FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bodewes, TCF Ultee, KHJ Soden, PA Zettervall, SL Deery, SE Shean, KE Moll, F Schermerhorn, ML AF Bodewes, Thomas C. F. Ultee, Klaas H. J. Soden, Peter A. Zettervall, Sara L. Deery, Sarah E. Shean, Katie E. Moll, Frans Schermerhorn, Marc L. TI The Impact of Prior Revascularization on Perioperative Outcomes of Infrainguinal Bypass Surgery SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT Vascular Annual Meeting of the Society-for-Vascular-Surgery CY JUN 08-11, 2016 CL National Harbor, MD SP Soc Vasc Surg C1 [Bodewes, Thomas C. F.; Soden, Peter A.; Zettervall, Sara L.; Schermerhorn, Marc L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ultee, Klaas H. J.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Deery, Sarah E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shean, Katie E.] Beth Israel Deaconess Med Ctr, Billerica, MA USA. [Moll, Frans] Univ Med Ctr Utrecht, Utrecht, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2016 VL 63 IS 6 SU S MA PC152 BP 198S EP 199S PG 2 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DM3EW UT WOS:000376230600316 ER PT J AU Felmlee, DJ Coilly, A Chung, RT Samuel, D Baumert, TF AF Felmlee, Daniel J. Coilly, Audrey Chung, Raymond T. Samuel, Didier Baumert, Thomas F. TI New perspectives for preventing hepatitis C virus liver graft infection SO LANCET INFECTIOUS DISEASES LA English DT Review ID BROADLY NEUTRALIZING ANTIBODIES; HCV GENOTYPE 1; ANTIVIRAL THERAPY; TRANSPLANT RECIPIENTS; MONOCLONAL-ANTIBODY; DECOMPENSATED CIRRHOSIS; HUMANIZED MICE; ENTRY FACTOR; VIRAL ENTRY; PEGYLATED-INTERFERON AB Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease that necessitates liver transplantation. The incidence of virus-induced cirrhosis and hepatocellular carcinoma continues to increase, making liver transplantation increasingly common. Infection of the engrafted liver is universal and accelerates progression to advanced liver disease, with 20-30% of patients having cirrhosis within 5 years of transplantation. Treatments of chronic HCV infection have improved dramatically, albeit with remaining challenges of failure and access, and therapeutic options to prevent graft infection during liver transplantation are emerging. Developments in directed use of new direct-acting antiviral agents (DAAs) to eliminate circulating HCV before or after transplantation in the past 5 years provide renewed hope for prevention and treatment of liver graft infection. Identification of the ideal regimen and use of DAAs reveals new ways to treat this specific population of patients. Complementing DAAs, viral entry inhibitors have been shown to prevent liver graft infection in animal models and delay graft infection in clinical trials, which shows their potential for use concomitant to transplantation. We review the challenges and pathology associated with HCV liver graft infection, highlight current and future strategies of DAA treatment timing, and discuss the potential role of entry inhibitors that might be used synergistically with DAAs to prevent or treat graft infection. C1 [Felmlee, Daniel J.; Baumert, Thomas F.] Inst Rech Malad Virales & Hepat, INSERM, U1110, Strasbourg, France. [Felmlee, Daniel J.; Baumert, Thomas F.] Univ Strasbourg, Strasbourg, France. [Felmlee, Daniel J.] Univ Plymouth, Hepatol Res Grp, Peninsula Sch Med & Dent, Plymouth PL4 8AA, Devon, England. [Coilly, Audrey; Samuel, Didier] Hop Paul Brousse, AP HP, Ctr Hepatobiliaire, Villejuif, France. [Coilly, Audrey; Samuel, Didier] Univ Paris 13, UMR S 1193, Villejuif, France. [Coilly, Audrey; Samuel, Didier] INSERM, U1193, F-94800 Villejuif, France. [Chung, Raymond T.; Baumert, Thomas F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Baumert, Thomas F.] Hop Univ Strasbourg, Inst Hosp Univ, Pole Hepatodigest, F-67000 Strasbourg, France. RP Samuel, D (reprint author), INSERM, U1193, F-94800 Villejuif, France.; Baumert, TF (reprint author), Hop Univ Strasbourg, INSERM, U1110, 3 Rue Koeberle, F-67000 Strasbourg, France. EM didier.samuel@aphp.fr; thomas.baumert@unistra.fr FU European Union (ERC-AdG-HEPCENT); European Union [ERC-AdG-2014-671231-HEPCIR, H2020-2015-667273-HEP-CAR]; European Union (FP7 HepaMab); European Union (Interreg IV FEDERHepato-Regio-Net); National Institutes of Heatlth NIAID [U19AI123862]; Agence Nationale de Recherche sur le SIDA et les hepatities virales (ANRS); Direction Generale de l'Offre de Soins [A12027MS]; NIH [DK078772] FX We thank Mirjam Zeisel and Che Colpitts (Inserm U1110, University of Strasbourg, France) for critical reading of the manuscript. TFB acknowledges grant support from the European Union (ERC-2008-AdG-HEPCENT, ERC-AdG-2014-671231-HEPCIR, FP7 HepaMab, and Interreg IV FEDERHepato-Regio-Net 2012, H2020-2015-667273-HEP-CAR), the National Institutes of Heatlth NIAID U19AI123862, the Agence Nationale de Recherche sur le SIDA et les hepatities virales (ANRS), and the Direction Generale de l'Offre de Soins (A12027MS). RTC receives grant support from NIH DK078772. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the Future Programme. NR 139 TC 7 Z9 7 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2016 VL 16 IS 6 BP 735 EP 745 PG 11 WC Infectious Diseases SC Infectious Diseases GA DM6QC UT WOS:000376476500052 PM 27301929 ER PT J AU Li, R Hermann, G Baldini, E Chen, A Jackman, D Kozono, D Nguyen, P Nohria, A Powell, G Mak, R AF Li, Richard Hermann, Gretchen Baldini, Elizabeth Chen, Aileen Jackman, David Kozono, David Nguyen, Paul Nohria, Anju Powell, Graham Mak, Raymond TI Advanced nodal stage predicts venous thromboembolism in patients with locally advanced non-small cell lung cancer SO LUNG CANCER LA English DT Article DE Lung cancer; Deep venous thrombosis; Pulmonary embolism; Risks ID CLINICAL-PRACTICE GUIDELINE; DEEP-VEIN THROMBOSIS; RECEIVING CHEMOTHERAPY; PULMONARY-EMBOLISM; AMERICAN SOCIETY; COMPETING RISK; THROMBOPROPHYLAXIS; GEMCITABINE; CARCINOMA; EVENTS AB Objectives: Patients with non-small cell lung cancer (NSCLC) are known to be at high risk for venous thromboembolism (VTE), but previous studies have not specifically analyzed locally advanced disease. We performed a retrospective VTE risk analysis in a cohort of locally advanced NSCLC treated with definitive intent including radiation therapy. Materials and methods: The cohort consisted of 629 patients with stage II-III NSCLC treated at a single institution from January 2003 to December 2012. All patients received treatment with curative intent, including radiation therapy. Fine and Gray's competing-risks regression model, accounting for death and distant metastasis as competing risks, was used to identify significant predictors of VTE risk, and cumulative incidence estimates were generated using the competing-risks model. Results and conclusion: At a median follow-up of 31 months, 127 patients developed a VTE, with 80% of events occurring in the first year after treatment initiation. 1-year and 3-year overall cumulative incidence estimates were 13.5% and 15.4%, respectively. On univariate analysis, stage IIIB and N3 nodal disease were associated with increased VTE risk. In the final multivariable model, N3 nodal disease was associated with increased VTE risk (Hazard ratio 1.64; 95% CI 1.06-2.54; p = 0.027). In conclusion, patients with locally advanced NSCLC are at high risk for VTE, especially in the first year after treatment initiation, with a 1-year cumulative incidence of 13.5%. N3 nodal staging was associated with significantly higher VTE risk compared to NO-N2 staging. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Li, Richard; Hermann, Gretchen; Baldini, Elizabeth; Chen, Aileen; Kozono, David; Nguyen, Paul; Powell, Graham; Mak, Raymond] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Li, Richard; Baldini, Elizabeth; Chen, Aileen; Jackman, David; Kozono, David; Nguyen, Paul; Nohria, Anju; Mak, Raymond] Harvard Univ, Sch Med, Boston, MA USA. [Jackman, David] Dana Farber Canc Inst, Med Oncol, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Nohria, Anju] Brigham & Womens Hosp, Dana Farber Canc Inst, Cardiooncol Program, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Mak, R (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM rmak@partners.org NR 35 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JUN PY 2016 VL 96 BP 41 EP 47 DI 10.1016/j.lungcan.2016.03.004 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DM7MW UT WOS:000376545700008 PM 27133748 ER PT J AU Karmacharya, R Haggarty, SJ AF Karmacharya, Rakesh Haggarty, Stephen J. TI Stem cell models of neuropsychiatric disorders SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Editorial Material C1 [Karmacharya, Rakesh; Haggarty, Stephen J.] Harvard Univ, Sch Med, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. [Karmacharya, Rakesh; Haggarty, Stephen J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Karmacharya, Rakesh] Broad Inst Harvard & MIT, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Karmacharya, Rakesh] McLean Hosp, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02478 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Dept Neurol, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. RP Karmacharya, R (reprint author), Harvard Univ, Sch Med, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM karmacharya@mcb.harvard.edu OI Karmacharya, Rakesh/0000-0002-0565-5482; Haggarty, Stephen J./0000-0002-7872-168X NR 10 TC 2 Z9 2 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 EI 1095-9327 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD JUN PY 2016 VL 73 BP 1 EP 2 DI 10.1016/j.mcn.2016.03.007 PG 2 WC Neurosciences SC Neurosciences & Neurology GA DM3CV UT WOS:000376225300001 PM 27013423 ER PT J AU Watmuff, B Berkovitch, SS Huang, JH Iaconelli, J Toffel, S Karmacharya, R AF Watmuff, Bradley Berkovitch, Shaunna S. Huang, Joanne H. Iaconelli, Jonathan Toffel, Steven Karmacharya, Rakesh TI Disease signatures for schizophrenia and bipolar disorder using patient-derived induced pluripotent stem cells SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Review DE Schizophrenia; Bipolar disorder; Stem cells; IPSC; Microglia; Gene-environment; Neuronal differentiation ID COMORBIDITY SURVEY REPLICATION; CORTICAL PYRAMIDAL NEURONS; DENDRITIC SPINE DENSITY; TERM LITHIUM TREATMENT; HUMAN CEREBRAL-CORTEX; HUMAN FIBROBLASTS; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; BRAIN-DEVELOPMENT; NATURAL-HISTORY AB Schizophrenia and bipolar disorder are complex psychiatric disorders that present unique challenges in the study of disease biology. There are no objective biological phenotypes for these disorders, which are characterized by complex genetics and prominent roles for gene-environment interactions. The study of the neurobiology underlying these severe psychiatric disorders has been hindered by the lack of access to the tissue of interest neurons from patients. The advent of reprogramming methods that enable generation of induced pluripotent stem cells (iPSCs) from patient fibroblasts and peripheral blood mononuclear cells has opened possibilities for new approaches to study relevant disease biology using iPSC-derived neurons. While early studies with patient iPSCs have led to promising and intriguing leads, significant hurdles remain in our attempts to capture the complexity of these disorders in vitro. We present here an overview of studies to date of schizophrenia and bipolar disorder using iPSC-derived neuronal cells and discuss potential future directions that can result in the identification of robust and valid cellular phenotypes that in turn can lay the groundwork for meaningful clinical advances. (C) 2016 Elsevier Inc. All rights reserved. C1 [Watmuff, Bradley; Berkovitch, Shaunna S.; Huang, Joanne H.; Iaconelli, Jonathan; Toffel, Steven; Karmacharya, Rakesh] Harvard Univ, Sch Med, Ctr Expt Drugs & Diagnost, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA 02114 USA. [Watmuff, Bradley; Berkovitch, Shaunna S.; Huang, Joanne H.; Iaconelli, Jonathan; Toffel, Steven; Karmacharya, Rakesh] Massachusetts Gen Hosp, 185 Cambridge St, Boston, MA 02114 USA. [Watmuff, Bradley; Toffel, Steven; Karmacharya, Rakesh] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Watmuff, Bradley; Berkovitch, Shaunna S.; Huang, Joanne H.; Iaconelli, Jonathan; Toffel, Steven; Karmacharya, Rakesh] Broad Inst Harvard & MIT, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Karmacharya, Rakesh] McLean Hosp, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02478 USA. RP Karmacharya, R (reprint author), Massachusetts Gen Hosp, 185 Cambridge St, Boston, MA 02114 USA.; Karmacharya, R (reprint author), Harvard Univ, Ctr Human Genet Res, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. EM karmacharya@mgh.harvard.edu OI Karmacharya, Rakesh/0000-0002-0565-5482 FU National Institute of Mental Health [MH086846]; Doris Duke Charitable Foundation; Harvard Stem Cell Institute; Ryan Licht Sang Bipolar Foundation; Phyllis & Jerome Lyle Rappaport Foundation FX Our research has been supported by funding from the National Institute of Mental Health (MH086846), Doris Duke Charitable Foundation, Harvard Stem Cell Institute, Ryan Licht Sang Bipolar Foundation, and Phyllis & Jerome Lyle Rappaport Foundation and from Steve Willis and Elissa Freud. NR 140 TC 3 Z9 3 U1 6 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 EI 1095-9327 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD JUN PY 2016 VL 73 BP 96 EP 103 DI 10.1016/j.mcn.2016.01.003 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DM3CV UT WOS:000376225300009 PM 26777134 ER PT J AU Haggarty, SJ Silva, MC Cross, A Brandon, NJ Perlis, RH AF Haggarty, Stephen J. Silva, M. Catarina Cross, Alan Brandon, Nicholas J. Perlis, Roy H. TI Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Review DE Human stem cells; iPSC models; Drug discovery; CRISPR-Cas9; High-throughput screening; High-content imaging; Neuropharmacology; Bipolar disorder; Schizophrenia; Autism spectrum disorders; Dementia ID FRAGILE-X-SYNDROME; IPSC-DERIVED NEURONS; BIPOLAR DISORDER; RETT-SYNDROME; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; PSYCHIATRIC-DISORDERS; MENTAL-RETARDATION; NEURODEGENERATIVE DISEASES; IDENTIFY COMPOUNDS AB Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced pluripotent stem cells (iPSCs) now affords the ability to generate neuronal cell-based models that recapitulate key aspects of human disease. In the context of neuropsychiatric disorders, where access to physiologically active and relevant cell types of the central nervous system for research is extremely limiting, iPSC-derived in vitro culture of human neurons and glial cells is transformative. Potential applications relevant to early stage drug discovery, include support of quantitative biochemistry, functional genomics, proteomics, and perhaps most notably, high-throughput and high-content chemical screening. While many phenotypes in human iPSC-derived culture systems may prove adaptable to screening formats, addressing the question of which in vitro phenotypes are ultimately relevant to disease pathophysiology and therefore more likely to yield effective pharmacological agents that are disease-modifying treatments requires careful consideration. Here, we review recent examples of studies of neuropsychiatric disorders using human stem cell models where cellular phenotypes linked to disease and functional assays have been reported. We also highlight technical advances using genome-editing technologies in iPSCs to support drug discovery efforts, including the interpretation of the functional significance of rare genetic variants of unknown significance and for the purpose of creating cell type- and pathway-selective functional reporter assays. Additionally, we evaluate the potential of in vitro stem cell models to investigate early events of disease pathogenesis, in an effort to understand the underlying molecular mechanism, including the basis of selective cell-type vulnerability, and the potential to create new cell-based diagnostics to aid in the classification of patients and subsequent selection for clinical trials. A number of key challenges remain, including the scaling of iPSC models to larger cohorts and integration with rich clinicopathological information and translation of phenotypes. Still, the overall use of iPSC-based human cell models with functional cellular and biochemical assays holds promise for supporting the discovery of next-generation neuropharmacological agents for the treatment and ultimately prevention of a range of severe mental illnesses. (C) 2016 Elsevier Inc. All rights reserved. C1 [Haggarty, Stephen J.; Silva, M. Catarina] Harvard Univ, Chem Neurobiol Lab, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. [Haggarty, Stephen J.; Silva, M. Catarina; Perlis, Roy H.] Harvard Univ, Ctr Human Genet Res, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. [Haggarty, Stephen J.; Silva, M. Catarina; Perlis, Roy H.] Harvard Univ, Ctr Expt Drugs & Diagnost, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. [Haggarty, Stephen J.; Silva, M. Catarina; Perlis, Roy H.] Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. [Haggarty, Stephen J.; Silva, M. Catarina] Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. [Cross, Alan; Brandon, Nicholas J.] AstraZeneca Neurosci iMED, 141 Portland St, Cambridge, MA 02139 USA. RP Haggarty, SJ (reprint author), Harvard Univ, Chem Neurobiol Lab, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Univ, Ctr Human Genet Res, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Univ, Ctr Expt Drugs & Diagnost, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. EM shaggarty@mgh.harvard.edu RI Cross, Alan/L-5456-2016; OI Cross, Alan/0000-0002-2992-2258; Silva, M. Catarina/0000-0001-5421-6673; Haggarty, Stephen J./0000-0002-7872-168X FU Sunovion Pharmaceuticals; Biogen-Idec; AstraZeneca; Genomind; Nestle Health; Perfect Health; Pfizer; Proteus Biomedical; PsyBrain; RID Ventures FX Dr. Haggarty has served on scientific advisory boards for Rodin Therapeutics and PsyBrain; and has received speaker honoraria and/or consulting fees from Sunovion Pharmaceuticals, Biogen-Idec, and AstraZeneca. Dr. Perlis has served on scientific advisory boards or received consulting fees from Genomind, Nestle Health, Perfect Health, Pfizer, Proteus Biomedical, PsyBrain, and RID Ventures. He receives royalties from Bracket (a Medco subsidiary). Dr. Cross and Dr. Brandon are employees and shareholders of AstraZeneca, PLC. NR 119 TC 3 Z9 3 U1 13 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 EI 1095-9327 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD JUN PY 2016 VL 73 BP 104 EP 115 DI 10.1016/j.mcn.2016.01.011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DM3CV UT WOS:000376225300010 PM 26826498 ER PT J AU Kim, J Mouw, KW Polak, P Braunstein, LZ Kamburov, A Tiao, G Kwiatkowski, DJ Rosenberg, JE Van Allen, EM D'Andrea, AD Getz, G AF Kim, Jaegil Mouw, Kent W. Polak, Paz Braunstein, Lior Z. Kamburov, Atanas Tiao, Grace Kwiatkowski, David J. Rosenberg, Jonathan E. Van Allen, Eliezer M. D'Andrea, Alan D. Getz, Gad TI Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors SO NATURE GENETICS LA English DT Article ID DNA-REPAIR GENES; CHRONIC LYMPHOCYTIC-LEUKEMIA; CISPLATIN-BASED CHEMOTHERAPY; INVASIVE BLADDER-CANCER; ARISTOLOCHIC ACID; URINARY-BLADDER; WHOLE-GENOME; TRANSCRIPTION; SMOKING; DAMAGE AB Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide-excision repair (NER) pathway has not yet been identified. Here we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts demonstrates a strong association between somatic ERCC2 mutations and the activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between the activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify an NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping tumor mutational landscape. C1 [Kim, Jaegil; Polak, Paz; Braunstein, Lior Z.; Kamburov, Atanas; Tiao, Grace; Van Allen, Eliezer M.; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA USA. [Mouw, Kent W.; D'Andrea, Alan D.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Mouw, Kent W.; Polak, Paz; Braunstein, Lior Z.; Kamburov, Atanas; Kwiatkowski, David J.; Van Allen, Eliezer M.; D'Andrea, Alan D.; Getz, Gad] Harvard Univ, Sch Med, Boston, MA USA. [Polak, Paz; Kamburov, Atanas; Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Polak, Paz; Kamburov, Atanas; Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Kwiatkowski, David J.] Brigham & Womens Hosp, Div Pulm Med, 75 Francis St, Boston, MA 02115 USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA. [Van Allen, Eliezer M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [D'Andrea, Alan D.] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02115 USA. RP Getz, G (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA.; Getz, G (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Getz, G (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Getz, G (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. EM gadgetz@broadinstitute.org RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU NIH TCGA Genome Data Analysis Center [U24CA143845]; American Society of Clinical Oncology (ASCO); American Society of Radiation Oncology (ASTRO); Starr Cancer Consortium; Memorial Sloan Kettering Geoffrey Beane Center; Damon Runyon Clinical Investigator Award; Massachusetts General Hospital; Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital FX G.G. and J.K. were partially funded by the NIH TCGA Genome Data Analysis Center (U24CA143845). P.P. and A.K. were funded by the startup funds of G.G. at Massachusetts General Hospital. K.W.M. was partially funded by an American Society of Clinical Oncology (ASCO) Young Investigator Award and an American Society of Radiation Oncology (ASTRO) Junior Faculty Career Research Training Award. J.E.R. was partially funded by the Starr Cancer Consortium and the Memorial Sloan Kettering Geoffrey Beane Center. E.M.V.A. was partially funded by a Damon Runyon Clinical Investigator Award. A.D.D'A. was partially funded by the Starr Cancer Consortium. G.G. was partially funded by the Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital. NR 48 TC 7 Z9 7 U1 8 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2016 VL 48 IS 6 BP 600 EP + DI 10.1038/ng.3557 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DN0HE UT WOS:000376744200006 PM 27111033 ER PT J AU Campbell, JD Alexandrov, A Kim, J Wala, J Berger, AH Pedamallu, CS Shukla, SA Guo, GW Brooks, AN Murray, BA Imielinski, M Hu, X Ling, SY Akbani, R Rosenberg, M Cibulskis, C Ramachandran, A Collisson, EA Kwiatkowski, DJ Lawrence, MS Weinstein, JN Verhaak, RGW Wu, CJ Hammerman, PS Cherniack, AD Getz, G Artyomov, MN Schreiber, R Govindan, R Meyerson, M AF Campbell, Joshua D. Alexandrov, Anton Kim, Jaegil Wala, Jeremiah Berger, Alice H. Pedamallu, Chandra Sekhar Shukla, Sachet A. Guo, Guangwu Brooks, Angela N. Murray, Bradley A. Imielinski, Marcin Hu, Xin Ling, Shiyun Akbani, Rehan Rosenberg, Mara Cibulskis, Carrie Ramachandran, Aruna Collisson, Eric A. Kwiatkowski, David J. Lawrence, Michael S. Weinstein, John N. Verhaak, Roel G. W. Wu, Catherine J. Hammerman, Peter S. Cherniack, Andrew D. Getz, Gad Artyomov, Maxim N. Schreiber, Robert Govindan, Ramaswamy Meyerson, Matthew CA Canc Genome Atlas Res Network TI Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas SO NATURE GENETICS LA English DT Article ID COPY-NUMBER ALTERATION; MUTATIONAL PROCESSES; SEQUENCING DATA; HUMAN CANCER; DRIVER MUTATIONS; NEVER-SMOKERS; LANDSCAPE; DISCOVERY; TARGETS; KINASE AB To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase-Ras-Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes. C1 [Campbell, Joshua D.; Kim, Jaegil; Wala, Jeremiah; Berger, Alice H.; Pedamallu, Chandra Sekhar; Shukla, Sachet A.; Guo, Guangwu; Brooks, Angela N.; Murray, Bradley A.; Imielinski, Marcin; Rosenberg, Mara; Cibulskis, Carrie; Ramachandran, Aruna; Kwiatkowski, David J.; Lawrence, Michael S.; Wu, Catherine J.; Hammerman, Peter S.; Cherniack, Andrew D.; Getz, Gad; Meyerson, Matthew] Eli & Edythe L Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA. [Campbell, Joshua D.; Wala, Jeremiah; Berger, Alice H.; Pedamallu, Chandra Sekhar; Shukla, Sachet A.; Guo, Guangwu; Brooks, Angela N.; Murray, Bradley A.; Imielinski, Marcin; Ramachandran, Aruna; Wu, Catherine J.; Hammerman, Peter S.; Cherniack, Andrew D.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Alexandrov, Anton; Artyomov, Maxim N.; Schreiber, Robert] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Alexandrov, Anton] ITMO Univ, Comp Technol Lab, St Petersburg, Russia. [Imielinski, Marcin] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Hu, Xin; Ling, Shiyun; Akbani, Rehan; Weinstein, John N.; Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Collisson, Eric A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kwiatkowski, David J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Govindan, Ramaswamy] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Meyerson, M (reprint author), Eli & Edythe L Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA.; Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Govindan, R (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.; Meyerson, M (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM rgovinda@dom.wustl.edu; matthew_meyerson@dfci.harvard.edu FU National Cancer Institute as part of The Cancer Genome Atlas project [U24CA126546, U24CA143867, U24CA143845, U24CA126544, U24CA143883]; National Cancer Institute [K08CA163677, R35CA197568]; government of the Russian Federation [074-U01]; US Department of Defense [W81XWH-12-1-0269]; American Cancer Society Research Professor Award FX This work was supported by grants from the National Cancer Institute as part of The Cancer Genome Atlas project: U24CA126546, U24CA143867, U24CA143845, U24CA126544, and U24CA143883. Additionally, this work was funded by National Cancer Institute grant K08CA163677 (P.S.H.), grant 074-U01 from the government of the Russian Federation (A.A.), US Department of Defense contract W81XWH-12-1-0269 (M.M.), the American Cancer Society Research Professor Award (M.M.), and National Cancer Institute grant R35CA197568 (M.M.). NR 68 TC 18 Z9 18 U1 7 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2016 VL 48 IS 6 BP 607 EP + DI 10.1038/ng.3564 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DN0HE UT WOS:000376744200007 PM 27158780 ER PT J AU Cui, X Lu, FL Qiu, Q Zhou, B Gu, LF Zhang, SB Kang, YY Cui, XK Ma, X Yao, QQ Ma, JB Zhang, XY Cao, XF AF Cui, Xia Lu, Falong Qiu, Qi Zhou, Bing Gu, Lianfeng Zhang, Shuaibin Kang, Yanyuan Cui, Xiekui Ma, Xuan Yao, Qingqing Ma, Jinbiao Zhang, Xiaoyu Cao, Xiaofeng TI REF6 recognizes a specific DNA sequence to demethylate H3K27me3 and regulate organ boundary formation in Arabidopsis SO NATURE GENETICS LA English DT Article ID TRANSCRIPTION FACTORS; MERISTEM FORMATION; FLOWERING TIME; SHOOT MERISTEM; CHIP-SEQ; THALIANA; GENE; PROTEINS; POLYCOMB; GENOME AB RELATIVE OF EARLY FLOWERING 6 (REF6, also known as JMJ12) counteracts Polycomb-mediated gene silencing by removing methyl groups from trimethylated histone H3 lysine 27 (H3K27me3) in hundreds of genes in Arabidopsis thaliana(1). Here we show that REF6 function and genome-wide targeting require its four Cys(2)His(2) zinc fingers, which directly recognize a CTCTGYTY motif. Motifs bound by REF6 tend to cluster and reside in loci with active chromatin states. Furthermore, REF6 targets CUP-SHAPED COTYLEDON 1 (CUC1), which harbors CTCTGYTY motifs, to modulate H3K27me3 levels and activate CUC1 expression. Loss of REF6 causes CUC1 repression and defects in cotyledon separation. In contrast, REF6 does not bind CUC2, encoding a close homolog of CUC1, which lacks the CTCTGYTY motif. Collectively, these results identify a new targeting mechanism of an H3K27 demethylase to counteract Polycomb-mediated gene silencing that regulates plant development, including organ boundary formation. C1 [Cui, Xia; Lu, Falong; Qiu, Qi; Zhou, Bing; Gu, Lianfeng; Zhang, Shuaibin; Kang, Yanyuan; Cui, Xiekui; Ma, Xuan; Cao, Xiaofeng] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Plant Genom, Beijing, Peoples R China. [Cui, Xia; Lu, Falong; Qiu, Qi; Zhou, Bing; Gu, Lianfeng; Zhang, Shuaibin; Kang, Yanyuan; Cui, Xiekui; Ma, Xuan; Cao, Xiaofeng] Chinese Acad Sci, Inst Genet & Dev Biol, Natl Ctr Plant Gene Res, Beijing, Peoples R China. [Lu, Falong; Zhang, Shuaibin; Kang, Yanyuan; Cui, Xiekui] Univ Chinese Acad Sci, Beijing, Peoples R China. [Ma, Xuan] Shenzhen Univ, Coll Life Sci, Shenzhen Key Lab Microbial Genet Engn, Shenzhen, Peoples R China. [Yao, Qingqing; Ma, Jinbiao; Cao, Xiaofeng] Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China. [Yao, Qingqing; Ma, Jinbiao; Cao, Xiaofeng] Collaborat Innovat Ctr Genet & Dev, Shanghai, Peoples R China. [Zhang, Xiaoyu; Cao, Xiaofeng] Univ Georgia, Dept Plant Biol, Athens, GA 30602 USA. [Cao, Xiaofeng] Chinese Acad Sci, Inst Genet & Dev Biol, CAS Ctr Excellence Mol Plant Sci, Beijing, Peoples R China. [Cui, Xia] Chinese Acad Agr Sci, Inst Vegetables & Flowers, Beijing 100193, Peoples R China. [Lu, Falong] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Zhou, Bing] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Gu, Lianfeng] Fujian Agr & Forestry Univ, Haixia Inst Sci & Technol, Fuzhou, Peoples R China. RP Cao, XF (reprint author), Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Plant Genom, Beijing, Peoples R China.; Cao, XF (reprint author), Chinese Acad Sci, Inst Genet & Dev Biol, Natl Ctr Plant Gene Res, Beijing, Peoples R China.; Cao, XF (reprint author), Collaborat Innovat Ctr Genet & Dev, Shanghai, Peoples R China.; Cao, XF (reprint author), Chinese Acad Sci, Inst Genet & Dev Biol, CAS Ctr Excellence Mol Plant Sci, Beijing, Peoples R China. EM xfcao@genetics.ac.cn RI Lu, Falong/Q-3013-2016; OI Zhou, Bing/0000-0003-2846-1813 FU National Basic Research Program of China [2013CB967300, 2013CB835200]; National Natural Science Foundation of China [31210103901, 31271363, 31428011]; State Key Laboratory of Plant Genomics [2014B0227-01, 2015B0129-01]; National Science Foundation [0960425]; China Postdoctoral Science Foundation [2012M520020, 2014M550874, 2014M550101] FX We thank Q. Zhu for technical assistance and W. Qian for discussion. We thank the Arabidopsis Biological Resource Center for providing T-DNA insertion lines. This work was supported by the National Basic Research Program of China (grants 2013CB967300 to Xia Cui and 2013CB835200 to X. Cao), the National Natural Science Foundation of China (grants 31210103901 to X. Cao, 31271363 to Xia Cui, and 31428011 to X.Z.), and the State Key Laboratory of Plant Genomics (2014B0227-01 and 2015B0129-01). Research in the laboratory of X.Z. was supported by National Science Foundation grant 0960425. B.Z., Xiekui Cui, and X.M. were supported by the China Postdoctoral Science Foundation (2012M520020, 2014M550874, and 2014M550101, respectively). NR 44 TC 5 Z9 5 U1 21 U2 33 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2016 VL 48 IS 6 BP 694 EP + DI 10.1038/ng.3556 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DN0HE UT WOS:000376744200019 PM 27111035 ER PT J AU Jahani-Asl, A Yin, H Soleimani, VD Haque, T Luchman, HA Chang, NC Sincennes, MC Puram, SV Scott, AM Lorimer, IAJ Perkins, TJ Ligon, KL Weiss, S Rudnicki, MA Bonni, A AF Jahani-Asl, Arezu Yin, Hang Soleimani, Vahab D. Haque, Takrima Luchman, H. Artee Chang, Natasha C. Sincennes, Marie-Claude Puram, Sidharth V. Scott, Andrew M. Lorimer, Ian A. J. Perkins, Theodore J. Ligon, Keith L. Weiss, Samuel Rudnicki, Michael A. Bonni, Azad TI Control of glioblastoma tumorigenesis by feed-forward cytokine signaling SO NATURE NEUROSCIENCE LA English DT Article ID GROWTH-FACTOR RECEPTOR; SQUAMOUS-CELL CARCINOMA; ONCOSTATIN M RECEPTOR; STEM-CELL; THERAPEUTIC TARGET; MALIGNANT GLIOMAS; EGFR; IDENTIFICATION; PROLIFERATION; PATHWAY AB EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of these mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis. C1 [Jahani-Asl, Arezu; Puram, Sidharth V.; Bonni, Azad] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Jahani-Asl, Arezu; Bonni, Azad] Washington Univ, Sch Med, Dept Neurosci, St Louis, MO USA. [Jahani-Asl, Arezu; Yin, Hang; Chang, Natasha C.; Sincennes, Marie-Claude; Lorimer, Ian A. J.; Perkins, Theodore J.; Rudnicki, Michael A.] Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Jahani-Asl, Arezu; Haque, Takrima] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Jahani-Asl, Arezu; Soleimani, Vahab D.; Haque, Takrima] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. [Yin, Hang; Chang, Natasha C.; Sincennes, Marie-Claude; Perkins, Theodore J.; Rudnicki, Michael A.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada. [Yin, Hang] Univ Georgia, Dept Biochem, Athens, GA 30602 USA. [Yin, Hang] Univ Georgia, Mol Biol Ctr Mol Med, Athens, GA 30602 USA. [Soleimani, Vahab D.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Luchman, H. Artee; Weiss, Samuel] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB, Canada. [Scott, Andrew M.] La Trobe Univ, Sch Canc Med, Olivia Newton John Canc Res Inst, Melbourne, Vic, Australia. [Lorimer, Ian A. J.; Perkins, Theodore J.] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada. [Ligon, Keith L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Jahani-Asl, A; Bonni, A (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA.; Jahani-Asl, A; Bonni, A (reprint author), Washington Univ, Sch Med, Dept Neurosci, St Louis, MO USA.; Jahani-Asl, A; Rudnicki, MA (reprint author), Ottawa Hosp Res Inst, Ottawa, ON, Canada.; Jahani-Asl, A (reprint author), McGill Univ, Dept Oncol, Montreal, PQ, Canada.; Jahani-Asl, A (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada.; Rudnicki, MA (reprint author), Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada. EM arezu.jahani@mcgill.ca; mrudnicki@ohri.ca; bonni@wustl.edu OI Perkins, Theodore J./0000-0002-6622-8003 FU US National Institutes for Health [NS064007, R01AR044031]; Mathers Foundation; Canadian Institutes for Health Research (CIHR) [MOP-81288]; new investigator startup funds at the LDI/McGill University; Canada Research Chair in Molecular Genetics; Canada research chair in stem cell epigenetics; CIHR; Alberta Cancer Foundation; Stem Cell Network; National Health and Medical Research Council FX These studies were carried out with support of grants to A.B. from the US National Institutes for Health (NS064007) and the Mathers Foundation, to M.A.R. from the US National Institutes for Health (R01AR044031), the Canadian Institutes for Health Research (CIHR, MOP-81288), and to A.J.-A. from the new investigator startup funds at the LDI/McGill University. M.A.R. is funded as the Canada Research Chair in Molecular Genetics. V.D.S. is funded as the Canada research chair in stem cell epigenetics.A.J.-A.,H.Y. and N.C.C. were supported by postdoctoral fellowships from the CIHR. H.A.L. and S.W. are supported by grants from the Alberta Cancer Foundation and the Stem Cell Network. A.M.S. is supported by National Health and Medical Research Council grant and the Operational Infrastructure Support Program provided by the Victorian Government. We thank C. Porter at the Ottawa Hospital Research Institute for critical help with genomic data analyses. NR 43 TC 5 Z9 5 U1 4 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUN PY 2016 VL 19 IS 6 BP 798 EP + DI 10.1038/nn.4295 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DN0HI UT WOS:000376744600010 PM 27110918 ER PT J AU Rooks, MG Garrett, WS AF Rooks, Michelle G. Garrett, Wendy S. TI Gut microbiota, metabolites and host immunity SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID CHAIN FATTY-ACIDS; REGULATORY T-CELLS; ARYL-HYDROCARBON RECEPTOR; INTESTINAL MICROBIOTA; STAPHYLOCOCCUS-AUREUS; INFLAMMATORY RESPONSES; DEACETYLASE INHIBITION; HISTONE DEACETYLASES; METAGENOMIC DATASETS; DIETARY POLYAMINES AB The microbiota - the collection of microorganisms that live within and on all mammals - provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host-microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system. C1 [Rooks, Michelle G.; Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Garrett, Wendy S.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Garrett, WS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.; Garrett, WS (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA.; Garrett, WS (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.; Garrett, WS (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. EM wgarrett@hsph.harvard.edu FU Burroughs Wellcome Career in Medical Sciences Award; Searle Scholars Award; [R01 CA154426]; [R01 GM099531] FX The authors thank the members of the Garrett laboratory for their helpful discussions. The work relevant to this Review is supported by the grants R01 CA154426 and R01 GM099531, a Burroughs Wellcome Career in Medical Sciences Award and a Searle Scholars Award to W.S.G. NR 126 TC 35 Z9 35 U1 45 U2 86 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD JUN PY 2016 VL 16 IS 6 BP 341 EP 352 DI 10.1038/nri.2016.42 PG 12 WC Immunology SC Immunology GA DN0GP UT WOS:000376742700008 PM 27231050 ER PT J AU Silva, PS Horton, MB Clary, D Lewis, DG Sun, JK Cavallerano, JD Aiello, LP AF Silva, Paolo S. Horton, Mark B. Clary, Dawn Lewis, Drew G. Sun, Jennifer K. Cavallerano, Jerry D. Aiello, Lloyd Paul TI Identification of Diabetic Retinopathy and Ungradable Image Rate with Ultrawide Field Imaging in a National Teleophthalmology Program SO OPHTHALMOLOGY LA English DT Article ID PERIPHERAL LESIONS; PHOTOGRAPHY; SEVERITY AB Purpose: To compare diabetic retinopathy (DR) identification and ungradable image rates between non-mydriatic ultrawide field (UWF) imaging and nonmydriatic multifield fundus photography (NMFP) in a large multistate population-based DR teleophthalmology program. Design: Multiple-site, nonrandomized, consecutive, cross-sectional, retrospective, uncontrolled imaging device evaluation. Participants: Thirty-five thousand fifty-two eyes (17 526 patients) imaged using NMFP and 16 218 eyes (8109 patients) imaged using UWF imaging. Methods: All patients undergoing Joslin Vision Network (JVN) imaging with either NMFP or UWF imaging from May 1, 2014, through August 30, 2015, within the Indian Health Service-JVN program, which serves American Indian and Alaska Native communities at 97 sites across 25 states, were evaluated. All retinal images were graded using a standardized validated protocol in a centralized reading center. Main Outcome Measures: Ungradable rate for DR and diabetic macular edema (DME). Results: The ungradable rate per patient for DR and DME was significantly lower with UWF imaging compared with NMFP (DR, 2.8% vs. 26.9% [P < 0.0001]; DME, 3.8% vs. 26.2% [P < 0.0001]). Identification of eyes with either DR or referable DR (moderate nonproliferative DR or DME or worse) was increased using UWF imaging from 11.7% to 24.2% (P < 0.0001) and from 6.2% to 13.6% (P < 0.0001), respectively. In eyes with DR imaged with UWF imaging (n = 3926 eyes of 2402 patients), the presence of predominantly peripheral lesions suggested a more severe level of DR in 7.2% of eyes (9.6% of patients). Conclusions: In a large, widely distributed DR ocular telehealth program, as compared with NMFP, nonmydriatic UWF imaging reduced the number of ungradable eyes by 81%, increased the identification of DR nearly 2-fold, and identified peripheral lesions suggesting more severe DR in almost 10% of patients, thus demonstrating significant benefits of this imaging method for large DR teleophthalmology programs. (C) 2016 by the American Academy of Ophthalmology. C1 [Silva, Paolo S.; Sun, Jennifer K.; Cavallerano, Jerry D.; Aiello, Lloyd Paul] Joslin Diabet Ctr, Beetham Eye Inst, 1 Joslin Pl, Boston, MA 02215 USA. [Silva, Paolo S.; Sun, Jennifer K.; Cavallerano, Jerry D.; Aiello, Lloyd Paul] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Horton, Mark B.; Clary, Dawn] Indian Hlth Serv, Joslin Vis Network Natl Reading Ctr, Phoenix, AZ USA. [Lewis, Drew G.] Estenda Solut Inc, Conshohocken, PA USA. RP Silva, PS (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, 1 Joslin Pl, Boston, MA 02215 USA. EM paoloantonio.silva@joslin.harvard.edu FU Optos plc (Dunfermline, Scotland) FX The author(s) have made the following disclosure(s): L.P.A.: Financial support - Optos plc (Dunfermline, Scotland). NR 11 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUN PY 2016 VL 123 IS 6 BP 1360 EP 1367 DI 10.1016/j.ophtha.2016.01.043 PG 8 WC Ophthalmology SC Ophthalmology GA DM7BD UT WOS:000376506400034 PM 26949120 ER PT J AU Kulkarni, T Willoughby, J Lara, MDA Kim, YI Ramachandran, R Alexander, CB Luckhardt, T Thannickal, VJ de Andrade, JA AF Kulkarni, Tejaswini Willoughby, John Lara, Maria del Pilar Acosta Kim, Young-il Ramachandran, Rekha Alexander, C. Bruce Luckhardt, Tracy Thannickal, Victor J. de Andrade, Joao A. TI A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival SO RESPIRATORY MEDICINE LA English DT Article DE Idiopathic pulmonary fibrosis; Transplant-free survival; Bundled care ID INTERSTITIAL LUNG-DISEASE; HEART-FAILURE; MANAGEMENT; EFFICACY; TRIALS AB Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with poor prognosis and limited therapeutic options. The 2011 ATS/ERS/JRS/ALAT consensus statement provided a number of recommendations for the management of IPF patients. The primary objective of this study was to determine if "bundling" these recommendations in the management of patients with IPF impacts clinical outcomes. Methods: We conducted a single center, retrospective cohort study of 284 patients diagnosed with IPF. The proposed bundle of care (BOC) components were: (1) visits to a specialized interstitial lung diseases clinic with evaluation of pulmonary function tests at least twice yearly; (2) referral to pulmonary rehabilitation yearly; (3) timed walk test yearly; (4) echocardiogram yearly; and (5) gastroesophageal reflux therapy. Each component of the BOC was given a score of "1" per year of follow up, and the average sum of the scores (ranging from 0 to 5) was determined for the entire period of follow-up (BOCS), as well as during the first year of follow-up (BOCY1). The primary outcome measure was transplant-free survival. Results: Age, gender, smoking status, BMI, %FVC, %DLCO did not differ between levels of BOCS and BOCY1. Lowest BOCS (<= 1) was associated with a lower transplant-free survival independent of age and %FVC compared to patients with the highest BOCS (>4) (HR 2.274, CI 1.12-4.64, p = 0.024). Lower BOCY1 was associated with a higher risk for transplant or death independent of age and %FVC in comparison to patients with highest BOCY1 (<= 1 vs. >4, HR 2.23, p = 0.014; >1 to 2 vs. >4, HR 1.87, p = 0.011; >2 to 3 vs. >4, HR 1.72, p = 0.019). Conclusion: IPF patients with higher BOC scores had improved transplant-free survival. Prospective studies are needed to confirm these findings and determine the best strategies for the management of patients with IPF. Published by Elsevier Ltd. C1 [Kulkarni, Tejaswini; Willoughby, John; Lara, Maria del Pilar Acosta; Kim, Young-il; Ramachandran, Rekha; Luckhardt, Tracy; Thannickal, Victor J.; de Andrade, Joao A.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Dept Med, 1900 Univ Blvd,Tinsley Harrison Tower,Suite 422, Birmingham, AL 35294 USA. [Kim, Young-il; Ramachandran, Rekha] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Med Towers,Suite 621,1720 2nd Ave South, Birmingham, AL 35294 USA. [Alexander, C. Bruce] Univ Alabama Birmingham, Dept Pathol, P210 West Pavil,619 South 19th St, Birmingham, AL 35233 USA. [Kulkarni, Tejaswini; Lara, Maria del Pilar Acosta; Kim, Young-il; Thannickal, Victor J.; de Andrade, Joao A.] Birmingham VA Med Ctr, 700 South 19th St,6th Floor,Rm 6318, Birmingham, AL 35233 USA. RP de Andrade, JA (reprint author), 1900 Univ Blvd,513 THT, Birmingham, AL 35294 USA. EM joao@uab.edu FU UAB Interstitial Lung Disease Program; NIH [PO1HL114470] FX This study was funded by the UAB Interstitial Lung Disease Program and the NIH grant PO1HL114470. NR 21 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD JUN PY 2016 VL 115 BP 33 EP 38 DI 10.1016/j.rmed.2016.04.010 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DM7EE UT WOS:000376518200006 PM 27215501 ER PT J AU Boulouis, G Charidimou, A Greenberg, SM AF Boulouis, Gregoire Charidimou, Andreas Greenberg, Steven M. TI Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications SO SEMINARS IN NEUROLOGY LA English DT Article DE cerebral amyloid angiopathy; cerebral small vessel disease; intracerebral hemorrhage; dementia ID LOBAR INTRACEREBRAL HEMORRHAGE; CORTICAL SUPERFICIAL SIDEROSIS; PROGRESS PERINDOPRIL PROTECTION; WHITE-MATTER HYPERINTENSITIES; INTERSTITIAL FLUID DRAINAGE; APOLIPOPROTEIN-E EPSILON-2; TRANSIENT ISCHEMIC ATTACK; BLOOD-BRAIN-BARRIER; ALZHEIMERS-DISEASE; ENDOTHELIAL DYSFUNCTION AB Sporadic cerebral amyloid angiopathy is a small vessel disorder defined pathologically by progressive amyloid deposition in the walls of cortical and leptomeningeal vessels resulting from disruption of a complex balance between production, circulation, and clearance of amyloid-beta peptide (A beta) in the brain. Cerebral amyloid angiopathy is a major cause of lobar symptomatic intracerebral hemorrhage, transient focal neurologic episodes, and a key contributor to vascular cognitive impairment. The mechanisms and consequences of amyloid-beta deposition at the pathological level and its neuroimaging manifestations, clinical consequences, and implications for patient care are addressed in this review. C1 [Boulouis, Gregoire; Charidimou, Andreas; Greenberg, Steven M.] Harvard Univ, Sch Med, Ctr Stroke Res, Massachusetts Gen Hosp,Dept Neurol, Boston, MA 02114 USA. RP Greenberg, SM (reprint author), Harvard Univ, Sch Med, Ctr Stroke Res, Massachusetts Gen Hosp,Dept Neurol, Boston, MA 02114 USA. EM sgreenberg@mgh.harvard.edu OI Boulouis, Gregoire/0000-0001-8422-9205 FU J. William Fulbright Research Scholar Grant; Monahan Foundation Biomedical Research Grant FX Gregoire Boulouis was supported by a J. William Fulbright Research Scholar Grant and a Monahan Foundation Biomedical Research Grant. NR 138 TC 3 Z9 3 U1 0 U2 5 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD JUN PY 2016 VL 36 IS 3 BP 233 EP 243 DI 10.1055/s-0036-1581993 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA DM9TQ UT WOS:000376709000004 PM 27214698 ER PT J AU Falcone, GJ Rosand, J AF Falcone, Guido J. Rosand, Jonathan TI Genetic Determinants of Risk, Severity, and Outcome in Intracerebral Hemorrhage SO SEMINARS IN NEUROLOGY LA English DT Article DE stroke genetics; intracerebral hemorrhage; hemorrhagic stroke; genetic risk factors ID CEREBRAL AMYLOID ANGIOPATHY; APOLIPOPROTEIN-E GENOTYPE; GENOME-WIDE ASSOCIATION; SMALL-VESSEL DISEASE; BLOOD-PRESSURE; MENDELIAN RANDOMIZATION; CLINICAL SPECTRUM; COL4A1 MUTATIONS; STROKE; HERITABILITY AB Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is the most severe manifestation of common forms of cerebral small vessel disease. Although ICH represents only 15% of all strokes, it accounts for a large proportion of stroke-related costs and mortality. Preventive and acute treatments remain limited. Because genetic variation contributes substantially to ICH, genomic analyses constitute a powerful tool to identify new biological mechanisms involved in its occurrence. Through translational research efforts, these newly identified mechanisms can become targets for innovative therapeutic interventions. Here, the authors summarize the most recent genetic discoveries for ICH. They also introduce the Platform for Accelerating Genetic Discovery for Cerebrovascular Disease, a newly created resource that aims to create a common workspace for genetic analyses that will bring together 100,000 stroke cases and suitable controls from numerous institutions in several countries. C1 [Falcone, Guido J.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 6810, Boston, MA 02114 USA. [Falcone, Guido J.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Falcone, Guido J.; Rosand, Jonathan] Broad Inst, Dept Med & Populat Genet, Cambridge, MA USA. RP Falcone, GJ (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 6810, Boston, MA 02114 USA. EM gfalcone@mail.harvard.edu RI Falcone, Guido/L-2287-2016 OI Falcone, Guido/0000-0002-6407-0302 FU National Institutes of Health; National Institute for Neurological Disorders and Stroke [R01NS059727, P50NS061343] FX This work has been supported by the National Institutes of Health and the National Institute for Neurological Disorders and Stroke through the grants R01NS059727 and P50NS061343. NR 52 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD JUN PY 2016 VL 36 IS 3 BP 298 EP 305 DI 10.1055/s-0036-1582134 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DM9TQ UT WOS:000376709000011 PM 27214705 ER PT J AU Piotrowska, A Wierzbicka, J Slebioda, T Wozniak, M Tuckey, RC Slominski, AT Zmijewski, MA AF Piotrowska, Anna Wierzbicka, Justyna Slebioda, Tomasz Wozniak, Michal Tuckey, Robert C. Slominski, Andrzej T. Zmijewski, Michal A. TI Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes SO STEROIDS LA English DT Article DE Vitamin D; Vitamin D analogues; Keratinocytes; Reactive oxygen species; Oxidative stress; Cisplatin ID BREAST-CANCER CELLS; CYTOCHROME P450SCC CYP11A1; INDUCED DNA-DAMAGE; OXIDATIVE STRESS; 1,25-DIHYDROXYVITAMIN D-3; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; PROSTATE-CANCER; D-RECEPTOR; IN-VIVO; ANTIPROLIFERATIVE ACTIVITY AB Although the skin production of vitamin D is initiated by ultraviolet radiation type B (UVB), the role vitamin D plays in antioxidative or pro-oxidative responses remains to be elucidated. We have used immortalized human HaCaT keratinocytes as a model of proliferating epidermal cells to test the influence of vitamin Don cellular response to H2O2 or the anti-cancer drug, cisplatin. Incubation of keratinocytes with 1,25(OH)(2)D-3 or its low calcemic analogues, 20(OH)D-3, 21(OH)pD or calcipotriol, sensitized cells to ROS resulting in more potent inhibition of keratinocyte proliferation by H2O2 in the presence of vitamin D compounds. These results were supported by cell cycle and apoptosis analyses, and measurement of the mitochondrial transmembrane potentials (MMP), however some unique properties of individual sec asteroids were observed. Furthermore, in HaCaT keratinocytes treated with H2O2, 1,25(OH)(2)D-3, 21(OH) pD and calcipotriol stimulated the expression of SOD1 and CAT genes, but not SOD2, indicating a possible role of mitochondria in ROS-modulated cell death. 1,25(OH)(2)D-3 also showed a short-term, protective effect on HaCaT keratinocytes, as exemplified by the inhibition of apoptosis and the maintenance of MMP. However, with prolonged incubation with H2O2 or cisplatin, 1,25(OH)(2)D-3 caused an acceleration in the death of the keratinocytes. Therefore, we propose that lead vitamin D derivatives can protect the epidermis against neoplastic transformation secondary to oxidative or UV-induced stress through activation of vitamin D-signaling. Furthermore, our data suggest that treatment with low calcemic vitamin D analogues or the maintenance of optimal level of vitamin D by proper supplementation, can enhance the anticancer efficacy of cisplatin (C) 2016 Elsevier Inc. All rights reserved. C1 [Piotrowska, Anna; Wierzbicka, Justyna; Slebioda, Tomasz; Zmijewski, Michal A.] Med Univ Gdansk, Dept Histol, Ul Debinki 1a,Room 230, PL-80211 Gdansk, Pomorskie, Poland. [Wozniak, Michal] Med Univ Gdansk, Dept Med Chem, PL-80211 Gdansk, Pomorskie, Poland. [Tuckey, Robert C.] Univ Western Australia, Sch Chem & Biochem, Crawley, WA, Australia. [Slominski, Andrzej T.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL USA. [Slominski, Andrzej T.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL USA. [Slominski, Andrzej T.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Zmijewski, MA (reprint author), Med Univ Gdansk, Dept Histol, Ul Debinki 1a,Room 230, PL-80211 Gdansk, Pomorskie, Poland. EM mzmijewski@gumed.edu.pl OI Zmijewski, Michal/0000-0003-2206-3531 FU grant of Polish Ministry of Science and Higher Education [N405 623238, R21 AR066505-01A1, 1R01AR056666-01A2] FX The study was supported by a grant of the Polish Ministry of Science and Higher Education, Project No. N405 623238 to Michal A. Zmijewski, and in part and R21 AR066505-01A1 and 1R01AR056666-01A2 (A.S.). NR 120 TC 0 Z9 0 U1 4 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD JUN PY 2016 VL 110 BP 49 EP 61 DI 10.1016/j.steroids.2016.04.002 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DM9QO UT WOS:000376701000005 PM 27083311 ER PT J AU Brem, EA Letai, A AF Brem, Elizabeth A. Letai, Anthony TI BOK: Oddball of the BCL-2 Family SO TRENDS IN CELL BIOLOGY LA English DT Editorial Material ID MEMBER BOK; TISSUES; BAX C1 [Brem, Elizabeth A.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM anthony_letai@dfci.haravrd.edu NR 8 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD JUN PY 2016 VL 26 IS 6 BP 389 EP 390 DI 10.1016/j.tcb.2016.04.007 PG 2 WC Cell Biology SC Cell Biology GA DN1DW UT WOS:000376807500001 PM 27156889 ER PT J AU Das, A McDonald, DG Dixon-Mah, YN Jacqmin, DJ Samant, VN Vandergrift, WA Lindhorst, SM Cachia, D Varma, AK Vanek, KN Banik, NL Jenrette, JM Raizer, JJ Giglio, P Patel, SJ AF Das, Arabinda McDonald, Daniel G. Dixon-Mah, Yaenette N. Jacqmin, Dustin J. Samant, Vikram N. Vandergrift, William A., III Lindhorst, Scott M. Cachia, David Varma, Abhay K. Vanek, Kenneth N. Banik, Naren L. Jenrette, Joseph M., III Raizer, Jeffery J. Giglio, Pierre Patel, Sunil J. TI RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma SO TUMOR BIOLOGY LA English DT Article DE Apoptosis; Glioblastoma; Radiation necrosis; RIP ID CELL-DEATH; BRAIN; INFLAMMATION; THERAPY; PATHOPHYSIOLOGY; NECROPTOSIS; APOPTOSIS; DIAGNOSIS AB Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-kappa B, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-alpha-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma. C1 [Das, Arabinda; Dixon-Mah, Yaenette N.; Samant, Vikram N.; Vandergrift, William A., III; Lindhorst, Scott M.; Cachia, David; Varma, Abhay K.; Banik, Naren L.; Giglio, Pierre; Patel, Sunil J.] Med Univ S Carolina, Dept Neurosurg, Div Neurooncol, Charleston, SC 29425 USA. [Das, Arabinda; Dixon-Mah, Yaenette N.; Samant, Vikram N.; Vandergrift, William A., III; Lindhorst, Scott M.; Cachia, David; Varma, Abhay K.; Banik, Naren L.; Giglio, Pierre; Patel, Sunil J.] Med Univ S Carolina, MUSC Brain & Spine Tumor Program CSB 310, Charleston, SC 29425 USA. [McDonald, Daniel G.; Jacqmin, Dustin J.; Vanek, Kenneth N.; Jenrette, Joseph M., III] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Banik, Naren L.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Giglio, Pierre] Ohio State Univ, Dept Neurol Surg, Wexner Med Coll, Columbus, OH 43210 USA. [Raizer, Jeffery J.] