc, Lancaster, PA USA. Virginia Commonwealth Univ, Richmond, VA USA. Scripps Green Hosp, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA 83 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600081 ER PT J AU Van Cutsem, E Benedetti, FM Mizuguchi, H Mayer, RJ Falcone, A Garcia-Carbonero, R Tabernero, J Sobrero, AF Peeters, M Zaniboni, A Yoshino, T Shimada, Y Yamazaki, K Komatsu, Y Hochster, HS Lenz, HJ Tran, B Ohtsu, A AF Van Cutsem, Eric Benedetti, Fabio M. Mizuguchi, Hirokazu Mayer, Robert J. Falcone, Alfredo Garcia-Carbonero, Rocio Tabernero, Josep Sobrero, Alberto F. Peeters, Marc Zaniboni, Alberto Yoshino, Takayuki Shimada, Yasuhiro Yamazaki, Kentaro Komatsu, Yoshito Hochster, Howard S. Lenz, Heinz-Josef Ben Tran Ohtsu, Atsushi CA RECOURSE Study Grp TI TAS-102 versus placebo (PBO) in patients (pts) >= 65 years (y) with metastatic colorectal cancer (mCRC): An age-based analysis of the recourse trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ Hosp Leuven, Leuven, Belgium. Taiho Oncol Inc, Princeton, NJ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Azienda Osped Univ Pisana, Pisa, Italy. Hosp Univ Virgen del Rocio, Seville, Spain. Vall dHebron Univ Hosp, Barcelona, Spain. IRCCS AOU San Martino IST, Genoa, Italy. Univ Antwerp Hosp, Edegem, Belgium. Fdn Poliambulanza, Brescia, Italy. Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. Natl Canc Ctr, Chuo Ku, 1-1 Tsukiji 5 Chome, Tokyo, Japan. Saitama Canc Ctr, Saitama, Japan. Hokkaido Univ, Hosp Canc Ctr, Sapporo, Hokkaido, Japan. Yale Canc Ctr, New Haven, CT USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Royal Melbourne Hosp, Melbourne, Vic, Australia. Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan. RI Peeters, Marc/C-5525-2013 OI Peeters, Marc/0000-0003-4969-2303 NR 0 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 638 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600614 ER PT J AU Van Loon, K Hu, CY Cuddy, A Bekaii-Saab, TS Benson, A Hall, MJ Lai, LL Nurkin, SJ Skibber, JM Weiser, MR Schrag, D Chang, GJ AF Van Loon, Katherine Hu, Chung-Yuan Cuddy, Amanda Bekaii-Saab, Tanios S. Benson, Al Bowen Hall, Michael J. Lai, Lily L. Nurkin, Steven J. Skibber, John Michael Weiser, Martin R. Schrag, Deborah Chang, George J. TI How are colorectal cancer (CRC) patients treated following cancer recurrence during follow-up? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. City Hope Natl Med Ctr, Duarte, CA USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 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 FEB 1 PY 2016 VL 34 IS 4 SU S MA 645 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600621 ER PT J AU Zhu, AX Galle, PR Kudo, M Finn, RS Yang, L Abada, P Chang, SC Llovet, JM AF Zhu, Andrew X. Galle, Peter R. Kudo, Masatoshi Finn, Richard S. Yang, Ling Abada, Paolo Chang, Shao-Chun Llovet, Josep M. TI A randomized, double-blind, placebo-controlled phase III study of ramucirumab versus placebo as second-line treatment in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein following first-line sorafenib (REACH-2). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Gastrointestinal Cancers Symposium CY JAN 21-23, 2016 CL San Francisco, CA C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Med Ctr Mainz, Dept Internal Med 1, Mainz, Germany. Kinki Univ, Sch Med, Dept Gastroenterol & Hepatol, Osaka 589, Japan. Ronald Regan UCLA Med Ctr, Los Angeles, CA USA. Eli Lilly & Co, Bridgewater, NJ USA. Eli Lilly, Indianapolis, IN USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Mt Sinai Sch Med, Div Liver Dis, Liver Canc Program, New York, NY USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2016 VL 34 IS 4 SU S MA TPS478 PG 1 WC Oncology SC Oncology GA DO9MB UT WOS:000378109600460 ER PT J AU Arias, SA Miller, I Camargo, CA Sullivan, AF Goldstein, AB Allen, MH Manton, AP Boudreaux, ED AF Arias, Sarah A. Miller, Ivan Camargo, Carlos A., Jr. Sullivan, Ashley F. Goldstein, Amy B. Allen, Michael H. Manton, Anne P. Boudreaux, Edwin D. TI Factors Associated With Suicide Outcomes 12 Months After Screening Positive for Suicide Risk in the Emergency Department SO PSYCHIATRIC SERVICES LA English DT Article ID PHYSICAL ILLNESS AB Objective: The main objective was to identify which patient characteristics have the