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Raizer, Jeffery J.] Northwestern Univ, Feinberg Sch Med, Northwestern Brain Tumor Inst, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. RP Das, A (reprint author), Med Univ S Carolina, Dept Neurosurg, Div Neurooncol, Charleston, SC 29425 USA.; Das, A (reprint author), Med Univ S Carolina, MUSC Brain & Spine Tumor Program CSB 310, Charleston, SC 29425 USA. EM dasa@musc.edu FU MUSC Brain Tumor Research Fund; Department of Neurosurgery (MUSC) FX This investigation was supported by the MUSC Brain Tumor Research Fund and Department of Neurosurgery (MUSC). Alyssa Pierce assisted with revision of the final manuscript. We also appreciate the essential help of Philip Lee. NR 28 TC 4 Z9 5 U1 5 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD JUN PY 2016 VL 37 IS 6 BP 7525 EP 7534 DI 10.1007/s13277-015-4621-6 PG 10 WC Oncology SC Oncology GA DM6LT UT WOS:000376464700051 PM 26684801 ER PT J AU Kulemann, B Liss, AS Warshaw, AL Seifert, S Bronsert, P Glatz, T Pitman, MB Hoeppner, J AF Kulemann, Birte Liss, Andrew S. Warshaw, Andrew L. Seifert, Sindy Bronsert, Peter Glatz, Torben Pitman, Martha B. Hoeppner, Jens TI KRAS mutations in pancreatic circulating tumor cells: a pilot study SO TUMOR BIOLOGY LA English DT Article DE Pancreatic cancer; Circulating tumor cells; Molecular/genetic status; Prognosis ID CANCER-PATIENTS; COLORECTAL-CANCER; PROGNOSTIC-SIGNIFICANCE; DUCTAL ADENOCARCINOMA; PROSTATE-CANCER; SURVIVAL; GEMCITABINE; TRIAL; RESECTION; THERAPY AB Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCellA (R) filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p < 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS (mut)) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis. C1 [Kulemann, Birte; Seifert, Sindy; Glatz, Torben; Hoeppner, Jens] Univ Freiburg, Med Ctr, Dept Surg, Hugstetter Str 55, D-79106 Freiburg, Germany. [Liss, Andrew S.; Warshaw, Andrew L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. [Liss, Andrew S.; Warshaw, Andrew L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Andrew L Warshaw MD Inst Pancreat Canc Res, Boston, MA 02115 USA. [Bronsert, Peter] Univ Freiburg, Med Ctr, Dept Pathol, Hugstetter Str 55, D-79106 Freiburg, Germany. [Bronsert, Peter] Univ Freiburg, Med Ctr, Ctr Comprehens Canc, Hugstetter Str 55, D-79106 Freiburg, Germany. [Pitman, Martha B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kulemann, B (reprint author), Univ Freiburg, Med Ctr, Dept Surg, Hugstetter Str 55, D-79106 Freiburg, Germany. EM birte.kulemann@uniklinik-freiburg.de NR 33 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD JUN PY 2016 VL 37 IS 6 BP 7547 EP 7554 DI 10.1007/s13277-015-4589-2 PG 8 WC Oncology SC Oncology GA DM6LT UT WOS:000376464700053 PM 26684803 ER PT J AU Menschikowski, M Hagelgans, A Nacke, B Jandeck, C Mareninova, OA Asatryan, L Siegert, G AF Menschikowski, Mario Hagelgans, Albert Nacke, Brit Jandeck, Carsten Mareninova, Olga A. Asatryan, Liana Siegert, Gabriele TI Epigenetic control of group V phospholipase A(2) expression in human malignant cells SO TUMOR BIOLOGY LA English DT Article DE Group V sPLA2; Leukaemia; Solid cancer cells; DNA methylation ID HUMAN NEUTROPHILS; DNA METHYLATION; GENE-EXPRESSION; EMERGING ROLES; CANCER; MECHANISMS; ENZYMES; DISEASE; PROMOTER; HYDROLYSIS AB Secreted phospholipases A(2) (sPLA(2)) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA(2)s expression in cancer cells, but group V sPLA(2) (GV-PLA(2)) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA(2) expression in different cell lines originating from leukaemia and solid cancers. In blood leukocytes from leukaemic patients, levels of GV-PLA(2) transcripts were significantly lower in comparison to those from healthy individuals. Similarly, in DU-145 and PC-3 prostate and CAL-51 and MCF-7 mammary cancer cell lines, levels of GV-PLA(2) transcripts were significantly lower in relation to those found in normal epithelial cells of prostate or mammary. By sequencing and methylation-specific high-resolution melting (MS-HRM) analyses of bisulphite-modified DNA, distinct CpG sites in the GV-PLA(2) promoter region were identified that were differentially methylated in cancer cells in comparison to normal epithelial and endothelial cells. Spearman rank order analysis revealed a significant negative correlation between the methylation degree and the cellular expression of GV-PLA(2) (r = -0.697; p = 0.01). The effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on GV-PLA(2) transcription in the analysed cells confirmed the importance of DNA methylation and histone modification in the regulation of the GV-PLA(2) gene expression in leukaemic, prostate and mammary cancer cell lines. The exposure of tumour cells to human recombinant GV-PLA(2) resulted in a reduced colony forming activity of MCF-7, HepG2 and PC-3 cells, but not of DU-145 cells suggesting a cell-type-dependent effect of GV-PLA(2) on cell growth. In conclusion, our results suggest that epigenetic mechanisms such as DNA methylation and histone modification play an important role in downregulation of GV-PLA(2) expression in cancer cells. C1 [Menschikowski, Mario; Hagelgans, Albert; Nacke, Brit; Jandeck, Carsten; Siegert, Gabriele] Tech Univ Dresden, Carl Gustav Carus Univ Hosp, Inst Clin Chem & Lab Med, Fetscherstr 74, D-01307 Dresden, Germany. [Mareninova, Olga A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mareninova, Olga A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Asatryan, Liana] USC Sch Pharm, Titus Family Dept Clin Pharm, Los Angeles, CA USA. RP Menschikowski, M (reprint author), Tech Univ Dresden, Carl Gustav Carus Univ Hosp, Inst Clin Chem & Lab Med, Fetscherstr 74, D-01307 Dresden, Germany. EM Mario.Menschikowski@uniklinikum-dresden.de NR 47 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD JUN PY 2016 VL 37 IS 6 BP 8097 EP 8105 DI 10.1007/s13277-015-4670-x PG 9 WC Oncology SC Oncology GA DM6LT UT WOS:000376464700109 PM 26715269 ER PT J AU Louis, DN Perry, A Reifenberger, G von Deimling, A Figarella-Branger, D Cavenee, WK Ohgaki, H Wiestler, OD Kleihues, P Ellison, DW AF Louis, David N. Perry, Arie Reifenberger, Guido von Deimling, Andreas Figarella-Branger, Dominique Cavenee, Webster K. Ohgaki, Hiroko Wiestler, Otmar D. Kleihues, Paul Ellison, David W. TI The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary SO ACTA NEUROPATHOLOGICA LA English DT Review ID BRAF V600E MUTATION; LOW-GRADE GLIOMAS; MOLECULAR CHARACTERISTICS; GENETIC ALTERATIONS; DISTINCT SUBGROUPS; MALIGNANT GLIOMAS; GENOMIC ANALYSIS; INI1 EXPRESSION; GLIOBLASTOMA; DIFFUSE AB The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors. C1 [Louis, David N.] Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med, WRN225,55 Fruit St, Boston, MA 02114 USA. [Perry, Arie] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Reifenberger, Guido] Heinrich Heine Univ, Dept Neuropathol, Dusseldorf, Germany. [Reifenberger, Guido; von Deimling, Andreas] German Canc Consortium DKTK, Site Essen, Dusseldorf, Germany. [von Deimling, Andreas] Heidelberg Univ, Dept Neuropathol, Inst Pathol, Heidelberg, Germany. [Figarella-Branger, Dominique] Aix Marseille Univ, La Timone Hosp, Dept Pathol & Neuropathol, Marseille, France. [Cavenee, Webster K.] Univ Calif San Diego, Ludwig Inst Canc Res, San Diego, CA 92103 USA. [Ohgaki, Hiroko] IARC, Lyon, France. [Wiestler, Otmar D.] German Canc Res Ctr, Heidelberg, Germany. [Kleihues, Paul] Univ Zurich, Fac Med, Zurich, Switzerland. [Ellison, David W.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Louis, DN (reprint author), Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med, WRN225,55 Fruit St, Boston, MA 02114 USA. EM dlouis@mgh.harvard.edu RI von Deimling, Andreas/F-7774-2013 OI von Deimling, Andreas/0000-0002-5863-540X NR 52 TC 199 Z9 216 U1 42 U2 71 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUN PY 2016 VL 131 IS 6 BP 803 EP 820 DI 10.1007/s00401-016-1545-1 PG 18 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DM3WM UT WOS:000376277400001 PM 27157931 ER PT J AU Kang, JH Mollenhauer, B Coffey, CS Toledo, JB Weintraub, D Galasko, DR Irwin, DJ Van Deerlin, V Chen-Plotkin, AS Caspell-Garcia, C Waligorska, T Taylor, P Shah, N Pan, S Zero, P Frasier, M Marek, K Kieburtz, K Jennings, D Tanner, CM Simuni, T Singleton, A Toga, AW Chowdhury, S Trojanowski, JQ Shaw, LM AF Kang, Ju-Hee Mollenhauer, Brit Coffey, Christopher S. Toledo, Jon B. Weintraub, Daniel Galasko, Douglas R. Irwin, David J. Van Deerlin, Vivianna Chen-Plotkin, Alice S. Caspell-Garcia, Chelsea Waligorska, Teresa Taylor, Peggy Shah, Nirali Pan, Sarah Zero, Pawel Frasier, Mark Marek, Kenneth Kieburtz, Karl Jennings, Danna Tanner, Caroline M. Simuni, Tanya Singleton, Andrew Toga, Arthur W. Chowdhury, Sohini Trojanowski, John Q. Shaw, Leslie M. TI CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study SO ACTA NEUROPATHOLOGICA LA English DT Article DE Parkinson's disease; Cerebrospinal fluid biomarker; Parkinson's Progression Markers Initiative; A beta(1-42); Tau; Alpha-synuclein ID HEALTH-EXPLORATORY-TRIALS; NET-PD EXPERIENCE; ALPHA-SYNUCLEIN; AMYLOID-BETA; COGNITIVE PERFORMANCE; INCIDENT DEMENTIA; TAU; RISK; SUBTYPES; COHORT AB The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-na < ve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (alpha-syn), amyloid-beta1-42 (A beta(1-42)), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF alpha-syn, t-tau and p-tau levels, but not A beta(1-42), were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of alpha-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest A beta(1-42), or highest t-tau/A beta(1-42) and t-tau/alpha-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower alpha-syn was significantly associated with worse cognitive test performance. APOE epsilon 4 genotype was associated with lower levels of A beta(1-42), but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance. C1 [Kang, Ju-Hee; Toledo, Jon B.; Irwin, David J.; Van Deerlin, Vivianna; Waligorska, Teresa; Shah, Nirali; Pan, Sarah; Zero, Pawel; Trojanowski, John Q.; Shaw, Leslie M.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, 7-103 Founders Pavil 3400 Spruce St, Philadelphia, PA 19104 USA. [Kang, Ju-Hee] Inha Univ, Hypoxiarelated Dis Res Ctr, Sch Med, Dept Pharmacol, Inchon, South Korea. [Mollenhauer, Brit] Paracelsus Elena Klin, Kassel, Germany. [Mollenhauer, Brit] Univ Med Ctr Goettingen, Dept Neuropathol & Neurosurg, Gottingen, Germany. [Coffey, Christopher S.; Caspell-Garcia, Chelsea] Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA. [Toledo, Jon B.; Irwin, David J.; Van Deerlin, Vivianna; Chen-Plotkin, Alice S.; Trojanowski, John Q.; Shaw, Leslie M.] Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Inst Aging, Philadelphia, PA 19104 USA. [Weintraub, Daniel; Irwin, David J.; Chen-Plotkin, Alice S.; Trojanowski, John Q.] Univ Penn, Morris K Udall Ctr Excellence Parkinsons Dis Res, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Dept Vet Affairs, Philadelphia, PA USA. [Galasko, Douglas R.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Taylor, Peggy] BioLegend Inc, Dedham, MA USA. [Frasier, Mark; Chowdhury, Sohini] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Marek, Kenneth; Jennings, Danna] Inst Neurodegenerat Disorders, New Haven, CT USA. [Kieburtz, Karl] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY USA. [Tanner, Caroline M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Tanner, Caroline M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Simuni, Tanya] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Singleton, Andrew] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Toga, Arthur W.] Univ So Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA 90033 USA. RP Shaw, LM (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, 7-103 Founders Pavil 3400 Spruce St, Philadelphia, PA 19104 USA.; Shaw, LM (reprint author), Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Inst Aging, Philadelphia, PA 19104 USA. EM Les.Shaw@uphs.upenn.edu RI Singleton, Andrew/C-3010-2009; OI Toledo, Jon/0000-0003-4366-9268 FU Michael J. Fox Foundation for Parkinson's Research; Abbott; Avid Radiopharmaceuticals; BiogenIdec; Covance; Elan; Eli Lilly and Co; F. Hoffman-LaRoche Ltd; GE Healthcare; Genentech; Glaxo Smith Kline; Merck and Co; Pfizer Inc; UCB Pharma SA; Morris K. Udall Center of Excellence for Parkinson's Disease Research [P50NS053488-05]; Training in Age-Related Neurodegenerative Diseases from the National Institute on Aging, National Institutes of Health [T32-AG000255]; Intramural Research Program, National Institute on Aging, National Institutes of Health [Z01AG000949-06]; MRC FX This work was supported by The Michael J. Fox Foundation for Parkinson's Research, Abbott, Avid Radiopharmaceuticals, BiogenIdec, Covance, Elan, Eli Lilly and Co, F. Hoffman-LaRoche Ltd, GE Healthcare, Genentech, Glaxo Smith Kline, Merck and Co, Pfizer Inc, and UCB Pharma SA. Trojanowski and Chen-Plotkin were supported by core grant P50NS053488-05 from the Morris K. Udall Center of Excellence for Parkinson's Disease Research. Irwin was supported by Training in Age-Related Neurodegenerative Diseases grant T32-AG000255 from the National Institute on Aging, National Institutes of Health. Singleton was supported by Grant Z01AG000949-06 from the Intramural Research Program, National Institute on Aging, National Institutes of Health. Ju-Hee was supported by Grant MRC NR 43 TC 15 Z9 15 U1 4 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUN PY 2016 VL 131 IS 6 BP 935 EP 949 DI 10.1007/s00401-016-1552-2 PG 15 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DM3WM UT WOS:000376277400011 PM 27021906 ER PT J AU Perry, NS Taylor, SW Elsesser, S Safren, SA O'Cleirigh, C AF Perry, Nicholas S. Taylor, S. Wade Elsesser, Steven Safren, Steven A. O'Cleirigh, Conall TI The Predominant Relationship Between Sexual Environment Characteristics and HIV-Serodiscordant Condomless Anal Sex Among HIV-Positive Men Who Have Sex with Men (MSM) SO AIDS AND BEHAVIOR LA English DT Article DE Condomless sex; Sexual environment; Positive prevention; Men who have sex with men (MSM) ID RISK BEHAVIOR; UNITED-STATES; ANTIRETROVIRAL THERAPY; VIRAL SUPPRESSION; INFECTED ADULTS; BISEXUAL MEN; DAILY DIARY; VULNERABILITY; INTERCOURSE; ADHERENCE AB In some studies, situational factors have been shown to be stronger predictors of condomless sex than individual risk factors. Cross-sectional relationships between condomless anal sex (CAS) with HIV-serodiscordant partners and risk factors across ecological levels (individual, sexual environment) were examined using a sample (N = 60) of HIV-positive men who have sex with men (MSM) who reported multiple recent episodes of CAS. Negative binomial regressions were used to evaluate the association of contextual risk factors (e.g., substance use during sex, transactional sex, public sex, sex at a sex party) with recent condomless sex, controlling for demographics and mental health. Results demonstrated that sexual environment factors, particularly sex under the influence of drugs or alcohol (B = .019, p < .05), transactional sex (B = .035, p < .01), and public sex (B = .039, p < .01) explained a large proportion of the variance in CAS. Only sex at a sex party was not related to CAS (p = .39). For each additional sexual environment in which men engaged, their rates of CAS increased (B = .39, p < .01). Secondary prevention interventions that are tailored to the proximal sexual environment could be maximally effective, particularly if they address substance use and other challenging sexual situations. C1 [Perry, Nicholas S.; O'Cleirigh, Conall] Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. [Perry, Nicholas S.] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Taylor, S. Wade] Wheelock Coll, Dept Social Work, Boston, MA 02215 USA. [Taylor, S. Wade; Elsesser, Steven; Safren, Steven A.; O'Cleirigh, Conall] Fenway Hlth, Boston, MA 02215 USA. [Safren, Steven A.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [O'Cleirigh, Conall] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP O'Cleirigh, C (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA.; O'Cleirigh, C (reprint author), Fenway Hlth, Boston, MA 02215 USA.; O'Cleirigh, C (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM cocleirigh@mgh.harvard.edu FU Harvard University Center for AIDS Research [P30AI060354]; NIH [K24MH094214] FX We are very grateful to the participants for their time and efforts in the study. Support for the current study came from a feasibility grant (PI: Conall O'Cleirigh) from the Harvard University Center for AIDS Research (Parent Grant: P30AI060354, PI: Bruce Walker, MD) awarded to Dr. Conall O'Cleirigh. Investigator support for Dr. Steven Safren also came from NIH Grant K24MH094214. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 1 Z9 1 U1 4 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUN PY 2016 VL 20 IS 6 BP 1228 EP 1235 DI 10.1007/s10461-015-1202-z PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DM4FB UT WOS:000376300700008 PM 26395194 ER PT J AU Yang, CS Kroshinsky, D Cummings, BM AF Yang, Catherine S. Kroshinsky, Daniela Cummings, Brian M. TI Neonatal Junctional Epidermolysis Bullosa: Treatment Conundrums and Ethical Decision Making (vol 15, pg 445, 2014) SO AMERICAN JOURNAL OF CLINICAL DERMATOLOGY LA English DT Correction C1 [Yang, Catherine S.] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, 593 Eddy St,APC 1018, Providence, RI 02903 USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Cummings, Brian M.] Massachusetts Gen Hosp Children, Dept Pediat, Boston, MA USA. RP Yang, CS (reprint author), Brown Univ, Warren Alpert Med Sch, Dept Dermatol, 593 Eddy St,APC 1018, Providence, RI 02903 USA. EM catherine_yang@brown.edu NR 1 TC 0 Z9 0 U1 1 U2 2 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1175-0561 EI 1179-1888 J9 AM J CLIN DERMATOL JI Am. J. Clin. Dermatol. PD JUN PY 2016 VL 17 IS 3 BP 317 EP 317 DI 10.1007/s40257-016-0188-2 PG 1 WC Dermatology SC Dermatology GA DM1JR UT WOS:000376102000012 ER PT J AU Padanyi, R Paszty, K Hegedus, L Varga, K Papp, B Penniston, JT Enyedi, A AF Padanyi, Rita Paszty, Katalin Hegedus, Luca Varga, Karolina Papp, Bela Penniston, John T. Enyedi, Agnes TI Multifaceted plasma membrane Ca2+ pumps: From structure to intracellular Ca2+ handling and cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Plasma membrane Ca2+ ATPase; Ca2+-calmodulin; Phosphatidylinositol-4,5-bisphosphate binding; Ca2+ signaling; Differentiation; Tumor progression ID CALMODULIN-BINDING DOMAIN; RETICULUM CALCIUM-PUMP; SMOOTH-MUSCLE-CELLS; ATPASE ISOFORM; BREAST-CANCER; UP-REGULATION; CELLULAR CA2+; CA2+-ATPASE EXPRESSION; HIPPOCAMPAL-NEURONS; NA+-CA2+ EXCHANGER AB Plasma membrane Ca2+ ATPases (PMCAs) are intimately involved in the control of intracellular Ca2+ concentration. They reduce Ca2+ in the cytosol not only by direct ejection, but also by controlling the formation of inositol-1,4,5-trisphosphate and decreasing Ca2+ release from the endoplasmic reticulum Ca2+ pool. In mammals four genes (PMCA1-4) are expressed, and alternative RNA splicing generates more than twenty variants. The variants differ in their regulatory characteristics. They localize into highly specialized membrane compartments and respond to the incoming Ca2+ with distinct temporal resolution. The expression pattern of variants depends on cell type; a change in this pattern can result in perturbed Ca2+ homeostasis and thus altered cell function. Indeed, PMCAs undergo remarkable changes in their expression pattern during tumorigenesis that might significantly contribute to the unbalanced Ca2+ homeostasis of cancer cells. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. (C) 2015 Elsevier B.V. All rights reserved. C1 [Padanyi, Rita; Varga, Karolina; Enyedi, Agnes] Semmelweis Univ, Dept Pathol 2, Ulloi Ut 93, H-1091 Budapest, Hungary. [Paszty, Katalin] Hungarian Acad Sci, Mol Biophys Res Grp, Budapest, Hungary. [Paszty, Katalin] Semmelweis Univ, Dept Biophys, H-1091 Budapest, Hungary. [Hegedus, Luca] Med Univ Vienna, Dept Pathophysiol & Allergy Res, Vienna, Austria. [Papp, Bela] INSERM, UMR U978, Bobigny, France. [Papp, Bela] Univ Paris 13, PRES Sorbonne Paris Cite, Bobigny, France. [Penniston, John T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Enyedi, Agnes] Hungarian Acad Sci, Mol Oncol Res Grp, Budapest, Hungary. [Enyedi, Agnes] Semmelweis Univ, H-1091 Budapest, Hungary. RP Enyedi, A (reprint author), Semmelweis Univ, Dept Pathol 2, Ulloi Ut 93, H-1091 Budapest, Hungary. EM enyedi.agnes@med.semmelweis-univ.hu FU OTKA [ANN-110922, K 101064]; TRANSRAT [KMR_12-1-2012-0112] FX This work was supported by grants from OTKA (ANN-110922 and K 101064) (AE), and TRANSRAT KMR_12-1-2012-0112 (KP). NR 173 TC 1 Z9 1 U1 10 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JUN PY 2016 VL 1863 IS 6 SI SI BP 1351 EP 1363 DI 10.1016/j.bbamcr.2015.12.011 PN B PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL8IO UT WOS:000375885900004 PM 26707182 ER PT J AU Reisner, A AF Reisner, A. TI Academic assessment of arterial pulse contour analysis: missing the forest for the trees? SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Editorial Material ID PRESSURE WAVE-FORM; CARDIAC-OUTPUT; BISPECTRAL INDEX; TRIAL; ANESTHESIA; AWARENESS C1 [Reisner, A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. RP Reisner, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM areisner@partners.org NR 14 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 EI 1471-6771 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD JUN PY 2016 VL 116 IS 6 BP 733 EP 736 DI 10.1093/bja/aew110 PG 4 WC Anesthesiology SC Anesthesiology GA DM4HV UT WOS:000376309000070 PM 27199303 ER PT J AU Delaney-Busch, N Wilkie, G Kuperberg, G AF Delaney-Busch, Nathaniel Wilkie, Gianna Kuperberg, Gina TI Vivid: How valence and arousal influence word processing under different task demands SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Event-related potentials; ERP; LPC; LPP; Late positivity; Emotion; Valence; Arousal; Language; Word processing; Task ID EVENT-RELATED POTENTIALS; READING EMOTIONAL WORDS; BRAIN POTENTIALS; NEGATIVITY BIAS; TIME-COURSE; ELECTROCORTICAL RESPONSE; AFFECTIVE PRIMACY; VISUAL-ATTENTION; NEUTRAL WORDS; ERP AB In this study, we used event-related potentials to examine how different dimensions of emotion-valence and arousal-influence different stages of word processing under different task demands. In two experiments, two groups of participants viewed the same single emotional and neutral words while carrying out different tasks. In both experiments, valence (pleasant, unpleasant, and neutral) was fully crossed with arousal (high and low). We found that the task made a substantial contribution to how valence and arousal modulated the late positive complex (LPC), which is thought to reflect sustained evaluative processing (particularly of emotional stimuli). When participants performed a semantic categorization task in which emotion was not directly relevant to task performance, the LPC showed a larger amplitude for high-arousal than for low-arousal words, but no effect of valence. In contrast, when participants performed an overt valence categorization task, the LPC showed a large effect of valence (with unpleasant words eliciting the largest positivity), but no effect of arousal. These data show not only that valence and arousal act independently to influence word processing, but that their relative contributions to prolonged evaluative neural processes are strongly influenced by the situational demands (and by individual differences, as revealed in a subsequent analysis of subjective judgments). C1 [Delaney-Busch, Nathaniel; Wilkie, Gianna; Kuperberg, Gina] Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. [Wilkie, Gianna] Univ Massachusetts, Sch Med, Worcester, MA USA. [Kuperberg, Gina] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kuperberg, Gina] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. RP Delaney-Busch, N (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. EM Nathaniel.Delaney-Busch@tufts.edu FU National Institute of Mental Health [R01MH071635]; Sidney Baer Trust FX This study was funded by the National Institute of Mental Health (Grant No. R01MH071635 to G.R.K.) and by the Sidney Baer Trust. We thank several people who contributed to constructing the experimental materials, to data collection, and to technical support, including Arim Choi, Allison Fogel, Vivian Haime, Ju Hyung Kim, and Ann Yacoubian. We also thank Marianna Eddy, Eric Fields, Phil Holcomb, Ellen Lau, Katherine Midgley, Heather Urry, and three gracious anonymous reviewers for their insightful comments and technical guidance. NR 102 TC 2 Z9 2 U1 7 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD JUN PY 2016 VL 16 IS 3 BP 415 EP 432 DI 10.3758/s13415-016-0402-y PG 18 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DM4EU UT WOS:000376299800004 PM 26833048 ER PT J AU Beverly, EA Ritholz, MD Shepherd, C Weinger, K AF Beverly, Elizabeth A. Ritholz, Marilyn D. Shepherd, Chelsea Weinger, Katie TI The Psychosocial Challenges and Care of Older Adults with Diabetes: "Can't Do What I Used To Do; Can't Be Who I Once Was" SO CURRENT DIABETES REPORTS LA English DT Review DE Diabetes; Psychosocial challenges; Depression; Diabetes distress; Aging ID QUALITY-OF-LIFE; GENERALIZED ANXIETY DISORDER; SEROTONIN REUPTAKE INHIBITORS; COGNITIVE-BEHAVIORAL THERAPY; MAJOR DEPRESSIVE DISORDER; GERIATRIC DEPRESSION; GLYCEMIC CONTROL; MEXICAN-AMERICANS; SOCIAL SUPPORT; NEEDS DAWN AB The prevalence of diabetes is increasing in older populations worldwide. Older adults with diabetes have unique psychosocial and medical challenges that impact self-care and glycemic control. These challenges may include psychological factors such as depression or anxiety, social factors such loss of independence and removal from home environment/placement in a facility, and medical factors such as multiple comorbidities and polypharmacy. Importantly, these challenges interact and complicate the everyday life of the older adult with diabetes. Thus, timely identification and interventions for psychosocial and medical challenges are a necessary component of diabetes care. This review summarizes the current literature, research findings, and clinical recommendations for psychosocial care in older adults with diabetes. C1 [Beverly, Elizabeth A.; Shepherd, Chelsea] Ohio Univ, Heritage Coll Osteopath Med, Dept Family Med, Athens, OH 45701 USA. [Ritholz, Marilyn D.; Weinger, Katie] Joslin Diabet Ctr, Boston, MA 02215 USA. [Ritholz, Marilyn D.; Weinger, Katie] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ritholz, Marilyn D.] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. RP Beverly, EA (reprint author), Ohio Univ, Heritage Coll Osteopath Med, Dept Family Med, Athens, OH 45701 USA. EM beverle1@ohio.edu; marilyn.ritholz@joslin.harvard.edu; cs034312@ohio.edu; katie.weinger@joslin.harvard.edu FU NIDDK NIH HHS [P30 DK036836] NR 165 TC 0 Z9 0 U1 10 U2 14 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD JUN PY 2016 VL 16 IS 6 AR 48 DI 10.1007/s11892-016-0741-7 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM3YT UT WOS:000376283400003 PM 27085863 ER PT J AU McGinley, EL Gabbay, RA AF McGinley, Erin L. Gabbay, Robert A. TI The Impact of New Payment Models on Quality of Diabetes Care and Outcomes SO CURRENT DIABETES REPORTS LA English DT Review DE Diabetes; Payment models; Healthcare delivery; Primary care ID MEDICAL HOME; COST AB Historic changes in healthcare reimbursement and payment models due to the Affordable Care Act in the United States have the potential to transform how providers care for chronic diseases such as diabetes. Payment experimentation has provided insights into how changing incentives for primary care providers can yield improvements in the triple aim: improving patient experience, improving the health of populations, and reducing costs of healthcare. Much of this has involved leveraging widespread adoption of the patient-centered medical home (PCMH) with diabetes often the focus. While evidence is mounting that the PCMH can improve diabetes outcomes, some PCMH demonstrations have displayed mixed results. One of the first large-scale PCMH demonstrations developed around diabetes was conducted by the Commonwealth of Pennsylvania. Different payment models were employed across a series of staggered regional rollouts that provided a case study for the influence of innovative payment models. These learning laboratories provide insights into the role of reimbursement models and changes in how practice transformation is implemented. Ultimately, evolving payment systems focused on the total cost of care, such as Accountable Care Organizations, hold promise to transform diabetes care and produce significant cost savings through the prevention of complications. C1 [McGinley, Erin L.] Penn State Coll Med, Dept Family & Community Med, 500 Univ Dr, Hershey, PA 17033 USA. [Gabbay, Robert A.] Harvard Univ, Sch Med, Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. RP Gabbay, RA (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM emcginley@hmc.psu.edu; robert.gabbay@joslin.harvard.edu NR 17 TC 0 Z9 0 U1 2 U2 3 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD JUN PY 2016 VL 16 IS 6 AR 51 DI 10.1007/s11892-016-0743-5 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM3YT UT WOS:000376283400006 PM 27091445 ER PT J AU Meppelink, AM Wang, XH Bradica, G Barron, K Hiltz, K Liu, XH Goldman, SM Vacanti, JP Keating, A Hoganson, DM AF Meppelink, Amanda M. Wang, Xing-Hua Bradica, Gino Barron, Kathryn Hiltz, Kathleen Liu, Xiang-Hong Goldman, Scott M. Vacanti, Joseph P. Keating, Armand Hoganson, David M. TI Rapid isolation of bone marrow mesenchymal stromal cells using integrated centrifuge-based technology SO CYTOTHERAPY LA English DT Article DE bone marrow aspirate; cell isolation; differentiation; mesenchymal stromal cells ID ACUTE MYOCARDIAL-INFARCTION; STEM-CELLS; THERAPY; GROWTH AB Background aims. The use of bone marrow derived mesenchymal stromal cells (MSCs) in cell-based therapies is currently being developed for a number of diseases. Thus far, the clinical results have been inconclusive and variable, in part because of the variety of cell isolation procedures and culture conditions used in each study. A new isolation technique that streamlines the method of concentration and demands less time and attention could provide clinical and economic advantages compared with current methodologies. In this study, we evaluated the concentrating capability of an integrated centrifuge based technology compared with standard Ficoll isolation. Methods. MSCs were concentrated from bone marrow aspirate using the new device and the Ficoll method. The isolation capabilities of the device and the growth characteristics, secretome production, and differentiation capacity of the derived cells were determined. Results. The new MSC isolation device concentrated the bone marrow in 90 seconds and resulted in a mononuclear cell yield 10-fold higher and with a twofold increase in cell retention compared with Ficoll. The cells isolated using the device were shown to exhibit similar morphology and functional activity as assessed by growth curves and secretome production compared to the Ficoll-isolated cells. The surface marker and trilineage differentiation profile of the device-isolated cells was consistent with the known profile of MSCs. Discussion. The faster time to isolation and greater cell yield of the integrated centrifuge-based technology may make this an improved approach for MSC isolation from bone marrow aspirates. C1 [Meppelink, Amanda M.] Massachusetts Gen Hosp, Dept Surg, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Wang, Xing-Hua; Keating, Armand] Univ Hlth Network, Princess Margaret Hosp, Cell Therapy Program, Toronto, ON, Canada. [Bradica, Gino; Liu, Xiang-Hong; Goldman, Scott M.] DSM Biomed, Exton, PA USA. [Barron, Kathryn; Hiltz, Kathleen] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Vacanti, Joseph P.] Massachusetts Gen Hosp, Dept Surg, Ctr Regenerat Med, Boston, MA 02114 USA. [Hoganson, David M.] Boston Childrens Hosp, Dept Cardiac Surg, Boston, MA 02115 USA. RP Hoganson, DM (reprint author), Boston Childrens Hosp, Dept Pediat Cardiac Surg, 300 Longwood Ave,Bader 273, Boston, MA 02115 USA. EM david.hoganson@cardio.chboston.org FU DSM Biomedical FX Scott Goldman and Gino Bradica are employees of DSM Biomedical, which manufacturers the bone marrow concentrating device used in this work. David Hoganson receives research support and is a consultant for DSM Biomedical. Funding for the project was provided by DSM Biomedical. DSM Biomedical contributed to the study only in the FACS analysis. They had no role in the study design, interpretation of data, writing of the report, or decision to submit the paper for publication. The other authors have no commercial, proprietary or financial interest in the products or companies described in this article. NR 38 TC 0 Z9 0 U1 5 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2016 VL 18 IS 6 BP 729 EP 739 DI 10.1016/j.jcyt.2016.03.291 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DM3BU UT WOS:000376222600004 PM 27173749 ER PT J AU Cadoni, S Falt, P Sanna, S Argiolas, M Fanari, V Gallittu, P Liggi, M Mura, D Porcedda, ML Smajstrla, V Erriu, M Leung, FW AF Cadoni, Sergio Falt, Premysl Sanna, Stefano Argiolas, Mariangela Fanari, Viviana Gallittu, Paolo Liggi, Mauro Mura, Donatella Porcedda, Maria L. Smajstrla, Vit Erriu, Matteo Leung, Felix W. TI Insertion water exchange increases right colon adenoma and hyperplastic polyp detection rates during withdrawal SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Adenoma detection rate; Colon cleanliness; Interval colon cancer; Right colon hyperplastic polyps ID INTERVAL COLORECTAL-CANCER; QUALITY INDICATORS; NEGATIVE COLONOSCOPY; MISS RATE; IMMERSION; IMPACT; RISK; RECOMMENDATIONS; LESIONS; CLASSIFICATION AB Background: Single site studies in male Veterans in the U.S. reported increased detection of presumptive cancer precursors (adenomas, hyperplastic polyps) in the proximal colon (cecum-splenic flexure) by water exchange. Aims: Assess the reproducibility of the observation. Methods: Analysis of secondary outcomes collected prospectively in 3 similarly designed randomized controlled trials using water exchange, water immersion and insufflation (air or carbon dioxide). Main outcome: detection rates of adenomas and hyperplastic polyps in proximal, transverse and right colon (cecum-ascending). Results: 704 males (173 screening) were evaluated. In the proximal colon, WE showed increased detection of small adenomas (p = 0.009) and adenomas plus hyperplastic polyps (p = 0.015) (vs insufflation); increased detection of adenomas plus hyperplastic polyps of any size (p = 0.045) and of small size (p = 0.04) (vs water immersion). In the right colon water exchange increased detection of small adenomas (19% vs 12.1%, p = 0.04) (vs insufflation); small adenomas (19% vs 12%, p = 0.038), adenomas plus hyperplastic polyps of any size (25% vs 16.7%, p = 0.028) and of small size (23.7% vs 14.6%, p = 0.012) (vs water immersion). Water exchange significantly improved bowel cleanliness. Sedation had no impact on lesion detection. Conclusions: Water exchange is a superior insertion technique for detection of adenomas and hyperplastic polyps primarily in the right colon, especially those of small size. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 [Cadoni, Sergio; Gallittu, Paolo; Liggi, Mauro; Mura, Donatella] St Barbara Hosp, Digest Endoscopy Unit, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. [Falt, Premysl; Smajstrla, Vit] Vtkovice Hosp, Ctr Digest Dis, Ostrava, Czech Republic. [Sanna, Stefano; Argiolas, Mariangela; Fanari, Viviana; Porcedda, Maria L.] NS di Bonaria Hosp, Digest Endoscopy Unit, San Gavino Monreale, VS, Italy. [Erriu, Matteo] Univ Cagliari, Dept Surg Sci, Cagliari, CA, 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, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. EM cadonisergio@gmail.com NR 51 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD JUN PY 2016 VL 48 IS 6 BP 638 EP 643 DI 10.1016/j.dld.2016.03.004 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DL9HA UT WOS:000375951200012 PM 27017108 ER PT J AU Atkinson, C Singh, S Fisichella, PM AF Atkinson, Christopher Singh, Satish Fisichella, P. Marco TI Volumetric laser endomicroscopy in the detection of neoplastic lesions of the esophagus SO DIGESTIVE AND LIVER DISEASE LA English DT Editorial Material C1 [Atkinson, Christopher; Singh, Satish] Boston Univ, Div Gastroenterol, Boston VA Healthcare Syst, Boston, MA 02215 USA. [Fisichella, P. Marco] Harvard Univ, Sch Med, Dept Surg, Boston VA Healthcare Syst, Boston, MA 02115 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM piero.fisichella@va.gov NR 1 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD JUN PY 2016 VL 48 IS 6 BP 692 EP 692 DI 10.1016/j.dld.2016.02.013 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DL9HA UT WOS:000375951200026 PM 26976783 ER PT J AU Kokkaliaris, KD Lucas, D Beeman, I Kent, DG Perie, L AF Kokkaliaris, Konstantinos D. Lucas, Daniel Beeman, Isabel Kent, David G. Perie, Leila TI Understanding hematopoiesis from a single-cell standpoint SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID STEM-CELLS; BONE-MARROW; HETEROGENEITY; DIFFERENTIATION; POPULATIONS; COMPARTMENT; PROGENY AB The cellular diversity of the hematopoietic system has been extensively studied, and a plethora of cell surface markers have been used to discriminate and prospectively purify different blood cell types. However, even within phenotypically identical fractions of hematopoietic stem and progenitor cells or lineage-restricted progenitors, significant functional heterogeneity is observed when single cells are analyzed. To address these challenges, researchers are now using techniques to follow single cells and their progeny to improve our understanding of the underlying functional heterogeneity. On November 19, 2015, Dr. David Kent and Dr. Leila Perie, two emerging young group leaders, presented their recent efforts to dissect the functional properties of individual cells with a webinar series organized by the International Society for Experimental Hematology. Here, we provide a summary of the presented methods for cell labeling and clonal tracking and discuss how these different techniques have been employed to study hematopoiesis. (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. C1 [Kokkaliaris, Konstantinos D.] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Cell Syst Dynam Res Grp, Basel, Switzerland. [Lucas, Daniel] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI USA. [Beeman, Isabel] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Kent, David G.] Univ Cambridge, Dept Haematol, Wellcome Trust, Cambridge, England. [Kent, David G.] Univ Cambridge, MRC, Cambridge Stein Cell Inst, Cambridge, England. [Perie, Leila] PSL Res Univ, Inst Curie, Paris, France. RP Kokkaliaris, KD (reprint author), Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Cell Syst Dynam Res Grp, Basel, Switzerland. EM konstantinos.kokkaliaris@bsse.ethz.ch OI Kent, David/0000-0001-7871-8811 FU Medical Research Council [MC_PC_12009]; NIA NIH HHS [K01 AG050813] NR 27 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2016 VL 44 IS 6 BP 447 EP 450 DI 10.1016/j.exphem.2016.03.003 PG 4 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DM0SD UT WOS:000376055200003 PM 26997547 ER PT J AU McCormack, CA Lo Gullo, R Kalra, MK Louissaint, A Stone, JR AF McCormack, Carmen A. Lo Gullo, Roberto Kalra, Mannudeep K. Louissaint, Abner, Jr. Stone, James R. TI Reliability of body size measurements obtained at autopsy: impact on the pathologic assessment of the heart SO FORENSIC SCIENCE MEDICINE AND PATHOLOGY LA English DT Article DE Autopsy; Body length; Body weight; Body size; Edema ID WEIGHT; AGE AB Purpose Assessment of body size at autopsy is important for interpreting organ weight measurements and in some cases body identification. The reliability of post-mortem body size measurements, the causes for perturbations in these measurements from their corresponding pre-mortem values, and the impact of such perturbations on heart weight interpretation have not been fully explored. Methods Autopsy body length and weight measurements and pre-mortem height and body weight measurements were compared in 132 autopsies. Clinical records were evaluated for peripheral edema and serum albumin levels. Causes of death, body cavity fluid collections, and heart weights were obtained from the autopsy reports. A subset of patients underwent quantitative post-mortem computed tomography assessment of anasarca. Results At autopsy, body weight differed from the pre-mortem value by 11 +/- A 1 %, compared with -0.2 +/- A 0.3 % for body length (P < 0.0001). The percent change in body weight at autopsy correlated with the presence of peripheral edema (14 +/- A 2 % vs. 7 +/- A 2 %, P = 0.01), serum albumin < 3.0 g/dL (16 +/- A 2 % vs. 7 +/- A 2 %, P = 0.001), and the degree of anasarca (P = 0.01). In 4 % of autopsies, heart weights were abnormal based on the pre-mortem body weight, but would be classified as normal based on the elevated post-mortem body weight. Conclusions At autopsy, body weight is a less reliable parameter than body length in correlating with the corresponding pre-mortem measurement. Autopsy body weights are elevated in part due to peripheral edema/anasarca. Alterations in body weight at autopsy can confound the interpretation of organ weight measurements. C1 [McCormack, Carmen A.; Louissaint, Abner, Jr.; Stone, James R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Simches Res Bldg Room 8236,185 Cambridge St CPZN, Boston, MA 02114 USA. [Lo Gullo, Roberto] Univ Milan, Dept Radiol, Milan, Italy. [Lo Gullo, Roberto; Kalra, Mannudeep K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Thorac Imaging,Dept Radiol, Boston, MA 02114 USA. [Stone, James R.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Stone, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Simches Res Bldg Room 8236,185 Cambridge St CPZN, Boston, MA 02114 USA.; Stone, JR (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM jrstone@partners.org NR 13 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1547-769X EI 1556-2891 J9 FORENSIC SCI MED PAT JI Forensic Sci. Med. Pathol. PD JUN PY 2016 VL 12 IS 2 BP 139 EP 145 DI 10.1007/s12024-016-9773-1 PG 7 WC Medicine, Legal; Pathology SC Legal Medicine; Pathology GA DM0FK UT WOS:000376018300003 PM 27020890 ER PT J AU Wu, XM Huang, YY Kushida, Y Bhayana, B Hamblin, MR AF Wu, Ximing Huang, Ying-Ying Kushida, Yu Bhayana, Brijesh Hamblin, Michael R. TI Broad-spectrum antimicrobial photocatalysis mediated by titanium dioxide and UVA is potentiated by addition of bromide ion via formation of hypobromite SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Antimicrobial photocatalysis; Bacteria; Titanium dioxide; Sodium bromide; Ultraviolet A; Reactive oxygen species; Hypobromite ID ESCHERICHIA-COLI; TIO2 PHOTOCATALYSIS; PHOTODYNAMIC INACTIVATION; HYDROGEN-PEROXIDE; SINGLET OXYGEN; IN-VITRO; WATER; BACTERIA; MYELOPEROXIDASE; DISINFECTION AB Antimicrobial photocatalysis involves the UVA excitation of titanium dioxide (TiO2) nanoparticles (particularly the anatase form) to produce reactive oxygen species (ROS) that kill microbial cells. For the first time we report that the addition of sodium bromide to photoactivated TiO2 (P25) potentiates the killing of Gram-positive, Gram-negative bacteria and fungi by up to three logs. The potentiation increased with increasing bromide concentration in the range of 0-10 mM. The mechanism of potentiation is probably due to generation of both short and long-lived oxidized bromine species including hypobromite as shown by the following observations. There is some antimicrobial activity remaining in solution after switching off the light, that lasts for 30 min but not 2 h, and oxidizes 3,3',5,5'-tetramethylbenzidine. N-acetyl tyrosine ethyl ester was brominated in a light dose-dependent manner, however no bromine or tribromide ion could be detected by spectrophotometry or LC-MS. The mechanism appears to have elements in common with the antimicrobial system (myeloperoxidase + hydrogen peroxide + bromide). (C) 2016 Elsevier Inc. All rights reserved. C1 [Wu, Ximing] Guangxi Med Univ, Dept Emergency, Affiliated Coll & Hosp 1, Nanning 530021, Peoples R China. [Wu, Ximing; Huang, Ying-Ying; Kushida, Yu; Bhayana, Brijesh; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wu, Ximing; Huang, Ying-Ying; Bhayana, Brijesh; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Kushida, Yu] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 1138654, Japan. [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. EM hamblin@helix.mgh.harvard.edu FU US NIH Grant [R01 A1050875]; Research Experience for Undergraduates (REU) Program of the National Science Foundation [EEC-1358296] FX This work was supported by US NIH Grant R01 A1050875. Yu Kushida was supported by the Research Experience for Undergraduates (REU) Program of the National Science Foundation under Award number EEC-1358296. We are grateful to Dr. Brijesh Bhayana for help with analytical chemistry. NR 47 TC 2 Z9 2 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN PY 2016 VL 95 BP 74 EP 81 DI 10.1016/j.freeradbiomed.2016.03.012 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DM2IH UT WOS:000376169800007 PM 27012419 ER PT J AU Brugge, WR AF Brugge, William R. TI Pancreatic cyst surveillance: Threat or opportunity? SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material ID INTERNATIONAL CONSENSUS GUIDELINES; PAPILLARY MUCINOUS NEOPLASMS; MANAGEMENT; DIAGNOSIS; IPMN C1 [Brugge, William R.] Massachusetts Gen Hosp, Pancreas Biliary Ctr, Boston, MA 02114 USA. RP Brugge, WR (reprint author), Massachusetts Gen Hosp, Pancreas Biliary Ctr, Boston, MA 02114 USA. NR 14 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JUN PY 2016 VL 83 IS 6 BP 1118 EP 1120 DI 10.1016/j.gie.2016.02.027 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DM2MU UT WOS:000376181700006 PM 27206581 ER PT J AU Bi, WL Wu, WW Santagata, S Reardon, DA Dunn, IF AF Bi, Wenya Linda Wu, Winona W. Santagata, Sandro Reardon, David A. Dunn, Ian F. TI Checkpoint inhibition in meningiomas SO IMMUNOTHERAPY LA English DT Review DE checkpoint inhibition; immunotherapy; meningioma; PD-1; PD-L1; targeted pharmacotherapy ID ATYPICAL CRANIAL MENINGIOMAS; CTLA-4 BLOCKADE; CANCER-IMMUNOTHERAPY; POTENTIAL MECHANISM; ADJUVANT RADIATION; CLINICAL BENEFIT; IMMUNE EVASION; NF2 GENE; EXPRESSION; CELL AB Meningiomas are increasingly appreciated to share similar features with other intra-axial central nervous system neoplasms as well as systemic cancers. Immune checkpoint inhibition has emerged as a promising therapy in a number of cancers, with durable responses of years in a subset of patients. Several lines of evidence support a role for immune-based therapeutic strategies in the management of meningiomas, especially high-grade subtypes. Meningiomas frequently originate juxtaposed to venous sinuses, where an anatomic conduit for lymphatic drainage resides. Multiple populations of immune cells have been observed in meningiomas. PD-1/PD-L1 mediated immunosuppression has been implicated in high-grade meningiomas, with association between PD-L1 expression with negative prognostic outcome. These data point to the promise of future combinatorial therapeutic strategies in meningioma. C1 [Bi, Wenya Linda; Wu, Winona W.; Dunn, Ian F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. [Santagata, Sandro] Harvard Univ, Sch Med, Dept Pathol, Div Neuropathol,Brigham & Womens Hosp, Boston, MA 02115 USA. [Reardon, David A.] Harvard Univ, Sch Med, Ctr Neurooncol, Dana Farber Canc Inst, Boston, MA USA. RP Dunn, IF (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. EM idunn@partners.org NR 79 TC 1 Z9 1 U1 1 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-743X EI 1750-7448 J9 IMMUNOTHERAPY-UK JI Immunotherapy PD JUN PY 2016 VL 8 IS 6 BP 721 EP 731 DI 10.2217/imt-2016-0017 PG 11 WC Immunology SC Immunology GA DM1QW UT WOS:000376122300007 PM 27197540 ER PT J AU Coveler, AL Ko, AH Catenacci, DVT Von Hoff, D Becerra, C Whiting, NC Yang, J Wolpin, B AF Coveler, Andrew L. Ko, Andrew H. Catenacci, Daniel V. T. Von Hoff, Daniel Becerra, Carlos Whiting, Nancy C. Yang, Jing Wolpin, Brian TI A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Solid tumor; ASG-5ME; Antibody-drug conjugate; ADC ID BRENTUXIMAB VEDOTIN; PLUS GEMCITABINE; III TRIAL; CHEMOTHERAPY; FOLFIRINOX; LYMPHOMA AB Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity. C1 [Coveler, Andrew L.] Univ Washington, Seattle Canc Care Alliance, 825 Eastlake Ave E, Seattle, WA 98109 USA. [Ko, Andrew H.] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Catenacci, Daniel V. T.] Univ Chicago, Chicago, IL 60637 USA. [Von Hoff, Daniel] TGen Clin Res Serv Scottsdale Healthcare, Scottsdale, AZ USA. [Becerra, Carlos] Baylor Sammons Canc Ctr, Texas Oncol, Dallas, TX USA. [Whiting, Nancy C.; Yang, Jing] Seattle Genet Inc, Bothell, WA USA. [Wolpin, Brian] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Coveler, AL (reprint author), Univ Washington, Seattle Canc Care Alliance, 825 Eastlake Ave E, Seattle, WA 98109 USA. EM acoveler@u.washington.edu FU Seattle Genetics, Inc., Bothell, WA, USA FX This work was supported by Seattle Genetics, Inc., Bothell, WA, USA. NR 17 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD JUN PY 2016 VL 34 IS 3 BP 319 EP 328 DI 10.1007/s10637-016-0343-x PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DM1TJ UT WOS:000376129000006 PM 26994014 ER PT J AU McGrath, LM Oates, JM Dai, YG Dodd, HF Waxler, J Clements, CC Weill, S Hoffnagle, A Anderson, E MacRae, R Mullett, J McDougle, CJ Pober, BR Smoller, JW AF McGrath, Lauren M. Oates, Joyce M. Dai, Yael G. Dodd, Helen F. Waxler, Jessica Clements, Caitlin C. Weill, Sydney Hoffnagle, Alison Anderson, Erin MacRae, Rebecca Mullett, Jennifer McDougle, Christopher J. Pober, Barbara R. Smoller, Jordan W. TI Attention Bias to Emotional Faces Varies by IQ and Anxiety in Williams Syndrome SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Williams syndrome; Anxiety; Attention bias; Social dot-probe; Emotional faces ID MENTAL-HEALTH PROBLEMS; DEVELOPMENTAL DISORDERS; SELECTIVE ATTENTION; LONGITUDINAL COURSE; ADOLESCENT ANXIETY; MODIFICATION ABM; PARENT-REPORT; CHILDREN; INDIVIDUALS; THREAT AB Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N = 46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ. C1 [McGrath, Lauren M.] Amer Univ, Sch Educ, Gray Hall,4400 Massachusetts Ave NW, Washington, DC 20016 USA. [Oates, Joyce M.] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Dai, Yael G.; Weill, Sydney; Hoffnagle, Alison; Anderson, Erin; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Dodd, Helen F.] Univ Reading, Sch Psychol & Clin Language Sci, Reading, Berks, England. [Waxler, Jessica; Mullett, Jennifer; McDougle, Christopher J.; Pober, Barbara R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Clements, Caitlin C.] Univ Penn, Dept Psychol, 3815 Walnut St, Philadelphia, PA 19104 USA. [Clements, Caitlin C.] Childrens Hosp Philadelphia, Ctr Autism Res, Philadelphia, PA 19104 USA. [MacRae, Rebecca] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mullett, Jennifer; McDougle, Christopher J.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP McGrath, LM (reprint author), Amer Univ, Sch Educ, Gray Hall,4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM mcgrath@american.edu OI McGrath, Lauren/0000-0001-6928-9656 FU American University; NIH [T32-MH16259, K24-MH094614]; Tepper Family MGH Scholars award; Nancy Lurie Marks Family Foundation FX This work was supported by an American University Faculty Research Support Grant (L.M.M.), NIH grant T32-MH16259 (L.M.M.), NIH Grant K24-MH094614 (J.W.S), the Tepper Family MGH Scholars award (J.W.S), and the Nancy Lurie Marks Family Foundation (C.J.M). NR 66 TC 1 Z9 1 U1 5 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD JUN PY 2016 VL 46 IS 6 BP 2174 EP 2185 DI 10.1007/s10803-016-2748-y PG 12 WC Psychology, Developmental SC Psychology GA DM1IZ UT WOS:000376100200025 PM 26886469 ER PT J AU Miller, KA Sofia, MK Weaver, JWA Seward, CH Dziejman, M AF Miller, Kelly A. Sofia, Madeline K. Weaver, Jacob W. A. Seward, Christopher H. Dziejman, Michelle TI Regulation by ToxR-Like Proteins Converges on vttR(B) Expression To Control Type 3 Secretion System-Dependent Caco2-BBE Cytotoxicity in Vibrio cholerae SO JOURNAL OF BACTERIOLOGY LA English DT Article ID VIRULENCE GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVATORS; MOLECULAR ANALYSIS; NON-O1; PROMOTER; DIARRHEA; INDIA; ENTEROTOXICITY; SEROGROUPS; EFFECTOR AB Genes carried on the type 3 secretion system (T3SS) pathogenicity island of Vibrio cholerae non-O1/non-O139 serogroup strain AM-19226 must be precisely regulated in order for bacteria to cause disease. Previously reported results showed that both T3SS function and the presence of bile are required to cause Caco2-BBE cell cytotoxicity during coculture with strain AM-19226. We therefore investigated additional parameters affecting in vitro cell death, including bacterial load and the role of three transmembrane transcriptional regulatory proteins, VttR(A), VttR(B), and ToxR. VttR(A) and VttR(B) are encoded on the horizontally acquired T3SS genomic island, whereas ToxR is encoded on the ancestral chromosome. While strains carrying deletions in any one of the three transcriptional regulatory genes are unable to cause eukaryotic cell death, the results of complementation studies point to a hierarchy of regulatory control that converges on vttR(B) expression. The data suggest both that ToxR and VttR(A) act upstream of VttR(B) and that modifying the level of either vttR(A) or vttR(B) expression can strongly influence T3SS gene expression. We therefore propose a model whereby T3SS activity and, hence, in vitro cytotoxicity are ultimately regulated by vttR(B) expression. IMPORTANCE In contrast to O1 and O139 serogroup V. cholerae strains that cause cholera using two main virulence factors (toxin-coregulated pilus [TCP] and cholera toxin [CT]), O39 serogroup strain AM-19226 uses a type 3 secretion system as its principal virulence mechanism. Although the regulatory network governing TCP and CT expression is well understood, the factors influencing T3SS-associated virulence are not. Using an in vitro mammalian cell model to investigate the role of three ToxR-like transmembrane transcriptional activators in causing T3SS-dependent cytotoxicity, we found that expression levels and a hierarchical organization were important for promoting T3SS gene expression. Furthermore, our results suggest that horizontally acquired, ToxR-like proteins act in concert with the ancestral ToxR protein to orchestrate T3SS-mediated pathogenicity. C1 [Miller, Kelly A.; Sofia, Madeline K.; Weaver, Jacob W. A.; Seward, Christopher H.; Dziejman, Michelle] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA. [Miller, Kelly A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Weaver, Jacob W. A.] NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. [Seward, Christopher H.] Univ Illinois, Inst Genom Biol, Urbana, IL USA. RP Dziejman, M (reprint author), Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA. EM michelle_dziejman@urmc.rochester.edu FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI073785, T32 AI007362, T32 AI118689] FX This work, including the efforts of Michelle Dziejman, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI073785). This work, including the efforts of Kelly A. Miller, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (T32 AI007362). This work, including the efforts of Madeline K. Sofia, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (T32 AI118689). NR 40 TC 1 Z9 1 U1 7 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2016 VL 198 IS 11 BP 1675 EP 1682 DI 10.1128/JB.00130-16 PG 8 WC Microbiology SC Microbiology GA DM2VN UT WOS:000376206300014 PM 27021561 ER PT J AU Jonas, O Calligaris, D Methuku, KR Poe, MM Francois, JP Tranghese, F Changelian, A Sieghart, W Ernst, M Krummel, DAP Cook, JM Pomeroy, SL Cima, M Agar, NYR Langer, R Sengupta, S AF Jonas, Oliver Calligaris, David Methuku, Kashi Reddy Poe, Michael M. Francois, Jessica Pierre Tranghese, Frank Changelian, Armen Sieghart, Werner Ernst, Margot Krummel, Daniel A. Pomeranz Cook, James M. Pomeroy, Scott L. Cima, Michael Agar, Nathalie Y. R. Langer, Robert Sengupta, Soma TI First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development SO JOURNAL OF BIOMEDICAL NANOTECHNOLOGY LA English DT Article DE Medulloblastoma; Microdevice; Benzodiazepine Derivatives; Mass Spectrometry Imaging; Drug Delivery ID MYC-AMPLIFIED MEDULLOBLASTOMA; BLOOD-BRAIN-BARRIER; MODELS; INHIBITION; RECEPTORS AB Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABA(A) receptor alpha 5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function as alpha 5-GABA(A) receptor ligands. To compare their efficacy with that of standard-of-care treatments, we have employed a newly developed microscale implantable device that allows for high-throughput localized intratumor drug delivery and efficacy testing. Microdoses of each drug were delivered into small distinct regions of tumors, as confirmed by tissue mass spectrometry, and the local drug effect was determined by immunohistochemistry. We have identified a benzodiazepine derivative, KRM-II-08, as a new potent inhibitor in several alpha 5-GABA(A) receptor expressing tumor models. This is the first instance of in vivo testing of several benzodiazepine derivatives and standard chemotherapeutic drugs within the same tumor. Obtaining higIthroughput drug efficacy data within a native tumor microenvironment as detailed herein, prior to pharmacological optimization for bioavailability or safety and without systemic exposure or toxicity, may allow for rapid prioritization of drug 'candidates for further pharmacological optimization. C1 [Jonas, Oliver; Cima, Michael; Langer, Robert] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Calligaris, David; Changelian, Armen; Agar, Nathalie Y. R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. [Methuku, Kashi Reddy; Poe, Michael M.; Cook, James M.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Francois, Jessica Pierre; Tranghese, Frank; Pomeroy, Scott L.] Childrens Hosp, Dept Neurobiol, 300 Longwood Ave, Boston, MA 02115 USA. [Sieghart, Werner; Ernst, Margot] Med Univ Vienna, Ctr Brain Res, Spitalgasse 4, A-1090 Vienna, Austria. [Krummel, Daniel A. Pomeranz] Brandeis Univ, Dept Biochem, Waltham, MA 02453 USA. [Agar, Nathalie Y. R.] Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Agar, Nathalie Y. R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. [Sengupta, Soma] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol,Div Neurooncol, Boston, MA 02115 USA. RP Jonas, O (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Sengupta, S (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol,Div Neurooncol, Boston, MA 02115 USA. EM ojonas@mit.edu; ssengup1@bidmc.harvard.edu RI Sieghart, Werner/A-4877-2013 OI Sieghart, Werner/0000-0002-0443-0302 FU US National Institute of Health (NIH) Director's New Innovator Award [1DP2OD007383-01]; Dana-Farber PLGA Foundation; Daniel E. Ponton fund for the Neurosciences to NYRA; NSF [1157892]; NIH [NS076517, MH096463]; Bradley-Herschfield Foundation (UWMFDN); Koch Institute Frontier Award; NCI [R21CA177391]; FWF [W1232, P27746]; [K12CA090354]; [K08NS083626]; [R01CA109467] FX This study was supported by the following sources of funding:; Soma Sengupta's research was supported by K12CA090354 and K08NS083626 awards.; Agar laboratory work was funded in part by US National Institute of Health (NIH) Director's New Innovator Award (1DP2OD007383-01), Dana-Farber PLGA Foundation, and Daniel E. Ponton fund for the Neurosciences to NYRA.; Scott Pomeroy's laboratory is supported by R01CA109467.; Pomeranz Krummel's laboratory is supported by NSF Award No. 1157892.; Jim Cook's research was supported by NIH (NS076517,MH096463) grants, as well as the Bradley-Herschfield Foundation (UWMFDN).; Langer and Cima Labs: This work was funded in part by a Koch Institute Frontier Award and by NCI grant R21CA177391.; Margot Ernst laboratory: FWF grants W1232 and P27746. NR 20 TC 0 Z9 0 U1 6 U2 11 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1550-7033 EI 1550-7041 J9 J BIOMED NANOTECHNOL JI J. Biomed. Nanotechnol. PD JUN PY 2016 VL 12 IS 6 BP 1297 EP 1302 DI 10.1166/jbn.2016.2262 PG 6 WC Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Science & Technology - Other Topics; Materials Science GA DL9MX UT WOS:000375968500014 PM 27319222 ER PT J AU Hache, M Swoboda, KJ Sethna, N Farrow-Gillespie, A Khandji, A Xia, ST Bishop, KM AF Hache, Manon Swoboda, Kathryn J. Sethna, Navil Farrow-Gillespie, Alan Khandji, Alexander Xia, Shuting Bishop, Kathie M. TI Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE lumbar puncture; spinal muscular atrophy; antisense oligonucleotide; drug delivery ID POSTDURAL PUNCTURE HEADACHE; LUMBAR PUNCTURE; NEEDLE DESIGN; SUCCESS RATE; ANESTHESIA; ULTRASOUND; COMPLICATIONS; BACKACHE; INFANTS; PHASE-1 AB Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children. C1 [Hache, Manon] Columbia Univ, Med Ctr, Div Pediat Anesthesia, 622 W 168th St,BH 440-N, New York, NY 10032 USA. [Swoboda, Kathryn J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sethna, Navil] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Farrow-Gillespie, Alan] Univ Texas Southwestern Med Sch, Dept Anesthesiol & Pain Management, Dallas, TX USA. [Khandji, Alexander] Columbia Univ, Dept Radiol, New York, NY 10032 USA. [Xia, Shuting; Bishop, Kathie M.] Ionis Pharmaceut Inc, Carlsbad, CA USA. RP Hache, M (reprint author), Columbia Univ, Med Ctr, Div Pediat Anesthesia, 622 W 168th St,BH 440-N, New York, NY 10032 USA. EM mh2289@cumc.columbia.edu FU Ionis Pharmaceuticals, Inc.; Biogen FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Ionis Pharmaceuticals, Inc. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Funding for medical writing support was provided by Biogen. AF-G's institution has received funding from Ionis Pharmaceuticals, Inc. through other departments. The phase 1 (NCT01494701) and extension (NCT01780246) clinical studies were funded by Ionis Pharmaceuticals, Inc. NR 40 TC 13 Z9 13 U1 6 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD JUN PY 2016 VL 31 IS 7 BP 899 EP 906 DI 10.1177/0883073815627882 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DM3RU UT WOS:000376264800014 PM 26823478 ER PT J AU Brown, WV Ference, BA Kathiresan, S AF Brown, William Virgil Ference, Brian A. Kathiresan, Sekar TI JCL roundtable: Lessons from genetic variants altering lipoprotein metabolism SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE DNA; Genetics; Lipoprotein; Metabolism; Clinical vascular disease ID CORONARY-HEART-DISEASE; OF-FUNCTION MUTATIONS; CARDIOVASCULAR-DISEASE; RISK; NPC1L1; APOC3 AB Because the Human Genome Project reached its first major milestone in completing the full sequence of human DNA, many new discoveries have been made relating genetic variants to disease. The new methodology that allows much more rapid and focused analyses of selected genes and the ability to screen the entire exome of any individual has provided tools to examine literally thousands of individuals for a given study. Genetic analysis has become a large-scale epidemiologic tool for examining variants in gene structure and correlating them with phenotypic markers of human disorders. These genome-wide association studies have been quite revealing about the mechanism of disorders of many types. These tools have been applied to the appearance of clinical atherosclerosis and to the chronic metabolic risk factors for this disease process. We are joined by 2 individuals who have made very significant contributions to this area of research: Dr Brian Ference of Wayne State University School of Medicine and Dr Sekar Kathiresan from Massachusetts General Hospital and Harvard Medical School. In our discussion, we are going to focus on genetic variants, which lead to changes in lipoprotein concentrations and those that have an association with earlier onset of clinical vascular disease. This roundtable was recorded during the November 2016 American Heart Association Scientific Sessions in Orlando, Florida. (C) 2016 National Lipid Association. All rights reserved. C1 [Brown, William Virgil] Emory Univ, Sch Med, 3208 Habersham Rd NW, Atlanta, GA 30305 USA. [Ference, Brian A.] Wayne State Univ, Sch Med, Univ Hlth Ctr, Detroit, MI USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Brown, WV (reprint author), Emory Univ, Sch Med, 3208 Habersham Rd NW, Atlanta, GA 30305 USA. EM wbrow925@bellsouth.net NR 11 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD JUN PY 2016 VL 10 IS 3 BP 448 EP 457 DI 10.1016/j.jacl.2016.04.002 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM3AI UT WOS:000376218800002 PM 27206929 ER PT J AU Alyea, EP AF Alyea, Edwin P. TI Graft-Versus-Host Disease Prevention: Corticosteroids Revisited SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BIOMARKERS; PREDNISONE C1 [Alyea, Edwin P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Alyea, EP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 6 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 JUN 1 PY 2016 VL 34 IS 16 BP 1836 EP + DI 10.1200/JCO.2015.66.0902 PG 3 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900004 PM 27091715 ER PT J AU Shaffer, BC Ahn, KW Hu, ZH Nishihori, T Malone, AK Valcarcel, D Grunwald, MR Bacher, U Hamilton, B Kharfan-Dabaja, MA Saad, A Cutler, C Warlick, E Reshef, R Wirk, BM Sabloff, M Fasan, O Gerds, A Marks, D Olsson, R Wood, WA Costa, LJ Miller, AM Cortes, J Daly, A Kindwall-Keller, TL Kamble, R Rizzieri, DA Cahn, JY Gale, RP William, B Litzow, M Wiernik, PH Liesveld, J Savani, BN Vij, R Ustun, C Copelan, E Popat, U Kalaycio, M Maziarz, R Alyea, E Sobecks, R Pavletic, S Tallman, M Saber, W AF Shaffer, Brian C. Ahn, Kwang Woo Hu, Zhen-Huan Nishihori, Taiga Malone, Adriana K. Valcarcel, David Grunwald, Michael R. Bacher, Ulrike Hamilton, Betty Kharfan-Dabaja, Mohamed A. Saad, Ayman Cutler, Corey Warlick, Erica Reshef, Ran Wirk, Baldeep Mona Sabloff, Mitchell Fasan, Omotayo Gerds, Aaron Marks, David Olsson, Richard Wood, William Allen Costa, Luciano J. Miller, Alan M. Cortes, Jorge Daly, Andrew Kindwall-Keller, Tamila L. Kamble, Rammurti Rizzieri, David A. Cahn, Jean-Yves Gale, Robert Peter William, Basem Litzow, Mark Wiernik, Peter H. Liesveld, Jane Savani, Bipin N. Vij, Ravi Ustun, Celalettin Copelan, Edward Popat, Uday Kalaycio, Matt Maziarz, Richard Alyea, Edwin Sobecks, Ron Pavletic, Steven Tallman, Martin Saber, Wad TI Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; MONOSOMAL KARYOTYPE; DECISION-ANALYSIS; RISK; MDS; CLASSIFICATION; DISEASE; BLOOD; INDEX AB Purpose To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). Patients and Methods We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. Results Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 3 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (>= 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. Conclusion The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS. (C) 2016 by American Society of Clinical Oncology C1 [Shaffer, Brian C.; Tallman, Martin] Mem Sloan Kettering Canc Ctr, 12-b York Ave, New York, NY 10065 USA. [Malone, Adriana K.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Reshef, Ran] Columbia Univ, Med Ctr, New York, NY USA. [Litzow, Mark] Mayo Clin Rochester, Rochester, NY USA. [Liesveld, Jane] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Wiernik, Peter H.] Our Lady Mercy Med Ctr, Bronx, NY USA. [Ahn, Kwang Woo; Hu, Zhen-Huan; Saber, Wad] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Nishihori, Taiga; Kharfan-Dabaja, Mohamed A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Valcarcel, David] Hosp Valle De Hebron, Barcelona, Spain. [Grunwald, Michael R.; Fasan, Omotayo; Copelan, Edward] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Wood, William Allen] Univ N Carolina, Chapel Hill, NC USA. [Rizzieri, David A.] Duke Univ, Med Ctr, Durham, NC USA. [Bacher, Ulrike] Univ Med Gottingen, Gottingen, Germany. [Hamilton, Betty; Gerds, Aaron] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Kalaycio, Matt; Sobecks, Ron] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [William, Basem] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Saad, Ayman; Costa, Luciano J.] Univ Alabama Birmingham, Birmingham, AL USA. [Cutler, Corey; Alyea, Edwin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Warlick, Erica; Ustun, Celalettin] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Wirk, Baldeep Mona] Seattle Canc Care Alliance, Seattle, WA USA. [Sabloff, Mitchell] Univ Ottawa, Ottawa, ON, Canada. [Sabloff, Mitchell] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Daly, Andrew] Tom Baker Canc Clin, Calgary, AB, Canada. [Marks, David] Univ Hosp Bristol Natl Hlth Serv Trust, Bristol, Avon, England. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, London, England. [Olsson, Richard] Karolinska Inst, Stockholm, Sweden. [Miller, Alan M.] Baylor Univ, Med Ctr, Dallas, TX USA. [Kamble, Rammurti] Baylor Coll Med, Dallas, TX USA. [Cortes, Jorge; Popat, Uday] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kindwall-Keller, Tamila L.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Cahn, Jean-Yves] Univ Hosp Grenoble, La Tronche, France. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Vij, Ravi] Washington Univ, Sch Med, St Louis, MO USA. [Maziarz, Richard] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Pavletic, Steven] NCI, Bethesda, MD 20892 USA. RP Shaffer, BC (reprint author), Mem Sloan Kettering Canc Ctr, 12-b York Ave, New York, NY 10065 USA. EM shaffeb1@mskcc.org OI Saad, Ayman /0000-0003-0003-0130 FU Public Health Service Grant from the National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos, Inc.; Amgen, Inc.; Angioblast; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; THERAKOS, Inc.; Wellpoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants, N00014-06-1-0704 and N00014-08-1-0058, from the Office of Naval Research; and grants from Allos, Inc.; Amgen, Inc.; Angioblast; an anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; THERAKOS, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government. NR 29 TC 6 Z9 6 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 JUN 1 PY 2016 VL 34 IS 16 BP 1864 EP + DI 10.1200/JCO.2015.65.0515 PG 11 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900010 PM 27044940 ER PT J AU Desmedt, C Zoppoli, G Gundem, G Pruneri, G Larsimont, D Fornili, M Fumagalli, D Brown, D Rothe, F Vincent, D Kheddoumi, N Rouas, G Majjaj, S Brohee, S Van Loo, P Maisonneuve, P Salgado, R Van Brussel, T Lambrechts, D Bose, R Metzger, O Galant, C Bertucci, F Piccart-Gebhart, M Viale, G Biganzoli, E Campbell, PJ Sotiriou, C AF Desmedt, Christine Zoppoli, Gabriele Gundem, Gunes Pruneri, Giancarlo Larsimont, Denis Fornili, Marco Fumagalli, Debora Brown, David Rothe, Francoise Vincent, Delphine Kheddoumi, Naima Rouas, Ghizlane Majjaj, Samira Brohee, Sylvain Van Loo, Peter Maisonneuve, Patrick Salgado, Roberto Van Brussel, Thomas Lambrechts, Diether Bose, Ron Metzger, Otto Galant, Christine Bertucci, Francois Piccart-Gebhart, Martine Viale, Giuseppe Biganzoli, Elia Campbell, Peter J. Sotiriou, Christos TI Genomic Characterization of Primary Invasive Lobular Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; MUTATIONS; CARCINOMA; HER2; AMPLIFICATION; TAMOXIFEN; VARIANTS; COMPLEX; POINTS; PTEN AB Purpose Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. Methods From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features. Results Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse. Conclusion This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment. (C) 2016 by American Society of Clinical Oncology C1 [Desmedt, Christine; Zoppoli, Gabriele; Larsimont, Denis; Fumagalli, Debora; Brown, David; Rothe, Francoise; Vincent, Delphine; Kheddoumi, Naima; Rouas, Ghizlane; Majjaj, Samira; Brohee, Sylvain; Salgado, Roberto; Piccart-Gebhart, Martine; Sotiriou, Christos] Inst Jules Bordet, B-1000 Brussels, Belgium. [Galant, Christine] Clin Univ St Luc, B-1200 Brussels, Belgium. [Van Loo, Peter] Univ Leuven, Leuven, Belgium. [Van Brussel, Thomas; Lambrechts, Diether] VIB Vesalius Res Ctr, Leuven, Belgium. [Zoppoli, Gabriele] Univ Genoa, Genoa, Italy. [Zoppoli, Gabriele] Natl Canc Inst, Ist Ric Carattere Clin Sci San Martino, Genoa, Italy. [Pruneri, Giancarlo; Maisonneuve, Patrick; Viale, Giuseppe] European Inst Oncol, Milan, Italy. [Fornili, Marco; Biganzoli, Elia] Univ Milan, Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Gundem, Gunes; Campbell, Peter J.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Van Loo, Peter] Francis Crick Inst, London, England. [Bose, Ron] Washington Univ, Sch Med, St Louis, MO USA. [Metzger, Otto] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bertucci, Francois] Inst J Paoli I Calmettes, F-13009 Marseille, France. RP Desmedt, C (reprint author), Inst Jules Bordet, Breast Canc Translat Res Lab, 125 Blvd Waterloo, B-1000 Brussels, Belgium. EM christine.desmedt@bordet.be OI Desmedt, Christine/0000-0002-5223-5579 FU Susan G. Komen; Fondation MEDIC; Les Amis de Bordet; Fonds National de Recherche Scientifique; Breast Cancer Research Foundation; Wellcome Trust Clinical Research Training Fellowship Programs; Italian Association for Leukemia and Lymphoma; Italian Association for Cancer Research FX Supported by Susan G. Komen, Fondation MEDIC, Les Amis de Bordet, Fonds National de Recherche Scientifique, the Breast Cancer Research Foundation, the Wellcome Trust Clinical Research Training Fellowship Programs, the Italian Association for Leukemia and Lymphoma, and the Italian Association for Cancer Research. NR 33 TC 12 Z9 12 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 JUN 1 PY 2016 VL 34 IS 16 BP 1872 EP + DI 10.1200/JCO.2015.64.0334 PG 12 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900011 PM 26926684 ER PT J AU Dinh, KT Reznor, G Muralidhar, V Mahal, BA Nezolosky, MD Choueiri, TK Hoffman, KE Hu, JC Sweeney, CJ Trinh, QD Nguyen, PL AF Dinh, Kathryn T. Reznor, Gally Muralidhar, Vinayak Mahal, Brandon A. Nezolosky, Michelle D. Choueiri, Toni K. Hoffman, Karen E. Hu, Jim C. Sweeney, Christopher J. Quoc-Dien Trinh Nguyen, Paul L. TI Association of Androgen Deprivation Therapy With Depression in Localized Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; RECEIVING HORMONE-THERAPY; SEER-MEDICARE DATA; QUALITY-OF-LIFE; BIOAVAILABLE TESTOSTERONE; RADIATION-THERAPY; OLDER MEN; RADIOTHERAPY; DIAGNOSIS; SUPPRESSION AB Purpose Androgen deprivation therapy (ADT) may contribute to depression, yet several studies have not demonstrated a link. We aimed to determine whether receipt of any ADT or longer duration of ADT for prostate cancer (PCa) is associated with an increased risk of depression. Methods We identified 78,552 men older than age 65 years with stage I to III PCa using the SEER-Medicare-linked database from 1992 to 2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association between pharmacologic ADT and the diagnosis of depression or receipt of inpatient or outpatient psychiatric treatment using Cox proportional hazards regression. Drug data for treatment of depression were not available. Our secondary analysis investigated the association between duration of ADT and each end point. Results Overall, 43% of patients (n = 33,882) who received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2%, respectively), inpatient psychiatric treatment (2.8% v 1.9%, respectively), and outpatient psychiatric treatment (3.4% v 2.5%, respectively; all P < .001). Adjusted Cox analyses demonstrated that patients with ADT had a 23% increased risk of depression (adjusted hazard ratio [AHR], 1.23; 95% CI, 1.15 to 1.31), 29% increased risk of inpatient psychiatric treatment (AHR, 1.29; 95% CI, 1.17 to 1.41), and a nonsignificant 7% increased risk of outpatient psychiatric treatment (AHR, 1.07; 95% CI, 0.97 to 1.17) compared with patients without ADT. The risk of depression increased with duration of ADT, from 12% with < 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with >= 12 months of treatment (P trend,.001). A similar duration effect was seen for inpatient (P trend,.001) and outpatient psychiatric treatment (P trend,.001). Conclusion Pharmacologic ADT increased the risk of depression and inpatient psychiatric treatment in this large study of elderly men with localized PCa. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients before initiating treatment. (C) 2016 by American Society of Clinical Oncology C1 [Dinh, Kathryn T.; Muralidhar, Vinayak; Mahal, Brandon A.] Harvard Univ, Sch Med, Boston, MA USA. [Reznor, Gally; Mahal, Brandon A.; Nezolosky, Michelle D.; Choueiri, Toni K.; Sweeney, Christopher J.; Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Reznor, Gally; Mahal, Brandon A.; Nezolosky, Michelle D.; Choueiri, Toni K.; Sweeney, Christopher J.; Quoc-Dien Trinh; Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hu, Jim C.] James Buchanan Brady Fdn, Weill Cornell Med Coll, New York, NY USA. RP Nguyen, PL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu FU Prostate Cancer Foundation; Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital; Vattikuti Urology Institute; National Cancer Institute's SEER Program [HHSN261201000140C, HHSN261201000035C, HHSN261201000034C]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U58DP003862-01] FX Supported by Fitz's Cancer Warriors, David and Cynthia Chapin, the Prostate Cancer Foundation, Hugh Simons in honor of Frank and Anne Simons, Scott Forbes and Gina Ventre, Campbell family in honor of Joan Campbell, and a grant from an anonymous family foundation. Also supported by the Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital (Q.-D.T.) and an unrestricted educational grant from the Vattikuti Urology Institute (Q.-D.T.). The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, the National Cancer Institute's SEER Program under Contract No. HHSN261201000140C awarded to the Cancer Prevention Institute of California, Contract No. HHSN261201000035C awarded to the University of Southern California, and Contract No. HHSN261201000034C awarded to the Public Health Institute, and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under Agreement No. U58DP003862-01 awarded to the California Department of Public Health. NR 51 TC 7 Z9 7 U1 4 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 JUN 1 PY 2016 VL 34 IS 16 BP 1905 EP + DI 10.1200/JCO.2015.64.1969 PG 11 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900015 PM 27069075 ER PT J AU McKay, RR Zurita, AJ Werner, L Bruce, JY Carducci, MA Stein, MN Heath, EI Hussain, A Tran, HT Sweeney, CJ Ross, RW Kantoff, PW Slovin, SF Taplin, ME AF McKay, Rana R. Zurita, Amado J. Werner, Lillian Bruce, Justine Y. Carducci, Michael A. Stein, Mark N. Heath, Elisabeth I. Hussain, Arif Tran, Hai T. Sweeney, Christopher J. Ross, Robert W. Kantoff, Philip W. Slovin, Susan F. Taplin, Mary-Ellen TI A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy With or Without Bevacizumab for Patients With Recurrent Prostate Cancer After Definitive Local Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; DOUBLE-BLIND; 1ST-LINE THERAPY; DOCETAXEL; PLACEBO; PREDNISONE; CHEMOTHERAPY; COMBINATION; PROGRESSION AB Purpose Patients with recurrent prostate cancer after local treatment make up a heterogeneous population for whom androgen deprivation therapy (ADT) is the usual treatment. The purpose of this randomized phase II trial was to investigate the efficacy and toxicity of short-course ADT with or without bevacizumab in men with hormone-sensitive prostate cancer. Patients and Methods Eligible patients had an increasing prostate-specific antigen (PSA) of <= 50 ng/mL and PSA doubling time of less than 18 months. Patients had either no metastases or low burden, asymptomatic metastases (lymph nodes, 3 cm and five or fewer bone metastases). Patients were randomly assigned 2: 1 to a luteinizing hormone-releasing hormone agonist, bicalutamide and bevacizumab or ADT alone, for 6 months. The primary end point was PSA relapse-free survival (RFS). Relapse was defined as a PSA of more than 0.2 ng/mL for prostatectomy patients or PSA of more than 2.0 ng/mL for primary radiation therapy patients. Results Sixty-six patients received ADT + bevacizumab and 36 received ADT alone. Patients receiving ADT + bevacizumab had a statistically significant improvement in RFS compared with patients treated with ADT alone (13.3 months for ADT + bevacizumab v 10.2 months for ADT alone; hazard ratio, 0.47; 95% CI, 0.29 to 0.77; log-rank P = .002). Hypertension was the most common adverse event in patients receiving ADT + bevacizumab (36%). Conclusion ADT combined with bevacizumab resulted in an improved RFS for patients with hormone-sensitive prostate cancer. Long-term follow-up is needed to determine whether some patients have a durable PSA response and are able to remain off ADT for prolonged periods. Our data provide rationale for combining vascular endothelial growth factor-targeting therapy with ADT in hormone-sensitive prostate cancer. (C) 2016 by American Society of Clinical Oncology C1 [McKay, Rana R.; Werner, Lillian; Sweeney, Christopher J.; Kantoff, Philip W.; Taplin, Mary-Ellen] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Ross, Robert W.] Bluebird Bio, Cambridge, MA USA. [Zurita, Amado J.; Tran, Hai T.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bruce, Justine Y.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Carducci, Michael A.] Johns Hopkins Univ, Baltimore, MD USA. [Hussain, Arif] Greenebaum Canc Ctr, Baltimore, MD USA. [Stein, Mark N.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Heath, Elisabeth I.] Karmanos Canc Inst, Detroit, MI USA. [Kantoff, Philip W.; Slovin, Susan F.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Taplin, ME (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM mtaplin@partners.org FU Pfizer (Inst); Bayer Healthcare Pharmaceuticals (Inst); Pfizer; Janssen Pharmaceuticals (Inst); Medivation (Inst); Oncoceutics (Inst); Merck Sharp Dohme (Inst); Bavarian Nordic (Inst); AbbVie (Inst); Tokai Pharmaceuticals (Inst); Seattle Genetics (Inst); Agensys (Inst); Dendreon (Inst); Genentech (Inst); Millennium Pharmaceuticals (Inst); Celldex (Inst); Inovio Pharmaceuticals (Inst); Celgene (Inst); Amgen; Janssen Biotech (Inst); Exelixis (Inst); Astellas Pharma (Inst); Sanofi (Inst); OncoGenex (Inst); Aragon Pharmaceuticals (Inst); Amgen (Inst); Bayer (Inst); Medivation/Astellas Pharma (Inst); Janssen Oncology (Inst) FX Pfizer (Inst), Bayer Healthcare Pharmaceuticals (Inst); Pfizer; Janssen Pharmaceuticals (Inst), Medivation (Inst), Oncoceutics (Inst), Merck Sharp & Dohme (Inst), Bavarian Nordic (Inst), AbbVie (Inst); Tokai Pharmaceuticals (Inst), Seattle Genetics (Inst), Agensys (Inst), Dendreon (Inst), Genentech (Inst), Millennium Pharmaceuticals (Inst), Celldex (Inst), Inovio Pharmaceuticals (Inst), Celgene (Inst); Amgen; Janssen Biotech (Inst), Exelixis (Inst), Astellas Pharma (Inst); Medivation (Inst), Sanofi (Inst), OncoGenex (Inst), Aragon Pharmaceuticals (Inst), Amgen (Inst), Astellas Pharma (Inst), Bayer (Inst), Bavarian Nordic (Inst), Dendreon (Inst), Exelixis (Inst), Janssen (Inst); Genentech (Inst), Medivation/Astellas Pharma (Inst), Janssen Oncology (Inst), Bayer Healthcare Pharmaceuticals (Inst), Tokai Pharmaceuticals (Inst) NR 31 TC 2 Z9 2 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 JUN 1 PY 2016 VL 34 IS 16 BP 1913 EP + DI 10.1200/JCO.2015.65.3154 PG 17 WC Oncology SC Oncology GA DM6KU UT WOS:000376461900016 PM 27044933 ER PT J AU Scheinert, D Schmidt, A Zeller, T Muller-Hulsbeck, S Sixt, S Schroder, H Weiss, N Ketelsen, D Ricke, J Steiner, S Rosenfield, K AF Scheinert, Dierk Schmidt, Andrej Zeller, Thomas Mueller-Huelsbeck, Stefan Sixt, Sebastian Schroeder, Henrik Weiss, Norbert Ketelsen, Dominik Ricke, Jens Steiner, Sabine Rosenfield, Kenneth TI German Center Subanalysis of the LEVANT 2 Global Randomized Study of the Lutonix Drug-Coated Balloon in the Treatment of Femoropopliteal Occlusive Disease SO JOURNAL OF ENDOVASCULAR THERAPY LA English DT Article DE angioplasty; drug-coated balloon; drug-eluting balloon; geography; paclitaxel; peripheral vascular disease; restenosis ID ARTERY-DISEASE; FEMORAL-ARTERY; TRIAL; ANGIOPLASTY; PACLITAXEL; RESTENOSIS; STENTS; LEG AB Purpose: To report a subanalysis of the German centers enrolling patients in the prospective, global, multicenter, randomized LEVANT 2 pivotal trial (ClinicalTrials.gov identifier NCT01412541) of the Lutonix drug-coated balloon (DCB) for the treatment of femoropopliteal occlusive disease. Methods: Among the 476 patients in LEVANT 2, 126 patients (mean age 67.1 +/- 9.6 years; 79 men) were enrolled at the 8 participating German sites between August 2011 and July 2012 and were randomized 2:1 to treatment with the Lutonix DCB (n=83) vs an uncoated balloon during percutaneous transluminal angioplasty (PTA, n=43). All patients had intermittent claudication or rest pain (Rutherford categories 2-4). Average lesion length was 58 mm and average treated length was 100 mm. Severe calcification was present in 11% of lesions, and 23% were total occlusions. The efficacy outcome was primary patency at 12 months, and the safety outcome was 12-month freedom from a composite of perioperative death, index limb-related death, amputation (below or above the ankle), and index limb revascularization. Secondary endpoints included target lesion revascularization (TLR), major adverse events, and functional outcomes. Results: Demographic, clinical, and lesion characteristics were matched between Lutonix DCB and PTA groups, as were the final percent diameter stenosis (19%) and procedure success (91%). By Kaplan-Meier analysis, the 12-month primary patency rate was 80% vs 58% (p=0.015) and the composite safety endpoint rate was 94% vs 72% (p=0.001), respectively. Freedom from TLR was higher for DCBs (96%) vs PTA (82%, p=0.012). Major adverse events were similar for both groups. The benefit favoring DCB over PTA was observed in German men and women. Compared to the non-German LEVANT 2 cohort, there was a shorter time between insertion and inflation of treatment balloons (21.8 vs 39.5 seconds, p<0.001) in the German cohort. Balloons were inflated to higher pressures (9.0 vs 7.7 atm, p<0.001) but for a shorter period of time (130 vs 167 seconds, p<0.001), and although treated lesions in the German cohort had a higher baseline stenosis, final postprocedure diameter stenosis was lower (19% vs 22%, p=0.04) than in the non-German patients. Conclusion: Superiority of DCB over PTA in the German cohort of LEVANT 2 was demonstrated for primary patency, composite safety, and freedom from TLR. The benefit of DCB was also consistent for both genders. Geographic or regional differences in procedural variables may account for the different outcomes between the German and non-German cohorts. C1 [Scheinert, Dierk; Schmidt, Andrej; Steiner, Sabine] Univ Hosp Leipzig, Div Intervent Angiol, Leipzig, Germany. [Zeller, Thomas] Univ Herzzentrum Freiburg Bad Krozingen, Dept Angiol, Bad Krozingen, Germany. [Mueller-Huelsbeck, Stefan] Diakonissenanstalt Flensburg, Dept Radiol, Flensburg, Germany. [Sixt, Sebastian] Univ Hamburg, Cardiovasc Ctr, Hamburg, Germany. [Schroeder, Henrik] Jewish Hosp, Ctr Diagnost Radiol & Minimally Invas Therapy, Berlin, Germany. [Weiss, Norbert] Univ Klinikum Carl Gustav Carus, Ctr Vasc Med, Dresden, Germany. [Ketelsen, Dominik] Univ Tubingen, Dept Diagnost & Intervent Radiol, Tubingen, Germany. [Ricke, Jens] Univ Magdeburg, Clin Radiol & Nucl Med, D-39106 Magdeburg, Germany. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Scheinert, D (reprint author), Univ Hosp Leipzig, Chairman Div Intervent Angiol, Philipp Rosenthal Str 27 C,Bldg P, D-04103 Leipzig, Germany. EM dierk.scheinert@medizin.uni-leipzig.de RI Ketelsen, Dominik/A-1143-2012 OI Ketelsen, Dominik/0000-0002-7333-8024 FU Lutonix, Inc FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This clinical trial was sponsored by Lutonix, Inc, a subsidiary of C.R. Bard. NR 15 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1526-6028 EI 1545-1550 J9 J ENDOVASC THER JI J. Endovascular Ther. PD JUN PY 2016 VL 23 IS 3 BP 409 EP 416 DI 10.1177/1526602816644592 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DM4AD UT WOS:000376287000001 PM 27117972 ER PT J AU Pellegrini, CN Scheinman, MM AF Pellegrini, Cara N. Scheinman, Melvin M. TI Epidemiology and definition of inappropriate sinus tachycardia SO JOURNAL OF INTERVENTIONAL CARDIAC ELECTROPHYSIOLOGY LA English DT Review DE Inappropriate sinus tachycardia; Epidemiology; Clinical syndrome; Postural orthostatic tachycardia syndrome ID RADIOFREQUENCY ABLATION AB Inappropriate sinus tachycardia (IST) is a clinical syndrome lacking formal diagnostic criteria. It is generally defined as an elevated resting heart rate (HR; > 90-100 bpm) with an exaggerated response to physical or emotional stress and a clearly sinus mechanism. Clinical manifestations are broad from a complete lack of symptoms to incapacitating incessant tachycardia. Now understood to be relatively prevalent, it is observed to have a generally benign prognosis, though symptoms may persist for years. Whether IST is a single discrete entity or a heterogeneous condition with overlap to other syndromes such as postural orthostatic tachycardia syndrome remains a matter of debate. C1 [Pellegrini, Cara N.] San Francisco VA Med Ctr, 4150 Clement St,111C, San Francisco, CA 94121 USA. [Scheinman, Melvin M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Pellegrini, CN (reprint author), San Francisco VA Med Ctr, 4150 Clement St,111C, San Francisco, CA 94121 USA. EM cara.pellegrini@va.gov NR 15 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1383-875X EI 1572-8595 J9 J INTERV CARD ELECTR JI J. Interv. Card. Electrophysiol. PD JUN PY 2016 VL 46 IS 1 BP 29 EP 32 DI 10.1007/s10840-015-0039-8 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM3SX UT WOS:000376267900005 PM 26310298 ER PT J AU Haleem, MS Han, LX van Hemert, J Fleming, A Pasquale, LR Silva, PS Song, BJ Aiello, LP AF Haleem, Muhammad Salman Han, Liangxiu van Hemert, Jano Fleming, Alan Pasquale, Louis R. Silva, Paolo S. Song, Brian J. Aiello, Lloyd Paul TI Regional Image Features Model for Automatic Classification between Normal and Glaucoma in Fundus and Scanning Laser Ophthalmoscopy (SLO) Images SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Image processing and analysis; Machine learning; Computer-aided diagnosis; Glaucoma; Fundus camera; Scanning laser ophthalmoscope ID RETINAL IMAGES; OPTIC DISC; DIAGNOSIS AB Glaucoma is one of the leading causes of blindness worldwide. There is no cure for glaucoma but detection at its earliest stage and subsequent treatment can aid patients to prevent blindness. Currently, optic disc and retinal imaging facilitates glaucoma detection but this method requires manual post-imaging modifications that are time-consuming and subjective to image assessment by human observers. Therefore, it is necessary to automate this process. In this work, we have first proposed a novel computer aided approach for automatic glaucoma detection based on Regional Image Features Model (RIFM) which can automatically perform classification between normal and glaucoma images on the basis of regional information. Different from all the existing methods, our approach can extract both geometric (e. g. morphometric properties) and non-geometric based properties (e. g. pixel appearance/intensity values, texture) from images and significantly increase the classification performance. Our proposed approach consists of three new major contributions including automatic localisation of optic disc, automatic segmentation of disc, and classification between normal and glaucoma based on geometric and non-geometric properties of different regions of an image. We have compared our method with existing approaches and tested it on both fundus and Scanning laser ophthalmoscopy (SLO) images. The experimental results show that our proposed approach outperforms the state-of-the- art approaches using either geometric or non-geometric properties. The overall glaucoma classification accuracy for fundus images is 94.4 % and accuracy of detection of suspicion of glaucoma in SLO images is 93.9 %. C1 [Haleem, Muhammad Salman; Han, Liangxiu] Manchester Metropolitan Univ, Sch Comp Math & Digital Technol, Manchester M1 5GD, Lancs, England. [van Hemert, Jano; Fleming, Alan] Optos Plc, Queensferry House,Carnegie Business Campus, Dunfermline KY11 8GR, Fife, Scotland. [Pasquale, Louis R.; Song, Brian J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Silva, Paolo S.; Aiello, Lloyd Paul] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst,Dept Ophthalmol, Boston, MA 02115 USA. RP Haleem, MS (reprint author), Manchester Metropolitan Univ, Sch Comp Math & Digital Technol, Manchester M1 5GD, Lancs, England. EM m.haleem@mmu.ac.uk; l.han@mmu.ac.uk; jvanhemert@optos.com; afleming@optos.com; Louis_Pasquale@meei.harvard.edu; PaoloAntonio.Silva@Joslin.Harvard.edu; Brian_Song@meei.harvard.edu; LloydPaul.Aiello@joslin.harvard.edu OI Haleem, Muhammad Salman/0000-0001-5946-6567 FU EPSRC-DHPA [EP/J50063X/1]; Harvard Medical School Distinguished Scholar Award; NIH [5K12EY016335] FX This work is fully supported by EPSRC-DHPA funded project Automatic Detection of Features in Retinal Imaging to Improve Diagnosis of Eye Diseases and Optos plc. (Grant Ref: EP/J50063X/1). Harvard Medical school provided SLO image data and made contributions to data annotation and domain knowledge. Dr. Pasquale is supported by Harvard Medical School Distinguished Scholar Award. Dr. Song is supported by a departmental K12 grant from the NIH through the Harvard Vision Clinical Scientist Development Program with grant number 5K12EY016335. NR 48 TC 1 Z9 1 U1 4 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 EI 1573-689X J9 J MED SYST JI J. Med. Syst. PD JUN PY 2016 VL 40 IS 6 AR 132 DI 10.1007/s10916-016-0482-9 PG 19 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DM4AZ UT WOS:000376289200002 PM 27086033 ER PT J AU Yun, HJ Shah, RV Murthy, VL AF Yun, Hong Jun Shah, Ravi V. Murthy, Venkatesh L. TI Exercise and Bayes' Theorem: Some things never go out of style SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-PERFUSION SPECT; AMERICAN-HEART-ASSOCIATION; ALL-CAUSE MORTALITY; PROGNOSTIC VALUE; COMPUTED-TOMOGRAPHY; PHYSICAL-FITNESS; TASK-FORCE; FOLLOW-UP; MEN C1 [Yun, Hong Jun; Murthy, Venkatesh L.] Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Shah, Ravi V.] Beth Israel Deaconess Med Ctr, Dept Internal Med, Div Cardiovasc Med, Boston, MA 02215 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Nucl Med & Mol Imaging, Ann Arbor, MI 48109 USA. RP Murthy, VL (reprint author), Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA. EM vlmurthy@med.umich.edu OI Murthy, Venkatesh/0000-0002-7901-1321 NR 22 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD JUN PY 2016 VL 23 IS 3 BP 379 EP 383 DI 10.1007/s12350-015-0281-6 PG 5 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DM3ZA UT WOS:000376284100006 PM 26391502 ER PT J AU Saab, R Bajaj, NS Hage, FG AF Saab, Rayan Bajaj, Navkaranbir S. Hage, Fadi G. TI Caffeine does not significantly reduce the sensitivity of vasodilator stress myocardial perfusion imaging SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID CORONARY VASODILATION; BLOOD-FLOW; ADENOSINE; DIPYRIDAMOLE; HEMODYNAMICS; TOMOGRAPHY; ISCHEMIA; RESERVE C1 [Saab, Rayan; Bajaj, Navkaranbir S.; Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 19 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD JUN PY 2016 VL 23 IS 3 BP 442 EP 446 DI 10.1007/s12350-015-0364-4 PG 5 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DM3ZA UT WOS:000376284100014 PM 26667815 ER PT J AU Hage, FG AlJaroudi, WA AF Hage, Fadi G. AlJaroudi, Wael A. TI Review of Cardiovascular Imaging in the Journal of Nuclear Cardiology in 2015-Part 2 of 2: Myocardial perfusion imaging SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Review DE Myocardial perfusion imaging; SPECT; phase analysis; dyssynchrony; appropriateness; safety; regadenoson ID PROGNOSTIC VALUE; OBESE-PATIENTS; REGADENOSON; SPECT; STRESS; ERA AB In 2015, the Journal of Nuclear Cardiology (A (R)) published many high-quality articles. In this series, we will summarize key articles that have appeared in the Journal last year to provide for the interested reader a quick review of the advancements that have recently occurred in the field. In the first article of this 2-part series, we concentrated on publications dealing with plaque imaging, cardiac positron emission tomography, computed tomography, and magnetic resonance. This review will focus on myocardial perfusion imaging summarizing advances in the field including in diagnosis, prognosis, and appropriate use. C1 [Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. [AlJaroudi, Wael A.] Clemenceau Med Ctr, Div Cardiovasc Med, Cardiovasc Imaging, POB 11-2555, Beirut, Lebanon. RP AlJaroudi, WA (reprint author), Clemenceau Med Ctr, Div Cardiovasc Med, Cardiovasc Imaging, POB 11-2555, Beirut, Lebanon. EM wjaroudi@hotmail.com OI Hage, Fadi/0000-0002-1397-4942 NR 40 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD JUN PY 2016 VL 23 IS 3 BP 493 EP 498 DI 10.1007/s12350-016-0444-0 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DM3ZA UT WOS:000376284100022 PM 26892251 ER PT J AU Andrikopoulou, E Hage, FG AF Andrikopoulou, Efstathia Hage, Fadi G. TI Heart rate response to regadenoson: Making the case for its value in clinical practice SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID IMPAIRED CHRONOTROPIC RESPONSE; EMISSION COMPUTED-TOMOGRAPHY; STRESS MYOCARDIAL-PERFUSION; ALL-CAUSE MORTALITY; PROGNOSTIC VALUE; VASODILATOR STRESS; DIABETES-MELLITUS; CARDIAC DEATH; ADENOSINE; PREDICTOR C1 [Andrikopoulou, Efstathia; Hage, Fadi G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. [Andrikopoulou, Efstathia; Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 25 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD JUN PY 2016 VL 23 IS 3 BP 575 EP 580 DI 10.1007/s12350-015-0269-2 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DM3ZA UT WOS:000376284100034 PM 26310538 ER PT J AU Saab, R Bajaj, NS Hage, FG AF Saab, Rayan Bajaj, Navkaranbir S. Hage, Fadi G. TI Caffeine intake and myocardial perfusion imaging SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Letter C1 [Saab, Rayan; Bajaj, Navkaranbir S.; Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. [Bajaj, Navkaranbir S.; Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Saab, R (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. EM rsaab@uabmc.edu OI Hage, Fadi/0000-0002-1397-4942 NR 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD JUN PY 2016 VL 23 IS 3 BP 605 EP 605 DI 10.1007/s12350-016-0420-8 PG 1 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DM3ZA UT WOS:000376284100043 PM 26883777 ER PT J AU Pallanti, S Marras, A Salerno, L Makris, N Hollander, E AF Pallanti, Stefano Marras, Anna Salerno, Luana Makris, Nikos Hollander, Eric TI Better than treated as usual: Transcranial magnetic stimulation augmentation in selective serotonin reuptake inhibitor-refractory obsessive-compulsive disorder, mini-review and pilot open-label trial SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Repetitive transcranial magnetic stimulation; rTMS; obsessive-compulsive disorder; OCD; supplementary motor area; SMA; SSRI-refractory OCD ID SHAM-CONTROLLED TRIAL; DOUBLE-BLIND TRIAL; ANTIPSYCHOTIC AUGMENTATION; TOURETTE SYNDROME; DOPAMINE RELEASE; FRONTAL-CORTEX; MOTOR CORTEX; RTMS; PLACEBO; OCD AB Objective: 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area has been shown to be effective in a subset of obsessive-compulsive disorder (OCD) subjects, yet these results are still to be confirmed. This preliminary study compares the efficacy of augmentation with 1 Hz rTMS over the supplementary motor area and the usual augmentation treatment (TAU; treated as usual) with antipsychotics in a sample of selective serotonin reuptake inhibitor (SSRI)-refractory OCD patients. Method: Fifty SSRI-refractory OCD patients consecutively admitted were studied: 25 were treated with a three-week trial of 1Hz, bilateral rTMS over the supplementary motor area and 25 with antipsychotic drugs. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; primary outcome measure), Hamilton Depression and Hamilton Anxiety scales were administered at first, second and third week of treatment. Results: Y-BOCS showed a statistically significant time effect from the baseline to the third week, with a 68% of responders (Y-BOCS score reduction of 25%), in comparison with 24.0% in the TAU group. In the rTMS group, 17.6% of patients achieved remission. Conclusions: 1 Hz rTMS over the supplementary motor area appeared to be effective in approximately 2/3 of SSRI-refractory OCD subjects, whereas in the TAU group only 1/4 of subjects were responders. The supplementary motor area might be a new target area to be further explored with neuromodulation for OCD treatment. C1 [Pallanti, Stefano; Marras, Anna] Univ Florence, Area Farm & Salute Bambino NEUROFARBA, Dipartimento Neurosci, Psicol, Via Gore 2H, I-50134 Florence, Italy. [Pallanti, Stefano] UC Davis Hlth Syst, Dept Psychiat & Behav Sci, Sacramento, CA USA. [Pallanti, Stefano; Hollander, Eric] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, New York, NY USA. [Marras, Anna; Salerno, Luana] Inst Neurosci, Florence, Italy. [Makris, Nikos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Morphometr Anal,Dept Psychiat, Boston, MA USA. [Makris, Nikos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Pallanti, S (reprint author), Univ Florence, Area Farm & Salute Bambino NEUROFARBA, Dipartimento Neurosci, Psicol, Via Gore 2H, I-50134 Florence, Italy. EM stefanopallanti@yahoo.it NR 49 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 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD JUN PY 2016 VL 30 IS 6 BP 568 EP 578 DI 10.1177/0269881116628427 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DM2QU UT WOS:000376192600004 PM 26843373 ER PT J AU Sundt, TM AF Sundt, Thoralf M. TI Guidelines or gospels? SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE guidelines; randomized trial; evidence-based medicine ID MANAGEMENT; DISEASE AB In the interest of advancing evidenced-based medicine, enthusiasm for clinical practice guidelines has skyrocketed. They have a genuine impact on clinical practice and are frequently referenced in the literature. Their construction is complex and labor intensive, and has significant limitations given the necessary process as well as the data available. There has been less focus on their appropriate clinical application as dictated by these inherent limitations. It is worthwhile taking a step back and considering how we know what we think we know based on statistical analysis of biomedical data sets and the real implications of those population data for making predictions about the individual patient we encounter in the clinic. These data as used to establish guidelines for care should be the foundation and starting point for our thoughtful recommendations and decision making, not the final word. The importance of nuance in clinical judgment remains even in this "evidence-based'' world. C1 [Sundt, Thoralf M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg, 55 Fruit St, Boston, MA 02114 USA. RP Sundt, TM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg, 55 Fruit St, Boston, MA 02114 USA. EM tsundt@mgh.harvard.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUN PY 2016 VL 151 IS 6 BP 1472 EP 1474 DI 10.1016/j.jtcvs.2016.02.017 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DM2MM UT WOS:000376180900025 PM 26992602 ER PT J AU Mukherjee, R AF Mukherjee, Rupak TI Fire in the "hall''! Myocardial inflammation and recurrence of atrial fibrillation SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID SURGICAL-TREATMENT; CARDIOVERSION; MECHANISMS; HEART; LONE 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,Suite 338, Charleston, SC 29426 USA. EM mukherr@musc.edu NR 17 TC 0 Z9 0 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUN PY 2016 VL 151 IS 6 BP 1683 EP 1685 DI 10.1016/j.jtcvs.2016.02.043 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DM2MM UT WOS:000376180900068 PM 26992604 ER PT J AU Lanuti, M AF Lanuti, Michael TI Feasibility of a procedure does not always translate to what is most efficacious SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Lanuti, Michael] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Lanuti, Michael] Harvard Univ, Sch Med, Boston, MA USA. RP Lanuti, M (reprint author), 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM mlanuti@partners.org NR 3 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 JUN PY 2016 VL 151 IS 6 BP E109 EP E109 DI 10.1016/j.jtcvs.2016.03.004 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DM2MM UT WOS:000376180900008 PM 27016791 ER PT J AU Clouse, WD Ergul, EA Cambria, RP Brewster, DC Kwolek, CJ LaMuraglia, GM Patel, VI Conrad, MF AF Clouse, W. Darrin Ergul, Emel A. Cambria, Richard P. Brewster, David C. Kwolek, Christopher J. LaMuraglia, Glenn M. Patel, Virendra I. Conrad, Mark F. TI Retrograde stenting of proximal lesions with carotid endarterectomy increases risk SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID OCCLUSIVE DISEASE; BALLOON ANGIOPLASTY; STENOSIS; COMMON; RECONSTRUCTION; EXPERIENCE; INNOMINATE; MANAGEMENT; SAFETY; STROKE AB Objective: Concomitant carotid bifurcation and proximal ipsilateral arch branch disease is uncommon. A combined approach using carotid endarterectomy (CEA) with ipsilateral proximal endovascular (IPE) intervention (CEA + IPE) has been proposed as safe and durable, with similar results to isolated CEA. This study was conducted to identify diagnostic modalities and outcomes of this uncommon procedure at our institution. Methods: Operative records were used to identify patients who underwent CEA + IPE between May 2003 and July 2014. Patients were excluded if they underwent open retrograde access for endovascular intervention only, without CEA. The primary end points were freedom from neurologic event and need for reintervention. Results: Twenty-three patients (15 women [65%]) underwent CEA + IPE. Mean clinical follow-up was 44 6 35 months. Average age was 69 +/- 9 years. Most patients (22 [96%]) were taking a statin and at least one antiplatelet agent. Bilateral internal carotid stenosis (>50%) was present in 12 patients (52%), and eight (35%) were symptomatic. Seven patients (30%) had prior ipsilateral CEA. All patients underwent preoperative carotid duplex and axial imaging. Computed tomography angiography was the initial imaging assessment in 10 patients (43%). The proximal lesion was identified in 19 (83%) by blunted waveforms on carotid duplex. Most bifurcation operations were CEA with patch (20 [87%]), and 21 (91%) underwent the bifurcation procedure first, followed by IPE. All IPE included balloon-expandable stenting (22 of 23 [96%] bare-metal, 7 [30%] innominate artery, 16 [70%] left common carotid artery). Electroencephalographic changes occurred in two patients (9%). Shunting was used in three (13%). Three vessel dissections (13%) occurred at the IPE site; two required further stenting and one was complicated by stroke and death. There were two perioperative strokes (9%) and one death (4%). Mean imaging follow-up was 30.6. +/- 27.2 months, with restenosis identified in five patients (23%; four bifurcation, one IPE in-stent). One patient required open reintervention with subclavian-carotid bypass at 13 months for recurrent transient ischemic attack. The 4-year actuarial survival was 85%. Stroke-free survival and freedom from reintervention were 80% and 90% at 36 months, respectively. Conclusions: The stroke and death rate for CEA + IPE is higher than that of isolated CEA at our institution. Duplex findings can suggest proximal stenosis; however, confirmation with physical examination in conjunction with axial imaging are integral. This combined treatment strategy should be reserved for those with evident hemodynamically significant proximal stenosis and approached with caution in asymptomatic patients. C1 [Clouse, W. Darrin; Ergul, Emel A.; Cambria, Richard P.; Brewster, David C.; Kwolek, Christopher J.; LaMuraglia, Glenn M.; Patel, Virendra I.; Conrad, Mark F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, 15 Parkman St,WACC 440, Boston, MA 02114 USA. RP Clouse, WD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, 15 Parkman St,WACC 440, Boston, MA 02114 USA. EM wclouse@partners.org NR 20 TC 2 Z9 2 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2016 VL 63 IS 6 BP 1517 EP 1523 DI 10.1016/j.jvs.2016.01.028 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DM3FC UT WOS:000376231200014 PM 27106249 ER PT J AU Liang, NL Guedes, BD Duvvuri, U Singh, MJ Chaer, RA Makaroun, MS Sachdev, U AF Liang, Nathan L. Guedes, Brian D. Duvvuri, Umamaheswar Singh, Michael J. Chaer, Rabih A. Makaroun, Michel S. Sachdev, Ulka TI Outcomes of interventions for carotid blowout syndrome in patients with head and neck cancer SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID NASOPHARYNGEAL CARCINOMA; ENDOVASCULAR MANAGEMENT AB Background: The purpose of this study was to examine outcomes of a patient cohort undergoing intervention for carotid blowout syndrome associated with head and neck cancer. Methods: Patients with head and neck cancer who presented with carotid distribution bleeding from 2000 to 2014 were identified in the medical record. Primary outcomes were short- and midterm mortality and recurrent bleeding. Standard statistical methods and survival analysis were used to analyze study population characteristics and outcomes. Results: Thirty-seven patients were included in the study. The mean age was 60.1 +/- 11.4 years (74% male). All malignancies were squamous cell type, stage IV, in a variety of primary locations: 32% oral cavity, 24% larynx, 16% superficial neck, with the remainder in the oropharynx, nasopharynx, and hypopharynx. Fifty-one percent of bleeds were of common carotid, 29% external carotid, and 19% internal carotid origin. Among the patients, 68% presented with acute hemorrhage, 24% with impending bleed, and 8% with threatened bleed. All patients underwent intervention: 38% received endovascular coil embolization, 30% stent grafts, 22% surgical ligation, and 10% primary vessel repair or bypass grafting. Although major complications were rare, 10.8% of patients had perioperative stroke. Sixteen recurrent bleeding episodes involving 12 arteries occurred in 11 patients (29.73%). Median rebleeding time was 7 days (interquartile range, 6-49). Estimated recurrent bleeding risk at 30 days and 6 months was 24% and 34%, respectively. Of the patients, 91.9% survived to hospital discharge. The 90-day and 1-year estimated survivals were 60.9% and 36.6%, respectively. Conclusions: Carotid blowout syndrome associated with head and neck cancer carries poor mid-and long-term prognoses; however, mortality may be related more to the advanced stage of disease rather than carotid involvement or associated intervention. Both surgical and endovascular approaches may be efficacious in cases of acute hemorrhage but carry a significant risk of periprocedural stroke and recurrent bleeding. C1 [Liang, Nathan L.; Singh, Michael J.; Chaer, Rabih A.; Makaroun, Michel S.; Sachdev, Ulka] Univ Pittsburgh, Med Ctr, Dept Surg, Div Vasc Surg, Pittsburgh, PA USA. [Liang, Nathan L.; Guedes, Brian D.; Duvvuri, Umamaheswar; Singh, Michael J.; Chaer, Rabih A.; Makaroun, Michel S.; Sachdev, Ulka] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Duvvuri, Umamaheswar] Univ Pittsburgh, Dept Otolaryngol, Med Ctr, Pittsburgh, PA 15260 USA. [Duvvuri, Umamaheswar] VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. RP Liang, NL (reprint author), 200 Lothrop St,Ste A-1017, Pittsburgh, PA 15213 USA. EM liangnl@upmc.edu OI Liang, Nathan/0000-0003-2863-4008 FU National Institutes of Health [2T32HL098036-06]; Department of Veterans Affairs BLSRD FX Supported by grant 2T32HL098036-06 from the National Institutes of Health and in part by funds from the Department of Veterans Affairs BLSR&D (UD). This work does not reflect the views of the U.S. Government or the Department of Veterans Affairs. NR 16 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2016 VL 63 IS 6 BP 1525 EP 1530 DI 10.1016/j.jvs.2015.12.047 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DM3FC UT WOS:000376231200015 PM 26926937 ER PT J AU Haque, A Ray, SK Cox, A Banik, NL AF Haque, Azizul Ray, Swapan K. Cox, April Banik, Naren L. TI Neuron specific enolase: a promising therapeutic target in acute spinal cord injury SO METABOLIC BRAIN DISEASE LA English DT Review DE Neuron specific enolase (NSE); Plasmin; Matrix metalloproteinase (MMP); Major histocompatibility complex (MHC); Inflammation; Neuronal death; Spinal cord injury (SCI) ID TRAUMATIC BRAIN-INJURY; ALPHA-ENOLASE; CARDIAC-ARREST; CEREBROSPINAL-FLUID; MATRIX METALLOPROTEINASES; CEREBRAL-ISCHEMIA; RHEUMATOID-ARTHRITIS; PLASMINOGEN BINDING; MONOCLONAL-ANTIBODY; EARLY PREDICTOR AB Enolase is a multifunctional protein, which is expressed abundantly in the cytosol. Upon stimulatory signals, enolase can traffic to cell surface and contribute to different pathologies including injury, autoimmunity, infection, inflammation, and cancer. Cell-surface expression of enolase is often detected on activated macrophages, microglia/macrophages, microglia, and astrocytes, promoting extracellular matrix degradation, production of pro-inflammatory cytokines/chemokines, and invasion of inflammatory cells in the sites of injury and inflammation. Inflammatory stimulation also induces translocation of enolase from the cytosolic pool to the cell surface where it can act as a plasminogen receptor and promote extracellular matrix degradation and tissue damage. Spinal cord injury (SCI) is a devastating debilitating condition characterized by progressive pathological changes including complex and evolving molecular cascades, and insights into the role of enolase in multiple inflammatory events have not yet been fully elucidated. Neuronal damage following SCI is associated with an elevation of neuron specific enolase (NSE), which is also known to play a role in the pathogenesis of hypoxic-ischemic brain injury. Thus, NSE is now considered as a biomarker in ischemic brain damage, and it has recently been suggested to be a biomarker in traumatic brain injury (TBI), stroke and anoxic encephalopathy after cardiac arrest and acute SCI as well. This review article gives an overview of the current basic research and clinical studies on the role of multifunctional enolase in neurotrauma, with a special emphasis on NSE in acute SCI. C1 [Haque, Azizul] Med Univ S Carolina, Dept Microbiol & Immunol, Hollings Canc Ctr, 173 Ashley Ave,BSB-201, Charleston, SC 29425 USA. [Ray, Swapan K.] Univ S Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29209 USA. [Cox, April; Banik, Naren L.] Med Univ S Carolina, Dept Neurosurg, Charleston, SC 29425 USA. [Banik, Naren L.] Ralph H Johnson Vet Adm Med Ctr, 109 Bee St, Charleston, SC 29401 USA. RP Haque, A (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Hollings Canc Ctr, 173 Ashley Ave,BSB-201, Charleston, SC 29425 USA. EM haque@musc.edu FU South Carolina Spinal Cord Injury Research Fund [SCIRF 2015 P-01]; National Institutes of Health [R01 CA129560, R01 CA129560-S1]; MUSC Center for Global Health Faculty Pilot Program FX This work was supported by grants from the South Carolina Spinal Cord Injury Research Fund (SCIRF 2015 P-01), National Institutes of Health (R01 CA129560 and R01 CA129560-S1), and MUSC Center for Global Health Faculty Pilot Program to A. Haque. NR 84 TC 2 Z9 2 U1 2 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 EI 1573-7365 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD JUN PY 2016 VL 31 IS 3 BP 487 EP 495 DI 10.1007/s11011-016-9801-6 PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA DM1GY UT WOS:000376094700002 PM 26847611 ER PT J AU Smith, DJ Escott-Price, V Davies, G Bailey, MES Colodro-Conde, L Ward, J Vedernikov, A Marioni, R Cullen, B Lyall, D Hagenaars, SP Liewald, DCM Luciano, M Gale, CR Ritchie, SJ Hayward, C Nicholl, B Bulik-Sullivan, B Adams, M Couvy-Duchesne, B Graham, N Mackay, D Evans, J Smith, BH Porteous, DJ Medland, SE Martin, NG Holmans, P McIntosh, AM Pell, JP Deary, IJ O'Donovan, MC AF Smith, D. J. Escott-Price, V. Davies, G. Bailey, M. E. S. Colodro-Conde, L. Ward, J. Vedernikov, A. Marioni, R. Cullen, B. Lyall, D. Hagenaars, S. P. Liewald, D. C. M. Luciano, M. Gale, C. R. Ritchie, S. J. Hayward, C. Nicholl, B. Bulik-Sullivan, B. Adams, M. Couvy-Duchesne, B. Graham, N. Mackay, D. Evans, J. Smith, B. H. Porteous, D. J. Medland, S. E. Martin, N. G. Holmans, P. McIntosh, A. M. Pell, J. P. Deary, I. J. O'Donovan, M. C. TI Genome-wide analysis of over 106000 individuals identifies 9 neuroticism-associated loci SO MOLECULAR PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; COMMON SNPS EXPLAIN; PERSONALITY DIMENSIONS; GENETIC-VARIATION; SEX-DIFFERENCES; MOOD DISORDERS; PROTEIN; HERITABILITY; TRAITS; METAANALYSIS AB Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of similar to 15% (s.e. = 0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P = 1.5 x 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured similar to 1% of the variance in neuroticism in the GS: SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes. C1 [Smith, D. J.; Ward, J.; Cullen, B.; Lyall, D.; Nicholl, B.; Graham, N.; Mackay, D.; Evans, J.; Pell, J. P.] Univ Glasgow, Inst Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland. [Escott-Price, V.; Vedernikov, A.; Holmans, P.; O'Donovan, M. C.] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Davies, G.; Marioni, R.; Hagenaars, S. P.; Liewald, D. C. M.; Luciano, M.; Gale, C. R.; Ritchie, S. J.; Porteous, D. J.; McIntosh, A. M.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Bailey, M. E. S.] Univ Glasgow, Sch Life Sci, Coll Med Vet & Life Sci, Glasgow G12 8RZ, Lanark, Scotland. [Colodro-Conde, L.; Marioni, R.; Couvy-Duchesne, B.; Medland, S. E.; Martin, N. G.] QIMR Berghofer Med Res Inst, Herston, Qld, Australia. [Marioni, R.; Hayward, C.] Univ Edinburgh, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Gale, C. R.] Univ Southampton, Southampton Gen Hosp, Lifecourse Epidemiol Unit, MRC, Southampton, Hants, England. [Hayward, C.; Smith, B. H.; Porteous, D. J.; McIntosh, A. M.; Deary, I. J.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland. [Bulik-Sullivan, B.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Bulik-Sullivan, B.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Bulik-Sullivan, B.] Harvard Univ, Sch Med, Boston, MA USA. [Bulik-Sullivan, B.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Adams, M.; McIntosh, A. M.] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland. [Smith, B. H.] Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland. [Porteous, D. J.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland. RP Smith, DJ (reprint author), Univ Glasgow, Inst Hlth & Wellbeing, Publ Hlth, Room 112,1 Lilybank Gardens, Glasgow G12 8RZ, Lanark, Scotland. EM daniel.smith@glasgow.ac.uk RI Cullen, Breda/C-9154-2012; Luciano, Michelle/F-7277-2010; OI McIntosh, Andrew/0000-0002-0198-4588; Cullen, Breda/0000-0002-7259-9505; Luciano, Michelle/0000-0003-0935-7682; Escott-Price, Valentina/0000-0003-1784-5483; Holmans, Peter/0000-0003-0870-9412; Nicholl, Barbara/0000-0001-5639-0130; Smith, Blair/0000-0002-5362-9430; Medland, Sarah/0000-0003-1382-380X; Smith, Daniel/0000-0002-2267-1951 FU Welsh Assembly Government; British Heart Foundation; UK Biobank. Generation Scotland (GS: SFHS); Scottish Funding Council; Brain and Behaviour Research Foundation [21930]; Welcome Trust [104036/Z/14/Z]; Biotechnology and Biological Sciences Research Council (BBSRC); Medical Research Council (MRC); Age UK (The Disconnected Mind project); Fundacion Seneca (Seneca Foundation, Regional Agency for Science and Technology, Murcia, Spain) [19151/PD/13]; Australian Research Council FX This research was conducted using the UK Biobank resource. UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health, Scottish Government and Northwest Regional Development Agency. UK Biobank has also had funding from the Welsh Assembly Government and the British Heart Foundation. Data collection was funded by UK Biobank. Generation Scotland (GS: SFHS) receives core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. DJS is supported by an Independent Investigator Award from the Brain and Behaviour Research Foundation (21930). AMM, IJD and MA are supported by Welcome Trust Strategic Award 104036/Z/14/Z. Part of the work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the Biotechnology and Biological Sciences Research Council (BBSRC), Medical Research Council (MRC) is gratefully acknowledged. Age UK (The Disconnected Mind project) also provided support for the work undertaken at the University of Edinburgh [Deary]. LCC is supported by a postdoctoral fellowship from the Fundacion Seneca (Seneca Foundation, Regional Agency for Science and Technology, Murcia, Spain, 19151/PD/13). SEM is supported by a Future Fellowship from the Australian Research Council. The funders had no role in the design or analysis of this study, decision to publish, or preparation of the manuscript. We acknowledge support (QIMR study) from Grant W. Montgomery and Andrew C. Heath. NR 70 TC 11 Z9 10 U1 5 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2016 VL 21 IS 6 BP 749 EP 757 DI 10.1038/mp.2016.49 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DM2EN UT WOS:000376159600009 PM 27067015 ER PT J AU McCullumsmith, RE O'Donovan, SM Drummond, JB Benesh, FS Simmons, M Roberts, R Lauriat, T Haroutunian, V Meador-Woodruff, JH AF McCullumsmith, R. E. O'Donovan, S. M. Drummond, J. B. Benesh, F. S. Simmons, M. Roberts, R. Lauriat, T. Haroutunian, V. Meador-Woodruff, J. H. TI Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons? SO MOLECULAR PSYCHIATRY LA English DT Article ID MEDIODORSAL THALAMIC NUCLEUS; ELDERLY-PATIENTS; GLIAL GLUTAMATE; PREFRONTAL CORTEX; RAT-BRAIN; DIFFERENTIAL EXPRESSION; SYNAPTIC-TRANSMISSION; PROTEIN; GLT-1; GAMMA AB Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Converging evidence suggests that abnormalities in the astroglial glutamate transporter localization and function may underlie a disease mechanism with pathological glutamate spillover as well as alterations in the kinetics of perisynaptic glutamate buffering and uptake contributing to dysfunction of thalamo-cortical circuits in schizophrenia. We explored this hypothesis by performing cell-and region-level studies of EAAT1 and EAAT2 expression in the mediodorsal nucleus of the thalamus in an elderly cohort of subjects with schizophrenia. We found decreased protein expression for the typically astroglial-localized glutamate transporters in the mediodorsal and ventral tier nuclei. We next used laser-capture microdissection and quantitative polymerase chain reaction to assess cell-level expression of the transporters and their splice variants. In the mediodorsal nucleus, we found lower expression of transporter transcripts in a population of cells enriched for astrocytes, and higher expression of transporter transcripts in a population of cells enriched for relay neurons. We confirmed expression of transporter protein in neurons in schizophrenia using dual-label immunofluorescence. Finally, the pattern of transporter mRNA and protein expression in rodents treated for 9 months with antipsychotic medication suggests that our findings are not due to the effects of antipsychotic treatment. We found a compensatory increase in transporter expression in neurons that might be secondary to a loss of transporter expression in astrocytes. These changes suggest a profound abnormality in astrocyte functions that support, nourish and maintain neuronal fidelity and synaptic activity. C1 [McCullumsmith, R. E.; O'Donovan, S. M.] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, 231 Albert Sabin Way ML0583,POB 670583, Cincinnati, OH 45267 USA. [Drummond, J. B.; Benesh, F. S.; Simmons, M.; Roberts, R.; Meador-Woodruff, J. H.] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. [Lauriat, T.] Steward St Elizabeths Med Ctr, Dept Psychiat, Brighton, MA USA. [Haroutunian, V.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Haroutunian, V.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Haroutunian, V.] MIRECC, James J Peters VA Med Ctr, Bronx, NY USA. RP McCullumsmith, RE (reprint author), Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, 231 Albert Sabin Way ML0583,POB 670583, Cincinnati, OH 45267 USA. EM robert.mccullumsmith@uc.edu OI Lauriat, Tara/0000-0003-0729-9386 FU Doris Duke Clinical Scientist Award; Lindsay Brinkmeyer Schizophrenia Research Fund; [MH53327]; [MH88752]; [MH094445]; [MH074016] FX This work was supported by MH53327 (JHM-W), MH88752 (JHM-W), MH094445 (REM), MH074016 (REM) and Doris Duke Clinical Scientist Award (REM). This work was also supported by the Lindsay Brinkmeyer Schizophrenia Research Fund. NR 76 TC 0 Z9 0 U1 5 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2016 VL 21 IS 6 BP 823 EP 830 DI 10.1038/mp.2015.148 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DM2EN UT WOS:000376159600016 PM 26416546 ER PT J AU Howrigan, DP Simonson, MA Davies, G Harris, SE Tenesa, A Starr, JM Liewald, DC Deary, IJ Mcrae, A Wright, MJ Montgomery, GW Hansell, N Martin, NG Payton, A Horan, M Ollier, WE Abdellaoui, A Boomsma, DI DeRosse, P Knowles, EEM Glahn, DC Djurovic, S Melle, I Andreassen, OA Christoforou, A Steen, VM Hellard, SL Sundet, K Reinvang, I Espeseth, T Lundervold, AJ Giegling, I Konte, B Hartmann, AM Rujescu, D Roussos, P Giakoumaki, S Burdick, KE Bitsios, P Donohoe, G Corley, RP Visscher, PM Pendleton, N Malhotra, AK Neale, BM Lencz, T Keller, MC AF Howrigan, D. P. Simonson, M. A. Davies, G. Harris, S. E. Tenesa, A. Starr, J. M. Liewald, D. C. Deary, I. J. McRae, A. Wright, M. J. Montgomery, G. W. Hansell, N. Martin, N. G. Payton, A. Horan, M. Ollier, W. E. Abdellaoui, A. Boomsma, D. I. DeRosse, P. Knowles, E. E. M. Glahn, D. C. Djurovic, S. Melle, I. Andreassen, O. A. Christoforou, A. Steen, V. M. Hellard, S. L. Sundet, K. Reinvang, I. Espeseth, T. Lundervold, A. J. Giegling, I. Konte, B. Hartmann, A. M. Rujescu, D. Roussos, P. Giakoumaki, S. Burdick, K. E. Bitsios, P. Donohoe, G. Corley, R. P. Visscher, P. M. Pendleton, N. Malhotra, A. K. Neale, B. M. Lencz, T. Keller, M. C. TI Genome-wide autozygosity is associated with lower general cognitive ability SO MOLECULAR PSYCHIATRY LA English DT Article ID TEST BATTERIES; INTELLIGENCE; HOMOZYGOSITY; RUNS; POPULATIONS; DROSOPHILA AB Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P = 0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time. C1 [Howrigan, D. P.; Neale, B. M.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. [Howrigan, D. P.; Neale, B. M.] Harvard Univ, Sch Med, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. [Howrigan, D. P.; Neale, B. M.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Genet, Cambridge Ctr, Cambridge, MA USA. [Simonson, M. A.] MIT, Div Data Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Davies, G.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Harris, S. E.; Starr, J. M.; Liewald, D. C.; Deary, I. J.; Visscher, P. M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Harris, S. E.] Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Harris, S. E.] Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Tenesa, A.] Univ Edinburgh, Inst Genet & Mol Med, Western Gen Hosp, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Tenesa, A.] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin Inst, Roslin, Midlothian, Scotland. [Starr, J. M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [McRae, A.; Wright, M. J.; Montgomery, G. W.; Hansell, N.; Martin, N. G.; Visscher, P. M.] Queensland Inst Med Res Berghofer, Brisbane, Qld, Australia. [McRae, A.; Visscher, P. M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Payton, A.; Ollier, W. E.; Pendleton, N.] Univ Manchester, Ctr Integrated Genom Med Res, Inst Populat Hlth, Manchester, Lancs, England. [Horan, M.] Univ Manchester, Ctr Clin & Cognit Neurosci, Inst Brain Behav & Mental Hlth, Salford Royal NHS Fdn Trust, Salford, Lancs, England. [Abdellaoui, A.; Boomsma, D. I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Abdellaoui, A.; Boomsma, D. I.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Boomsma, D. I.] EMGO Inst Hlth & Care Res Amsterdam, Amsterdam, Netherlands. [DeRosse, P.; Malhotra, A. K.; Lencz, T.] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. [DeRosse, P.; Malhotra, A. K.; Lencz, T.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [DeRosse, P.; Malhotra, A. K.; Lencz, T.] Hofstra North Shore LIJ Sch Med, Dept Psychiat & Mol Med, Hempstead, NY USA. [Knowles, E. E. M.; Glahn, D. C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Djurovic, S.; Melle, I.; Andreassen, O. A.; Sundet, K.] NORMENT, KG Jebsen Ctr, Oslo, Norway. [Djurovic, S.; Melle, I.; Andreassen, O. A.] Oslo Univ Hosp, N-0450 Oslo, Norway. [Melle, I.; Andreassen, O. A.] Univ Oslo, Oslo, Norway. [Christoforou, A.; Steen, V. M.; Hellard, S. L.] Univ Bergen, KG Jebsen Ctr Psychosis Res, Dr Einar Martens Res Grp Biol Psychiat, Dept Clin Med, Bergen, Norway. [Christoforou, A.; Steen, V. M.; Hellard, S. L.] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Sundet, K.; Reinvang, I.; Espeseth, T.] Univ Oslo, Dept Psychol, Oslo, Norway. [Espeseth, T.] Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Norwegian Ctr Mental Disorders Res, N-0450 Oslo, Norway. [Lundervold, A. J.] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, Bergen, Norway. [Lundervold, A. J.] Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway. [Lundervold, A. J.] Haraldsplass Deaconess Hosp, Kavli Res Ctr Aging & Dementia, Bergen, Norway. [Giegling, I.; Konte, B.; Hartmann, A. M.; Rujescu, D.] Univ Halle, Dept Psychiat, Halle, Germany. [Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Dept Psychiat, Friedman Brain Inst Dept Genet & Genom Sci, New York, NY 10029 USA. [Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Roussos, P.] MIRECC, James J Peters VA Med Ctr, Bronx, NY USA. [Giakoumaki, S.] Univ Crete, Dept Psychol, Iraklion, Greece. [Bitsios, P.] Univ Crete, Fac Med, Dept Psychiat, Iraklion, Crete, Greece. [Bitsios, P.] Inst Comp Sci FORTH, Computat Med Lab, Iraklion, Greece. [Donohoe, G.] Natl Univ Ireland Galway, Sch Psychol, Galway, Ireland. [Corley, R. P.; Keller, M. C.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Visscher, P. M.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Keller, M. C.] Univ Colorado, Dept Psychol, Boulder, CO 80303 USA. RP Howrigan, DP (reprint author), Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA.; Howrigan, DP (reprint author), Harvard Univ, Sch Med, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA.; Keller, MC (reprint author), Univ Colorado, Dept Psychol, Boulder, CO 80303 USA. EM daniel.howrigan@gmail.com; matthew.c.keller@gmail.com RI Melle, Ingrid /B-4858-2011; Lencz, Todd/J-3418-2014; Hansell, Narelle/A-4553-2016; McRae, Allan/J-2644-2014; Roussos, Panos/J-7090-2013 OI Melle, Ingrid /0000-0002-9783-548X; Lencz, Todd/0000-0001-8586-338X; Hansell, Narelle/0000-0002-8229-9741; Donohoe, Gary/0000-0003-3037-7426; Wright, Margaret/0000-0001-7133-4970; Sundet, Kjetil/0000-0003-2850-3673; Payton, Antony/0000-0003-0335-152X; McRae, Allan/0000-0001-5286-5485; Roussos, Panos/0000-0002-4640-6239 FU National Institutes of Health [R01 MH079800, P50 MH080173, RC2 MH089964, R01 MH080912, K23 MH077807, K01 MH085812, R01 MH100141]; University of Crete [E.L.K.E. 1348]; Research Council of Norway [213837, 223273, 154313/V50, 177458/V50]; South-East Norway Health Authority [2013-123]; K.G. Jebsen Foundation; Bergen Research Foundation; University of Bergen; Research Council of Norway (FUGE, Psykisk Helse); Helse Vest RHF; Dr Einar Martens Fund FX We acknowledge Bruce Walsh, Ken Krauter and Brian Browning for their helpful comments and suggestions in the preparation of this manuscript. This work has been supported by grants from the National Institutes of Health: R01 MH079800 and P50 MH080173 to AKM. RC2 MH089964 to TL. R01 MH080912 to DCG K23 MH077807 to KEB. K01 MH085812 and R01 MH100141 to MCK. The LOGOS study was supported by the University of Crete Research Funds Account (E.L.K.E. 1348). The TOP Study Group was supported by the Research Council of Norway grants 213837 and 223273, South-East Norway Health Authority grants 2013-123, and K.G. Jebsen Foundation. The NCNG study was supported by Research Council of Norway grants 154313/V50 and 177458/V50. The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE, Psykisk Helse), Helse Vest RHF and Dr Einar Martens Fund. NR 44 TC 0 Z9 0 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2016 VL 21 IS 6 BP 837 EP 843 DI 10.1038/mp.2015.120 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DM2EN UT WOS:000376159600018 PM 26390830 ER PT J AU Ko, D Rahman, F Schnabel, RB Yin, XY Benjamin, EJ Christophersen, IE AF Ko, Darae Rahman, Faisal Schnabel, Renate B. Yin, Xiaoyan Benjamin, Emelia J. Christophersen, Ingrid E. TI Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID GENDER-RELATED DIFFERENCES; CONGESTIVE-HEART-FAILURE; PULMONARY VEIN CARDIOMYOCYTES; RISK STRATIFICATION SCHEMES; POPULATION-BASED COHORT; COMMUNITY-BASED COHORT; FOLLOW-UP; FAMILIAL AGGREGATION; MYOCARDIAL-INFARCTION; NATIONWIDE COHORT AB Atrial fibrillation (AF) is the most common sustained arrhythmia in women and men worldwide. During the past century, a range of risk factors has been associated with AF, severe complications from the arrhythmia have been identified, and its prevalence has been increasing steadily. Whereas evidence has accumulated regarding sex-specific differences in coronary heart disease and stroke, the differences between women and men with AF has received less attention. We review the current literature on sex-specific differences in the epidemiology of AF, including incidence, prevalence, risk factors, and genetics, and in the pathophysiology and the clinical presentation and prognosis of patients with this arrhythmia. We highlight current knowledge gaps and areas that warrant future research, which might advance understanding of variation in the risk factors and complications of AF, and ultimately aid more-tailored management of the arrhythmia. C1 [Christophersen, Ingrid E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. [Ko, Darae] Boston Univ, Sch Med, Boston Med Ctr, Sect Gen Internal Med, Boston, MA 02215 USA. [Rahman, Faisal] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med, Boston, MA 02215 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Martinistr 52, D-20246 Hamburg, Germany. [Schnabel, Renate B.] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, D-13347 Berlin, Germany. [Yin, Xiaoyan; Benjamin, Emelia J.] Boston Univ, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Yin, Xiaoyan; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Yin, Xiaoyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Sect Cardiovasc Med, 72 East Concord St, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Sect Prevent Med, 72 East Concord St, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St, Boston, MA 02118 USA. RP Christophersen, IE (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM ichristophersen@mgh.harvard.edu FU National Heart, Lung, and Blood Institute [5T32HL007224-38]; National Institutes of Health Clinical and Translational Science Award programme [UL1-TR000157]; European Research Council under the European Union's Horizon research and innovation programme [648131]; Junior Research Alliance symAtrial project - German Ministry of Research and Education [BMBF 01ZX1408A]; Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program [SCHN 1149/3-1]; NIH/NHLBI [HHSN268201500001I, N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, 1RC1HL101056]; Research Council of Norway [240149/F20] FX D. K. is supported by the National Heart, Lung, and Blood Institute award 5T32HL007224-38 and the National Institutes of Health Clinical and Translational Science Award programme award UL1-TR000157. R. B. S. is supported by European Research Council under the European Union's Horizon 2020 research and innovation programme (agreement No 648131), and Junior Research Alliance symAtrial project funded by the German Ministry of Research and Education (BMBF 01ZX1408A) e: Med - Systems Medicine programme and by Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program SCHN 1149/3-1. E.J.B. is supported in part through NIH/NHLBI HHSN268201500001I; N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, and 1RC1HL101056. I.E.C. is supported by a mobility grant from the Research Council of Norway (240149/F20). NR 174 TC 10 Z9 10 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD JUN PY 2016 VL 13 IS 6 BP 321 EP 332 DI 10.1038/nrcardio.2016.45 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM2SC UT WOS:000376196300004 PM 27053455 ER PT J AU Ceccaldi, R Sarangi, P D'Andrea, AD AF Ceccaldi, Raphael Sarangi, Prabha D'Andrea, Alan D. TI The Fanconi anaemia pathway: newyplayers and new functions SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID CROSS-LINK REPAIR; DOUBLE-STRAND BREAK; REPLICATION FORK RECOVERY; COMPLEMENTATION GROUP-M; DNA-POLYMERASE-ZETA; BONE-MARROW FAILURE; HOMOLOGOUS-RECOMBINATION; GENOME STABILITY; FANCD2 MONOUBIQUITINATION; XERODERMA-PIGMENTOSUM AB The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance. C1 [D'Andrea, Alan D.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02215 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02215 USA. EM alan_dandrea@dfci.harvard.edu FU Ovarian Cancer Research Fellowship (OCRF); Leukaemia and Lymphoma Society (LLS); Stand Up To Cancer (SU2C) - Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]; U.S. National Institutes of Health [R01DK43889, R37HL052725, P01HL048546]; Breast Cancer Research Foundation; Fanconi Anaemia Research Fund FX The authors apologize for the many articles that could not be cited owing to space limitations. R.C. is a recipient of the Ovarian Cancer Research Fellowship (OCRF) and Claudia Adams Barr Program. P.S. is a recipient of a Leukaemia and Lymphoma Society (LLS) fellowship. This work was supported by a Stand Up To Cancer (SU2C) - Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number SU2C-AACR-DT16-15). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. This work was also supported by grants from the U.S. National Institutes of Health (R01DK43889, R37HL052725 and P01HL048546), the Breast Cancer Research Foundation and the Fanconi Anaemia Research Fund (to A.D.D.). NR 137 TC 18 Z9 18 U1 10 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JUN PY 2016 VL 17 IS 6 BP 337 EP 349 DI 10.1038/nrm.2016.48 PG 13 WC Cell Biology SC Cell Biology GA DM7GU UT WOS:000376526400009 PM 27145721 ER PT J AU Fruhwald, MC Biegel, JA Bourdeaut, F Roberts, CWM Chi, SN AF Fruehwald, Michael C. Biegel, Jaclyn A. Bourdeaut, Franck Roberts, Charles W. M. Chi, Susan N. TI Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies SO NEURO-ONCOLOGY LA English DT Article DE AT/RT; BAF47; epigenetics; INI1; rhabdoid tumor; SMARCB1; SNF5; SWI/SNF ID CENTRAL-NERVOUS-SYSTEM; TERATOID RHABDOID TUMORS; CHROMATIN-REMODELING COMPLEXES; INTENSIVE MULTIMODAL THERAPY; MAMMALIAN SWI/SNF COMPLEXES; STANDARD ANTICANCER AGENTS; PROGENITOR-CELL RESCUE; HIGH-DOSE CHEMOTHERAPY; ADVANCED SOLID TUMORS; TARGETING CYCLIN D1 AB Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/ss-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT. C1 [Fruehwald, Michael C.] Childrens Hosp, Augsburg, Germany. [Fruehwald, Michael C.] Swabian Childrens Canc Ctr, Augsburg, Germany. [Biegel, Jaclyn A.] Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA. [Bourdeaut, Franck] Inst Curie, INSERM, U830, Lab Genet & Biol Cancers, Paris, France. [Bourdeaut, Franck] Inst Curie, Dept Pediat Oncol, Paris, France. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Ctr Comprehens Canc, 332 N Lauderdale St, Memphis, TN 38105 USA. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chi, Susan N.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Chi, Susan N.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Chi, Susan N.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Fruhwald, MC (reprint author), Klinikum Augsburg, Childrens Hosp Augsburg, Swabian Childrens Canc Ctr, Stenglinstr 2, D-86156 Augsburg, Germany. EM michael.fruehwald@klinikum-augsburg.de FU Deutsche Kinderkrebsstiftung; Gesellschaft fur Kinderkrebsforschung; Horizonte Weseke; Lichtblicke; National Institutes of Health [R0146274, R01CA172152, R01CA113794]; Ligue Nationale contre le Cancer [INSERM U830]; Societe Francaise des Cancers de l'Enfant (SFCE); Federation Enfants et Sante; Abigael; Marabout de Ficelles; Hubert Gouin-Enfance et Cancer; Cure AT/RT Now Fund; Avalanna Fund; Garrett B. Smith Foundation; Miles for Mary; Claudia Adams Barr Foundation; Alex's Lemonade Stand; Cookies for Kids' Cancer Foundation FX M.C.F. is supported by funds from the Deutsche Kinderkrebsstiftung, the Gesellschaft fur Kinderkrebsforschung, the parents organization Horizonte Weseke, as well as the parent's organization Lichtblicke to the European Registry for Rhabdoid Tumors.; J.A.B. acknowledges the support of a grant from the National Institutes of Health (R0146274).; F.B. acknowledges INSERM U830, which is supported by the Ligue Nationale contre le Cancer; the rhabdoid team of the Curie Institute SiRIC, supported by the Societe Francaise des Cancers de l'Enfant (SFCE), the Federation Enfants et Sante, and the associations Abigael, Marabout de Ficelles, and Hubert Gouin-Enfance et Cancer.; C.W.M.R. was supported by National Institutes of Health grants R01CA172152 and R01CA113794 and received additional support from the Cure AT/RT Now Fund, the Avalanna Fund, the Garrett B. Smith Foundation, Miles for Mary, the Claudia Adams Barr Foundation, and Alex's Lemonade Stand.; S.N.C. was supported in part by a grant from the Cookies for Kids' Cancer Foundation and the Cure AT/RT Now Fund. NR 116 TC 11 Z9 11 U1 5 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 IS 6 BP 764 EP 778 DI 10.1093/neuonc/nov264 PG 15 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DM2BO UT WOS:000376151200009 PM 26755072 ER PT J AU Armstrong, TS Grant, R Gilbert, MR Lee, JW Norden, AD AF Armstrong, Terri S. Grant, Robin Gilbert, Mark R. Lee, Jong Woo Norden, Andrew D. TI Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy SO NEURO-ONCOLOGY LA English DT Article DE anticonvulsant; epilepsy; glioma; seizure ID LOW-GRADE GLIOMAS; QUALITY STANDARDS SUBCOMMITTEE; MAJOR DEPRESSIVE DISORDER; TUMOR-ASSOCIATED EPILEPSY; ANTIEPILEPTIC DRUG-WITHDRAWAL; GAMMA-AMINOBUTYRIC-ACID; DIAGNOSED BRAIN-TUMORS; GLIOBLASTOMA-MULTIFORME; PRACTICE PARAMETER; AMERICAN-ACADEMY AB Seizures are a well-recognized symptom of primary brain tumors, and anticonvulsant use is common. This paper provides an overview of epilepsy and the use of anticonvulsants in glioma patients. Overall incidence and mechanisms of epileptogenesis are reviewed. Factors to consider with the use of antiepileptic drugs (AEDs) including incidence during the disease trajectory and prophylaxis along with considerations in the selection of anticonvulsant use (ie, potential side effects, drug interactions, adverse effects, and impact on survival) are also reviewed. Finally, areas for future research and exploring the pathophysiology and use of AEDs in this population are also discussed. C1 [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Dept Family Hlth, Houston, TX 77030 USA. [Grant, Robin] Edinburgh Ctr Neurooncol, Edinburgh, Midlothian, Scotland. [Gilbert, Mark R.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Gilbert, Mark R.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lee, Jong Woo] Brigham & Womens Hosp, Div EEG & Epilepsy, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Norden, Andrew D.