strongest association with suicide outcomes in the 12 months after an index emergency department (ED) visit. Methods: Data were analyzed fromthe first two phases of the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE). The ED-SAFE study, a quasi-experimental, interrupted time-series design, involved participation from eight general medical EDs across the United States. Participants included adults presenting to the ED with active suicidal ideation or an attempt in the past week. Data collection included baseline interview; six-and 12-month chart reviews; and six-, 12-, 24-, 36-, and 52-week telephone follow-up assessments. Regression analyses were conducted. Results: Among 874 participants, the median age was 37 years (interquartile range 27-47), with 56% of the sample being female (N=488), 74% white (N=649), and 13% Hispanic (N=113). At baseline, 577 (66%) participants had suicidal ideation only, whereas 297 (34%) had a suicide attempt in the past week. Data sufficient to determine outcomes were available for 782 (90%). In the 12 months after the index ED visit, 195 (25%) had documentation of at least one suicide attempt or suicide. High school education or less, an ED visit in the preceding six months, prior nonsuicidal self-injury, current alcohol misuse, and suicidal intent or plan were predictive of future suicidal behavior. Conclusions: Continuing to build an understanding of the factors associated with future suicidal behaviors for this population will help guide design and implementation of improved suicide screening and interventions in the ED and better allocation of scarce resources. C1 [Arias, Sarah A.; Miller, Ivan] Brown Univ, Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Camargo, Carlos A., Jr.; Sullivan, Ashley F.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Goldstein, Amy B.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Allen, Michael H.] Univ Colorado, Depress Ctr & Rocky Mt Crisis Partners, Aurora, CO USA. [Manton, Anne P.] Cape Cod Hosp, Ctr Behav Hlth Serv, Hyannis, MA USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA 01605 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01605 USA. RP Arias, SA (reprint author), Brown Univ, Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02912 USA. EM sarias@butler.org RI Allen, Michael/A-8776-2011; OI Arias, Sarah/0000-0003-1832-8824 FU National Institute of Mental Health [U01MH088278]; Novartis FX The project described was supported by award U01MH088278 from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.; Dr. Allen reports receiving research support from Novartis. He reports that he has also been a contractor for Sunovion and Ferrer, an employee of ProPhase, and an advisor for Teva. The other authors report no financial relationships with commercial interests. NR 20 TC 0 Z9 0 U1 0 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD FEB PY 2016 VL 67 IS 2 BP 206 EP 213 DI 10.1176/appi.ps.201400513 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DO4SZ UT WOS:000377775400016 PM 26620285 ER PT J AU Louapre, C Govindarajan, ST Gianni, C Cohen-Adad, J Gregory, MD Nielsen, AS Madigan, N Sloane, JA Kinkel, RP Mainero, C AF Louapre, Celine Govindarajan, Sindhuja T. Gianni, Costanza Cohen-Adad, Julien Gregory, Michael D. Nielsen, A. Scott Madigan, Nancy Sloane, Jacob A. Kinkel, Revere P. Mainero, Caterina TI Is the Relationship between Cortical and White Matter Pathologic Changes in Multiple Sclerosis Spatially Specific? A Multimodal 7-T and 3-T MR Imaging Study with Surface and Tract-based Analysis SO RADIOLOGY LA English DT Article ID NORMAL APPEARING WHITE; IN-VIVO; 7 T; COGNITIVE IMPAIRMENT; CEREBRAL-CORTEX; HUMAN BRAIN; CONTRAST; DISCONNECTION; DEMYELINATION; TRACTOGRAPHY AB Purpose: To investigate in vivo the spatial specificity of the interdependence between intracortical and white matter (WM) pathologic changes as function of cortical depth and distance from the cortex in multiple sclerosis (MS), and their independent contribution to physical and cognitive disability. Materials and Methods: This study was institutional review board-approved and participants gave written informed consent. In 34 MS patients and 17 age-matched control participants, 7-T quantitative T2* maps, 3-T T1-weighted anatomic images for cortical surface reconstruction, and 3-T diffusion tensor images (DTI) were obtained. Cortical quantitative T2* maps were sampled at 25%, 50%, 75% depth from pial surface. Tracts of interest were reconstructed by using probabilistic tractography. The relationship between DTI metrics voxelwise of the tracts and cortical integrity in the projection cortex was tested by using multilinear regression models. Results: In MS, DTI abnormal findings along tracts correlated with quantitative T2* changes (suggestive of iron and myelin loss) at each depth of the cortical projection area (P < .01, corrected). This association, however, was not spatially specific because abnormal findings in WM tracts also related to cortical pathologic changes outside of the projection cortex of the tract (P < .001). Expanded Disability Status Scale pyramidal score was predicted by axial diffusivity along the corticospinal tract (beta = 4.6 x 10(3); P < .001), Symbol Digit Modalities Test score by radial diffusivity along the cingulum (beta = -4.3 x 10(4); P < .01), and T2* in the cingulum cortical projection at 25% depth (beta = -1.7; P < .05). Conclusion: Intracortical and WM injury are concomitant pathologic processes in MS, which are not uniquely distributed according to a tract-cortex-specific pattern; their association may reflect a common stage-dependent mechanism. (C) RSNA, 2015 C1 [Louapre, Celine; Govindarajan, Sindhuja T.; Gianni, Costanza; Mainero, Caterina] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,Thirteenth St, Charlestown, MA 02129 USA. [Louapre, Celine; Gianni, Costanza; Mainero, Caterina] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Cohen-Adad, Julien] Ecole Polytech, Dept Elect Engn, Montreal, PQ H3C 3A7, Canada. [Gregory, Michael D.] NIMH, Sect Integrat Neuroimaging, NIH, Bethesda, MD 20892 USA. [Nielsen, A. Scott] Virginia Mason Med Ctr, Dept Neurol & Neurosurg, Seattle, WA 98101 USA. [Madigan, Nancy; Sloane, Jacob A.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Kinkel, Revere P.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. RP Mainero, C (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,Thirteenth St, Charlestown, MA 02129 USA.; Mainero, C (reprint author), Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. EM caterina@nmr.mgh.harvard.edu OI Gianni, Costanza/0000-0002-4018-169X FU National Institutes of Health [R01NS078322-01-A1, NCRR P41-RR14075, 5T32NS51151-5] FX This research was supported by the National Institutes of Health (grants R01NS078322-01-A1, NCRR P41-RR14075, and 5T32NS51151-5). NR 39 TC 1 Z9 1 U1 1 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2016 VL 278 IS 2 BP 524 EP 535 DI 10.1148/radiol.2015150486 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3SQ UT WOS:000377702200027 PM 26334679 ER PT J AU Harvey, HB Brink, JA Frush, DP AF Harvey, H. Benjamin Brink, James A. Frush, Donald P. TI Who Gets to Decide? Response SO RADIOLOGY LA English DT Letter ID CANCER-RISK; COMPUTED-TOMOGRAPHY; IONIZING-RADIATION; NERVOUS-SYSTEM; CT SCANS; CHILDHOOD; COHORT; EXPOSURE; TUMORS; BRAIN C1 [Harvey, H. Benjamin; Brink, James A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 175 Cambridge St,Suite 200, Boston, MA 02114 USA. [Frush, Donald P.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. RP Harvey, HB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 175 Cambridge St,Suite 200, Boston, MA 02114 USA. EM hbharvey@partners.org NR 16 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2016 VL 278 IS 2 BP 636 EP 637 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3SQ UT WOS:000377702200043 PM 27186612 ER PT J AU Peek, HS Beresin, E AF Peek, Holly S. Beresin, Eugene TI Reality Check: How Reality Television Can Affect Youth and How a Media Literacy Curriculum Can Help SO ACADEMIC PSYCHIATRY LA English DT Editorial Material DE Curriculum development; Media (TV films); Child psychiatry ID ADOLESCENT GIRLS; BODY DISSATISFACTION; RISK-FACTORS; MASS-MEDIA AB For the past decade, reality television programming has dominated the television market while inherently giving the impression that what occurs on the screen is in fact reality. Although mature audiences may he savvy about the differences between reality and reality television, for children and adolescents, these differences can he less clear. It is important to know what values youth are ascertaining from reality television, as studies have suggested that these media images may have a negative impact on adolescent values. Fortunately, media literacy education has shown promising results in counteracting the negative impact of some television programming. The goals of this paper are to show the potential benefits for the development of a media literacy cuniculum for psychiatry residents, including critical media literacy skills, media history taking, and counseling concepts. Our hopes are that trained residents may learn to effectively teach these literacy skills to their patients, patients' families, educators, and other health professionals as a preventive measure against potential negative mental health effects of reality television. C1 [Peek, Holly S.] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Beresin, Eugene] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Peek, HS (reprint author), Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. EM hpeek85@gmail.com NR 19 TC 0 Z9 0 U1 16 U2 32 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD FEB PY 2016 VL 40 IS 1 BP 177 EP 181 DI 10.1007/s40596-015-0382-1 PG 5 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DN5HL UT WOS:000377097100033 PM 26108397 ER PT J AU Michaels, AY Keraliya, AR Tirumani, H Shinagare, AB Ramaiya, NH AF Michaels, Aya Y. Keraliya, Abhishek R. Tirumani, Harsha Shinagare, Atul B. Ramaiya, Nikhil H. TI Systemic treatment in breast cancer: a primer for radiologists SO INSIGHTS INTO IMAGING LA English DT Review DE Breast cancer; Hormonal therapy; Molecular-targeted therapy; CT; MRI ID POSITRON-EMISSION-TOMOGRAPHY; POSTMENOPAUSAL WOMEN; NEOADJUVANT CHEMOTHERAPY; SOLID TUMORS; CARDIAC TOLERABILITY; HEPATIC METASTASES; TREATMENT RESPONSE; TARGETED THERAPY; LIVER METASTASES; BONE METASTASES AB Cytotoxic chemotherapy, hormonal therapy and molecular targeted therapy are the three major classes of drugs used to treat breast cancer. Imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), F-18-FDG positron emission tomography (PET)/CT and bone scintigraphy each have a distinct role in monitoring response and detecting drug toxicities associated with these treatments. The purpose of this article is to elucidate the various systemic therapies used in breast cancer, with an emphasis on the role of imaging in assessing treatment response and detecting treatment-related toxicities. Teaching Points Cytotoxic chemotherapy is often used in combination with HER2-targeted and endocrine therapies. Endocrine and HER2-targeted therapies are recommended in hormone-receptor-and HER2-positive cases. CT is the workhorse for assessment of treatment response in breast cancer metastases. Alternate treatment response criteria can help in interpreting pseudoprogression in metastasis. Unique toxicities are associated with cytotoxic chemotherapy and with endocrine and HER2-targeted therapies. C1 [Michaels, Aya Y.; Keraliya, Abhishek R.; Tirumani, Harsha; Shinagare, Atul B.; Ramaiya, Nikhil H.] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, 75 Francis St, Boston, MA 02115 USA. [Keraliya, Abhishek R.; Tirumani, Harsha; Shinagare, Atul B.; Ramaiya, Nikhil H.] Harvard Univ, Dana Farber Canc Inst, Dept Imaging, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA. RP Tirumani, H (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, 75 Francis St, Boston, MA 02115 USA.; Tirumani, H (reprint author), Harvard Univ, Dana Farber Canc Inst, Dept Imaging, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA. EM Sreeharsha_Tirumani@DFCI.HARVARD.EDU NR 68 TC 1 Z9 1 U1 3 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1869-4101 J9 INSIGHTS IMAGING JI Insights Imaging PD FEB PY 2016 VL 7 IS 1 BP 131 EP 144 DI 10.1007/s13244-015-0447-4 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DN4FW UT WOS:000377020000011 PM 26567115 ER PT J AU Prat, J Young, RH AF Prat, Jaime Young, Robert H. TI Letter to the Editor on "Should All Cases of High-Grade Serous Ovarian, Tubal, and Primary Peritoneal Carcinomas Be Reclassified as Tubo-Ovarian Serous Carcinoma?" Int J Gynecol Cancer 2015; 25: 1201-1207 SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Letter ID INTRAEPITHELIAL-CARCINOMA; MOLECULAR PATHOGENESIS; RISK REDUCTION; WOMEN; ORIGIN; BRCA1; MODEL C1 [Prat, Jaime] Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Prat, J (reprint author), Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Barcelona, Spain. EM jprat@santpau.cat NR 14 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 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD FEB PY 2016 VL 26 IS 2 BP 226 EP 227 DI 10.1097/IGC.0000000000000617 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DN5YB UT WOS:000377146500002 PM 26807559 ER PT J AU Sun, SY Melamed, A Joseph, NT Gockley, AA Goldstein, DP Bernstein, MR Horowitz, NS Berkowitz, RS AF Sun, Sue Yazaki Melamed, Alexander Joseph, Naima T. Gockley, Allison Ann Goldstein, Donald Peter Bernstein, Marilyn R. Horowitz, Neil S. Berkowitz, Ross Stuart TI Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Complete hydatidiform mole; First-trimester pregnancy; Partial hydatidiform mole; Postmolar neoplasia; Vaginal bleeding ID EARLY-DIAGNOSIS; PREGNANCY; NEOPLASIA; MANAGEMENT; FEATURES AB Objective: The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. Methods: This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. Results: The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). Conclusions: This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation. C1 [Sun, Sue Yazaki] UNIFESP Sao Paulo Fed Univ, Dept Obstet, Sao Paulo, SP, Brazil. [Sun, Sue Yazaki] UNIFESP Sao Paulo Fed Univ, Paulista Sch Med, Sao Paulo Hosp, Trophoblast Dis Ctr, Sao Paulo, SP, Brazil. [Melamed, Alexander; Joseph, Naima T.; Gockley, Allison Ann; Goldstein, Donald Peter; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross Stuart] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. [Melamed, Alexander; Joseph, Naima T.; Gockley, Allison Ann; Goldstein, Donald Peter; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross Stuart] Donald P Goldstein MD Trophoblast Tumor Registry, New England Trophoblast Dis Ctr, Boston, MA USA. [Melamed, Alexander; Joseph, Naima T.; Gockley, Allison Ann; Goldstein, Donald Peter; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross Stuart] Dana Farber Canc Inst, Harvard Canc Ctr, Boston, MA 02115 USA. [Melamed, Alexander; Joseph, Naima T.; Gockley, Allison Ann; Goldstein, Donald Peter; Bernstein, Marilyn R.; Horowitz, Neil S.; Berkowitz, Ross Stuart] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Berkowitz, RS (reprint author), Brigham & Womens Hosp, ASBI, Div Gynecol Oncol, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. EM ross_berkowitz@dfci.harvard.edu FU CNPq, Science Without Borders, Brazil [200756/2014-1]; Donald P. Goldstein, MD, Trophoblastic Tumor Registry Endowment; Dyett Family Trophoblastic Disease Research and Registry Endowment FX This research was supported by a grant from the CNPq 200756/2014-1, Science Without Borders, Brazil, to support the work of S.Y.S. and the Donald P. Goldstein, MD, Trophoblastic Tumor Registry Endowment and the Dyett Family Trophoblastic Disease Research and Registry Endowment. NR 27 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 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD FEB PY 2016 VL 26 IS 2 BP 367 EP 370 DI 10.1097/IGC.0000000000000608 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DN5YB UT WOS:000377146500023 PM 26588240 ER PT J AU Hartman, RI Storer, M Kimball, AB AF Hartman, Rebecca Ivy Storer, Molly Kimball, Alexa Boer TI Dermatology's Researchers of the Future: Our Workforce Pipeline and Richest Opportunities SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID ACADEMIC DERMATOLOGY; CAREER CHOICES; GLOBAL BURDEN; SKIN-DISEASE; RESIDENTS; SATISFACTION; PROGRAM; TRENDS; IMPACT C1 [Hartman, Rebecca Ivy] Harvard Univ, Sch Med, Combined Dermatol Residency Program, Boston, MA USA. [Storer, Molly] Univ Massachusetts, Sch Med, Worcester, MA USA. [Kimball, Alexa Boer] Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 240, Boston, MA 02114 USA. [Kimball, Alexa Boer] Harvard Univ, Sch Med, Boston, MA USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 29 TC 0 Z9 0 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2016 VL 136 IS 2 BP 345 EP 348 DI 10.1016/j.jid.2015.12.014 PG 4 WC Dermatology SC Dermatology GA DN6XE UT WOS:000377219000004 PM 26802229 ER EF