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Norden, Andrew D.] Brigham & Womens Hosp, Dept Neurol, Div Canc Neurol, 75 Francis St, Boston, MA 02115 USA. [Norden, Andrew D.] Harvard Univ, Sch Med, Boston, MA USA. RP Armstrong, TS (reprint author), Room 577,6901 Bertner Ave, Houston, TX 77030 USA. EM terri.s.armstrong@uth.tmc.edu RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU UCB FX There was no funding support for the preparation of this manuscript. fee donated from UCB direct to UK Brain Tumour Charity. Terri Armstrong: consultant for ABBvie, Immunocellular Therapeutics, and Tocagen. NR 137 TC 5 Z9 5 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 IS 6 BP 779 EP 789 DI 10.1093/neuonc/nov269 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DM2BO UT WOS:000376151200010 PM 26527735 ER PT J AU Lee, EQ Muzikansky, A Drappatz, J Kesari, S Wong, ET Fadul, CE Reardon, DA Norden, AD Nayak, L Rinne, ML Alexander, BM Arvold, ND Doherty, L Stefanik, J LaFrankie, D Ruland, SF Pulverenti, J Smith, KH Gaffey, SC Hammond, S Wen, PY AF Lee, Eudocia Q. Muzikansky, Alona Drappatz, Jan Kesari, Santosh Wong, Eric T. Fadul, Camilo E. Reardon, David A. Norden, Andrew D. Nayak, Lakshmi Rinne, Mikael L. Alexander, Brian M. Arvold, Nils D. Doherty, Lisa Stefanik, Jennifer LaFrankie, Debra Ruland, Sandra F. Pulverenti, Julee Smith, Katrina H. Gaffey, Sarah C. Hammond, Samantha Wen, Patrick Y. TI A randomized, placebo-controlled pilot trial of armodafinil for fatigue in patients with gliomas undergoing radiotherapy SO NEURO-ONCOLOGY LA English DT Article DE armodafinil; clinical trial; fatigue; glioblastoma; glioma ID BRAIN-TUMOR PATIENTS; DOUBLE-BLIND; CANCER-PATIENTS; METHYLPHENIDATE; VALIDATION; MODAFINIL; THERAPY; SCALE AB Background. Fatigue is common among glioma patients undergoing radiotherapy (RT) and impacts quality of life (QOL). We evaluated whether armodafinil, a wakefulness-promoting medication, improves fatigue in glioma patients undergoing RT. Methods. Eligibility criteria included age >= 18 years, Karnofsky performance status >= 60, and grade 2-4 glioma undergoing RT to a total dose of 50-60 Gy. Patients were randomized 1:1 to armodafinil or placebo for 8 weeks beginning within 10 days of starting RT. Fatigue and QOL were assessed at baseline, day 22, day 43, and day 56 with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy - General (FACT-G), the Brief Fatigue Inventory (BFI), and the Cancer Fatigue Scale (CFS). The primary aim was to detect a difference in the 42-day change in FACIT-F fatigue subscale between the 2 groups using a 2-sample Wilcoxon statistic. Results. We enrolled 81 patients total (42 armodafinil and 39 placebo). Armodafinil did not significantly improve fatigue or QOL based on the 42-day change in FACIT-F fatigue subscale, FACT-G, CFS, or BFI. Further analysis suggests no difference between the arms even after accounting for the potential bias of missing data. Treatment was well tolerated with few grade 3 or 4 toxicities. Conclusions. While treatment was well-tolerated, an 8-week course of armodafinil did not improve fatigue or QOL in glioma patients undergoing RT in this pilot study. Further studies are needed to determine whether pharmacologic treatment improves fatigue in glioma patients undergoing RT. C1 [Lee, Eudocia Q.; Reardon, David A.; Norden, Andrew D.; Nayak, Lakshmi; Rinne, Mikael L.; Alexander, Brian M.; Arvold, Nils D.; Doherty, Lisa; Stefanik, Jennifer; LaFrankie, Debra; Ruland, Sandra F.; Pulverenti, Julee; Smith, Katrina H.; Gaffey, Sarah C.; Hammond, Samantha; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lee, Eudocia Q.; Wong, Eric T.; Reardon, David A.; Norden, Andrew D.; Nayak, Lakshmi; Rinne, Mikael L.; Alexander, Brian M.; Arvold, Nils D.; Wen, Patrick Y.] Harvard Univ, Sch Med, Boston, MA USA. [Muzikansky, Alona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Drappatz, Jan] Univ Pittsburgh, Pittsburgh, PA USA. [Kesari, Santosh] Univ Calif San Diego, La Jolla, CA 92093 USA. [Wong, Eric T.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Fadul, Camilo E.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Fadul, Camilo E.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Lee, EQ (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave,Dana 2110, Boston, MA 02215 USA. EM eqlee@partners.org FU National Brain Tumor Society; Cephalon, Inc.; Teva Pharmaceuticals FX This study was supported by the National Brain Tumor Society and Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceuticals. NR 18 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 IS 6 BP 849 EP 854 DI 10.1093/neuonc/now007 PG 6 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DM2BO UT WOS:000376151200017 PM 26902850 ER PT J AU Hwang, WL Marciscano, AE Niemierko, A Kim, DW Stemmer-Rachamimov, AO Curry, WT Barker, FG Martuza, RL Loeffler, JS Oh, KS Shih, HA Larvie, M AF Hwang, William L. Marciscano, Ariel E. Niemierko, Andrzej Kim, Daniel W. Stemmer-Rachamimov, Anat O. Curry, William T. Barker, Fred G., II Martuza, Robert L. Loeffler, Jay S. Oh, Kevin S. Shih, Helen A. Larvie, Mykol TI Imaging and extent of surgical resection predict risk of meningioma recurrence better than WHO histopathological grade SO NEURO-ONCOLOGY LA English DT Article DE apparent diffusion coefficient; histopathological grade; meningioma; radiotherapy; Simpson grade ID APPARENT DIFFUSION-COEFFICIENT; CENTRAL-NERVOUS-SYSTEM; ATYPICAL MENINGIOMAS; ASYMPTOMATIC MENINGIOMAS; INTRACRANIAL MENINGIOMAS; ANAPLASTIC MENINGIOMAS; ADJUVANT RADIOTHERAPY; MALIGNANT MENINGIOMAS; PROLIFERATION INDEX; TUMORS AB Background. Risk stratification of meningiomas by histopathological grade alone does not reliably predict which patients will progress/recur after treatment. We sought to determine whether preoperative imaging and clinical characteristics could predict histopathological grade and/or improve prognostication of progression/recurrence (P/R). Methods. We retrospectively reviewed preoperative MR and CT imaging features of 144 patients divided into low-grade (2007 WHO grade I; n = 118) and high-grade (2007 WHO grades II/III; n = 26) groups that underwent surgery between 2002 and 2013 (median follow-up of 49 months). Results. Multivariate analysis demonstrated that the risk factors most strongly associated with high-grade histopathology were male sex, low apparent diffusion coefficient (ADC), absent calcification, and high peritumoral edema. Remarkably, multivariate Cox proportional hazards analysis demonstrated that, in combination with extent of resection, ADC outperformed WHO histopathological grade for predicting which patients will suffer P/R after initial treatment. Stratification of patients into 3 risk groups based on non-Simpson grade I resection and low ADC as risk factors correlated with the likelihood of P/R (P < .001). The high-risk group (2 risk factors; n = 39) had a 45% cumulative incidence of P/R, whereas the low-risk group (0 risk factors; n = 31) had no P/R events at 5 years after treatment. Independent of histopathological grade, high-risk patients who received adjuvant radiotherapy had a lower 5-year crude rate of P/R than those without (17% vs 59%; P = .04). Conclusions. Patients with non-Simpson grade I resection and low ADC meningiomas are at significantly increased risk of P/R and may benefit from adjuvant radiotherapy and/or additional surgery. C1 [Hwang, William L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hwang, William L.; Niemierko, Andrzej; Kim, Daniel W.; Loeffler, Jay S.; Oh, Kevin S.; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [Hwang, William L.; Larvie, Mykol] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. [Marciscano, Ariel E.] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA. [Kim, Daniel W.] Harvard Univ, Business Sch Leadership Fellows Program, Boston, MA 02115 USA. [Stemmer-Rachamimov, Anat O.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Curry, William T.; Barker, Fred G., II; Martuza, Robert L.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Shih, HA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA.; Larvie, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM hshih@mgh.harvard.edu; mlarvie@gmail.com FU National Institute of General Medical Sciences [T32GM007753] FX W.L.H. acknowledges support from the National Institute of General Medical Sciences (T32GM007753). NR 50 TC 2 Z9 2 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 IS 6 BP 863 EP 872 DI 10.1093/neuonc/nov285 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DM2BO UT WOS:000376151200019 PM 26597949 ER PT J AU Eaton, BR Esiashvili, N Kim, S Patterson, B Weyman, EA Thornton, LT Mazewski, C MacDonald, TJ Ebb, D MacDonald, SM Tarbell, NJ Yock, TI AF Eaton, Bree R. Esiashvili, Natia Kim, Sungjin Patterson, Briana Weyman, Elizabeth A. Thornton, Lauren T. Mazewski, Claire MacDonald, Tobey J. Ebb, David MacDonald, Shannon M. Tarbell, Nancy J. Yock, Torunn I. TI Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma SO NEURO-ONCOLOGY LA English DT Article DE endocrine; medulloblastoma; proton; photon; radiotherapy ID CHILDHOOD-CANCER SURVIVOR; RECEIVING CRANIOSPINAL IRRADIATION; GROWTH-HORMONE-SECRETION; PROPENSITY SCORE METHODS; BRAIN-TUMORS; PEDIATRIC MEDULLOBLASTOMA; RADIATION-THERAPY; POTENTIAL ROLE; CHILDREN; HYPOTHYROIDISM AB Background. Endocrine dysfunction is a common sequela of craniospinal irradiation (CSI). Dosimetric data suggest that proton radiotherapy (PRT) may reduce radiation-associated endocrine dysfunction but clinical data are limited. Methods. Seventy-seven children were treated with chemotherapy and proton (n = 40) or photon (n = 37) radiation between 2000 and 2009 with >= 3 years of endocrine screening. The incidence of multiple endocrinopathies among the proton and photon cohorts is compared. Multivariable analysis and propensity score adjusted analysis are performed to estimate the effect of radiotherapy type while adjusting for other variables. Results. The median age at diagnosis was 6.2 and 8.3 years for the proton and photon cohorts, respectively (P = .010). Cohorts were similar with respect to gender, histology, CSI dose, and total radiotherapy dose and whether the radiotherapy boost was delivered to the posterior fossa or tumor bed. The median follow-up time was 5.8 years for proton patients and 7.0 years for photon patients (P =.010). PRT was associated with a reduced risk of hypothyroidism (23% vs 69%, P,. 001), sex hormone deficiency (3% vs 19%, P =.025), requirement for any endocrine replacement therapy (55% vs 78%, P =.030), and a greater height standard deviation score (mean (+/- SD) 21.19 (+/- 1.22) vs 22 (+/- 1.35), P =.020) on both univariate and multivariate and propensity score adjusted analysis. There was no significant difference in the incidence of growth hormone deficiency (53% vs 57%), adrenal insufficiency (5% vs 8%), or precocious puberty (18% vs 16%). Conclusions. Proton radiotherapy may reduce the risk of some, but not all, radiation-associated late endocrine abnormalities. C1 [Eaton, Bree R.; Esiashvili, Natia] Emory Univ, Winship Canc Inst, Radiat Oncol, Atlanta, GA 30322 USA. [Patterson, Briana; Mazewski, Claire; MacDonald, Tobey J.] Emory Univ, Sch Med, Pediat, Atlanta, GA 30322 USA. [Patterson, Briana; Mazewski, Claire; MacDonald, Tobey J.] Aflac Canc & Blood Disorders Ctr Childrens Health, Atlanta, GA 30322 USA. [Kim, Sungjin] Cedars Sinai Med Ctr, Biostat & Bioinformat Res Ctr, Los Angeles, CA 90048 USA. [Ebb, David] Massachusetts Gen Hosp, Pediat, Boston, MA 02114 USA. [Eaton, Bree R.; Weyman, Elizabeth A.; Thornton, Lauren T.; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.] Massachusetts Gen Hosp, Radiat Oncol, Boston, MA 02114 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Proton Ctr, 55 Fruit St,Room 110, Boston, MA 02114 USA. EM tyock@partners.org FU National Cancer Institute [P01CA021239]; Federal Share of program income earned by Massachusetts General Hospital, Proton Therapy Research and Treatment Center [C06 CA059267] FX This work was supported in part by the National Cancer Institute, award number P01CA021239, and the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 32 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2016 VL 18 IS 6 BP 881 EP 887 DI 10.1093/neuonc/nov302 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DM2BO UT WOS:000376151200021 PM 26688075 ER PT J AU Warren, M McCarthy, MS Roberts, PR AF Warren, Malissa McCarthy, Mary S. Roberts, Pamela R. TI Practical Application of the Revised Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: A Case Study Approach SO NUTRITION IN CLINICAL PRACTICE LA English DT Article DE nutritional support; enteral nutrition; parenteral nutrition; critical care; critical illness; intensive care units; practice guidelines ID SEVERE ACUTE-PANCREATITIS; EARLY ENTERAL NUTRITION; RANDOMIZED CLINICAL-TRIAL; TOTAL PARENTERAL-NUTRITION; VENTILATOR-ASSOCIATED PNEUMONIA; INTENSIVE INSULIN THERAPY; RESIDUAL GASTRIC VOLUME; ACUTE KIDNEY INJURY; OPEN ABDOMEN; SURGICAL-PATIENTS AB Background: Nutrition therapy is an essential component of the care plan for critically ill and injured patients. There is consensus that critically ill patients are at risk for malnutrition, and the associated consequences of increased infectious morbidity, multiorgan dysfunction, prolonged hospitalization, and disproportionate mortality can be minimized with specialized enteral and/or parenteral nutrition therapy. Methods: In this article, we describe 2 case studies that are intended to introduce the nutrition support clinician to key updates in the recently released Guidelines for Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). Results: The case studies demonstrate a pragmatic approach to nutrition therapy in the intensive care unit (ICU) and are intended to elicit dialogue for timely, appropriate nutrition care at policy meetings, professional conferences, and ICU daily rounds. Conclusions: While explicitly stated in the formal document, it is worth repeating that the guidelines are directed toward generalized patient populations, but as with any therapeutic intervention in the ICU, nutrition therapy should be tailored to the individual patient. In addition, protocols and procedures should reflect the local institutional culture and meet with approval of critical care clinicians. C1 [Warren, Malissa] Portland VA Med Ctr, Portland, OR USA. [McCarthy, Mary S.] Madigan Army Med Ctr, Ctr Nursing Sci & Clin Inquiry, 9040 Jackson Ave, Tacoma, WA 98431 USA. [Roberts, Pamela R.] Univ Oklahoma, Coll Med, Dept Anesthesiol, Oklahoma City, OK 73190 USA. RP McCarthy, MS (reprint author), Madigan Army Med Ctr, Ctr Nursing Sci & Clin Inquiry, 9040 Jackson Ave, Tacoma, WA 98431 USA. EM Mary.s.mccarthy1.civ@mail.mil NR 70 TC 2 Z9 2 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0884-5336 EI 1941-2452 J9 NUTR CLIN PRACT JI Nutr. Clin. Pract. PD JUN PY 2016 VL 31 IS 3 BP 334 EP 341 DI 10.1177/0884533616640451 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DM4CW UT WOS:000376294200007 PM 27072854 ER PT J AU Robinson, L Aldridge, V Clark, EM Misra, M Micali, N AF Robinson, L. Aldridge, V. Clark, E. M. Misra, M. Micali, N. TI A systematic review and meta-analysis of the association between eating disorders and bone density SO OSTEOPOROSIS INTERNATIONAL LA English DT Review DE Anorexia nervosa; Bone; Bone density; Bulimia nervosa; Eating disorder; Osteoporosis ID TRABECULAR STRUCTURE-ANALYSIS; ANOREXIA-NERVOSA; MINERAL DENSITY; ADOLESCENT GIRLS; YOUNG-WOMEN; BULIMIA-NERVOSA; DISTAL RADIUS; WEIGHT-GAIN; VOLUME CT; MASS AB This meta-analysis investigates the effect of an eating disorder on bone mineral density in two eating disorder subtypes. Following conflicting findings in previous literature, this study finds that not only anorexia nervosa, but also bulimia nervosa has a detrimental effect on BMD. Key predictors of this relationship are discussed. This systematic review and meta-analysis investigates bone mineral density (BMD) in individuals with anorexia nervosa (AN) and bulimia nervosa (BN) in comparison to healthy controls (HCs). AN has been associated with low BMD and a risk of fractures and mixed results have been obtained for the relationship between BN and BMD. Deciphering the effect these two ED subtypes on BMD will determine the effect of low body weight (a characteristic of AN) versus the effects of periods of restrictive eating and malnutrition which are common to both AN and BN. We conducted a systematic search through the electronic databases MedLine, EMBASE and PsychInfo and the Cochrane Library to investigate and quantify this relationship. We screened 544 articles and included 27 studies in a random-effect meta-analysis and calculated the standardised mean difference (SMD) in BMD between women with a current diagnosis of AN (n = 785) vs HCs (n = 979) and a current diagnosis of BN (n = 187) vs HCs (n = 350). The outcome measures investigated were spinal, hip, femoral neck and whole body BMD measured by DXA or DPA scanning. A meta-regression investigated the effect of factors including age, duration since diagnosis, duration of amenorrhea and BMI on BMD. The mean BMI of participants was 16.65 kg/m(2) (AN), 21.16 kg/m(2) (BN) and 22.06 kg/m(2) (HC). Spine BMD was lowest in AN subjects (SMD, -3.681; 95 % CI, -4.738, -2.625; p < 0.0001), but also lower in BN subjects compared with HCs (SMD, -0.472; 95 % CI, -0.688, -0.255; p < 0.0001). Hip, whole body and femoral neck BMD were reduced to a statistically significant level in AN but not BN groups. The meta-regression was limited by the number of included studies and did not find any significant predictors. This meta-analysis confirms the association between low BMD and AN and presents a strong argument for assessing BMD not only in patients with AN, but also in patients with BN. C1 [Robinson, L.; Aldridge, V.; Micali, N.] UCL, Inst Child Hlth, Gower St, London WC1E 6BT, England. [Clark, E. M.] Univ Bristol, Musculoskeletal Res Unit, Bristol, Avon, England. [Misra, M.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Micali, N.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. RP Robinson, L (reprint author), UCL, Inst Child Hlth, Gower St, London WC1E 6BT, England. EM Lauren.robinson.14@ucl.ac.uk NR 64 TC 3 Z9 3 U1 10 U2 13 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUN PY 2016 VL 27 IS 6 BP 1953 EP 1966 DI 10.1007/s00198-015-3468-4 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM1JE UT WOS:000376100700002 PM 26782684 ER PT J AU Chhatwal, J He, TH Lopez-Olivo, MA AF Chhatwal, Jagpreet He, Tianhua Lopez-Olivo, Maria A. TI Systematic Review of Modelling Approaches for the Cost Effectiveness of Hepatitis C Treatment with Direct-Acting Antivirals SO PHARMACOECONOMICS LA English DT Review ID GENOTYPE 1 INFECTION; PEGYLATED INTERFERON-ALPHA; VIRUS-INFECTION; UNITED-STATES; UNTREATED PATIENTS; TRIPLE THERAPY; PROTEASE INHIBITORS; NATIONAL-HEALTH; PLUS RIBAVIRIN; SOFOSBUVIR AB New direct-acting antivirals (DAAs) are highly effective for hepatitis C virus (HCV) treatment. However, their prices have been widely debated. Decision-analytic models can project the long-term value of HCV treatment. Therefore, understanding of the methods used in these models and how they could influence results is important. Our objective was to describe and systematically review the methodological approaches in published cost-effectiveness models of chronic HCV treatment with DAAs. We searched several electronic databases, including Medline, Embase and EconLit, from 2011 to 2015. Study selection was performed by two reviewers independently. We included any cost-effectiveness analysis comparing DAAs with the old standard of care for HCV treatment. We excluded non-English-language studies and studies not reporting quality-adjusted life-years. One reviewer collected data and assessed the quality of reporting, using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Another reviewer crosschecked the abstracted information. The development methods of the included studies were synthetized on the basis of good modelling practice recommendations. Review of 304 citations revealed 36 cost-effectiveness analyses. The reporting quality scores of most articles were rated as acceptable, between 67 and 100 %. The majority of the studies were conducted in Europe (50 %), followed by the USA (44 %). Fifty-six percent of the 36 studies evaluated the cost effectiveness of HCV treatment in both treatment-naive and treatment-experienced patients, 97 % included genotype 1 patients and 53 % evaluated the cost effectiveness of second-generation or oral DAAs in comparison with the previous standard of care or other DAAs. Twenty-one models defined health states in terms of METAVIR fibrosis scores. Only one study used a discrete-event simulation approach, and the remainder used state-transition models. The time horizons varied; however, 89 % of studies used a lifetime horizon. One study was conducted from a societal perspective. Thirty-three percent of studies did not conduct any model validation. We also noted that none of the studies modelled HCV treatment as a prevention strategy, 86 % of models did not consider the possibility of re-infection with HCV after successful treatment, 97 % of studies did not consider indirect economic benefits resulting from HCV treatment and none of the studies evaluating oral DAAs used real-world data. The search was limited by date (from 1 January 2011 to 8 September 2015) and was also limited to English-language and published reports. Most modelling studies used a similar modelling structure and could have underestimated the value of HCV treatment. Future modelling efforts should consider the benefits of HCV treatment in preventing transmission, extra-hepatic and indirect economic benefits of HCV treatment, real-world cost-effectiveness analysis and cost effectiveness of HCV treatment in low- and middle-income countries. C1 [Chhatwal, Jagpreet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [He, Tianhua] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China. [Lopez-Olivo, Maria A.] Univ Texas MD Anderson Canc Ctr, Dept Gen Internal Med, Houston, TX 77030 USA. RP Chhatwal, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM jagchhatwal@mgh.harvard.edu NR 65 TC 4 Z9 5 U1 5 U2 12 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1170-7690 EI 1179-2027 J9 PHARMACOECONOMICS JI Pharmacoeconomics PD JUN PY 2016 VL 34 IS 6 BP 551 EP 567 DI 10.1007/s40273-015-0373-9 PG 17 WC Economics; Health Care Sciences & Services; Health Policy & Services; Pharmacology & Pharmacy SC Business & Economics; Health Care Sciences & Services; Pharmacology & Pharmacy GA DM1KS UT WOS:000376104800003 PM 26748919 ER PT J AU Miller, RE Sweeney, CJ AF Miller, R. E. Sweeney, C. J. TI Chemotherapy for metastatic castrate-sensitive prostate cancer SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Review ID ANDROGEN-DEPRIVATION THERAPY; PHASE-III TRIAL; GETUG-AFU 15; CHEMOHORMONAL THERAPY; ESTRAMUSTINE PHOSPHATE; INCREASED SURVIVAL; CROSS-RESISTANCE; DOCETAXEL; ABIRATERONE; CARCINOMA AB BACKGROUND: The role of docetaxel chemotherapy in combination with androgen deprivation therapy for metastatic castrate sensitive prostate cancer is emerging. METHODS: We reviewed the results from the pivotal randomized phase III trials in this area: GETUG15, CHAARTED and STAMPEDE. RESULTS: All three studies demonstrated a benefit in progression-free survival with the use of docetaxel. However, two of the studies demonstrated a clinically meaningful overall survival benefit (CHAARTED and STAMPEDE), whereas the GETUG15 study did not demonstrate a major benefit. CONCLUSIONS: Docetaxel is an important option to consider for men who are fit for chemotherapy with newly diagnosed metastatic prostate cancer commencing androgen deprivation therapy. C1 [Miller, R. E.] Univ Coll London Hosp, Dept Med Oncol, London, England. [Sweeney, C. J.] Dana Farber Canc Inst, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. RP Sweeney, CJ (reprint author), Dana Farber Canc Inst, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. EM Christopher_Sweeney@DFCI.HARVARD.EDU NR 40 TC 0 Z9 0 U1 1 U2 5 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 JUN PY 2016 VL 19 IS 2 BP 139 EP 144 DI 10.1038/pcan.2016.10 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DL8MO UT WOS:000375896300004 PM 26976365 ER PT J AU Sevcenco, S Mathieu, R Baltzer, P Klatte, T Fajkovic, H Seitz, C Karakiewicz, PI Roupret, M Rink, M Kluth, L Trinh, QD Loidl, W Briganti, A Scherr, DS Shariat, SF AF Sevcenco, S. Mathieu, R. Baltzer, P. Klatte, T. Fajkovic, H. Seitz, C. Karakiewicz, P. I. Roupret, M. Rink, M. Kluth, L. Trinh, Q-D Loidl, W. Briganti, A. Scherr, D. S. Shariat, S. F. TI The prognostic role of preoperative serum C-reactive protein in predicting the biochemical recurrence in patients treated with radical prostatectomy SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID CANCER RECURRENCE; 10-YEAR PROBABILITY; FREE SURVIVAL; ASSOCIATION; BIOMARKERS; LEVEL; CRP AB BACKGROUND: To assess the prognostic value of preoperative C-reactive protein (CRP) serum levels for prognostication of biochemical recurrence (BCR) after radical prostatectomy (RP) in a large multi-institutional cohort. METHODS: Data from 7205 patients treated with RP at five institutions for clinically localized prostate cancer (PCa) were retrospectively analyzed. Preoperative serum levels of CRP within 24 h before surgery were evaluated. A CRP level >= 0.5 mg dl(-1) was considered elevated. Associations of elevated CRP with BCR were evaluated using univariable and multivariable Cox proportional hazards regression models. Harrel's C-index was used to assess prognostic accuracy (PA). RESULTS: Patients with higher Gleason score on biopsy and RP, extracapsular extension, seminal vesicle invasion, lymph node metastasis, and positive surgical margins status had a significantly elevated preoperative CRP compared to those without these features. Patients with elevated CRP had a lower 5-year BCR survival proportion as compared to those with normal CRP (55% vs 76%, respectively, P < 0.0001). In pre- and postoperative multivariable models that adjusted for standard clinical and pathologic features, elevated CRP was independently associated with BCR (P < 0.001). However, the addition of preoperative CRP did not improve the accuracy of the standard pre- and postoperative models for prediction of BCR (70.9% vs 71% and 78.9% vs 78.7%, respectively). CONCLUSIONS: Preoperative CRP is elevated in patients with pathological features of aggressive PCa and BCR after RP. While CRP has independent prognostic value, it does not add prognostically or clinically significant information to standard predictors of outcomes. C1 [Sevcenco, S.; Mathieu, R.; Klatte, T.; Fajkovic, H.; Seitz, C.; Shariat, S. F.] Med Univ Vienna, Gen Hosp, Dept Urol, A-1090 Vienna, Austria. [Mathieu, R.] Rennes Univ Hosp, Dept Urol, Rennes, France. [Baltzer, P.] Med Univ Vienna, Dept Biomed Imaging & Image gUided Therapy, A-1090 Vienna, Austria. [Karakiewicz, P. I.] Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, Montreal, PQ, Canada. [Roupret, M.] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, Acad Dept Urol,Fac Med Pierre & Marie, Paris, France. [Rink, M.; Kluth, L.] Univ Med Ctr Hamburg Eppendorf, Dept Urol, Hamburg, Germany. [Trinh, Q-D] Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA. [Trinh, Q-D] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Surg,Div Urol,Med Sch, Boston, MA 02115 USA. [Loidl, W.] Krankenhaus Barmherzigen Schwestern, Dept Urol, Linz, Austria. [Briganti, A.] Univ Vita Salute San Raffaele, Urol Res Inst, San Raffaele Sci Inst, Milan, Italy. [Scherr, D. S.; Shariat, S. F.] Weill Cornell Med Coll, Dept Urol, New York, NY USA. [Shariat, S. F.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. RP Shariat, SF (reprint author), Med Univ Vienna, Vienna Gen Hosp, Dept Urol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.; Shariat, SF (reprint author), Med Univ Vienna, Vienna Gen Hosp, Ctr Comprehens Canc, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM shahrokh.shariat@meduniwien.ac.at OI Baltzer, Pascal/0000-0002-3755-5398 FU scholarship foundation of the Republic of Austria-OeAD; EUSP Scholarship-European Association of Urology FX RM is supported by the scholarship foundation of the Republic of Austria-OeAD and by the EUSP Scholarship-European Association of Urology. NR 28 TC 0 Z9 0 U1 0 U2 4 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 JUN PY 2016 VL 19 IS 2 BP 163 EP 167 DI 10.1038/pcan.2015.60 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DL8MO UT WOS:000375896300007 PM 26810014 ER PT J AU Sanchez, A Schoenfeld, JD Nguyen, PL Fiorentino, M Chowdhury, D Stampfer, MJ Sesso, HD Giovannucci, E Mucci, LA Shui, IM AF Sanchez, A. Schoenfeld, J. D. Nguyen, P. L. Fiorentino, M. Chowdhury, D. Stampfer, M. J. Sesso, H. D. Giovannucci, E. Mucci, L. A. Shui, I. M. TI Common variation in BRCA1 may have a role in progression to lethal prostate cancer after radiation treatment SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE NUCLEOTIDE POLYMORPHISMS; DNA-REPAIR; RADICAL PROSTATECTOMY; MISSENSE MUTATIONS; RADIOTHERAPY; THERAPY; VARIANTS; RISK; GENE AB BACKGROUND: To evaluate whether single-nucleotide polymorphisms (SNPs) reflecting common variation in the tumor suppressor BRCA1 affect prostate cancer outcomes. Because radiation therapy (RT) induces DNA damage, we hypothesized that common variation in BRCA1 has a role in progression to lethal prostate cancer, particularly in patients receiving RT. METHODS: We followed 802 men diagnosed with localized prostate cancer (cT1-T3/N0/M0) who were treated with RT in the US Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS), for progression to lethal prostate cancer. Six SNPs (rs3737559, rs1799950, rs799923, rs915945, rs4474733 and rs8176305) were genotyped in HPFS to capture common variation across BRCA1. rs4474733 and rs8176305 were also evaluated in the PHS cohort. Cox proportional hazards models were used to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) stratified by primary treatment. RESULTS: In the RT group (n=802), 71 men progressed to lethal disease during a mean follow-up of 12 years. We found that two SNPs, rs4473733 (HR: 0.65; 95% CI 0.42-0.99) and rs8176305 (HR: 2.03; 95% CI 1.33-3.10), were associated with lethal prostate cancer in men receiving RT. CONCLUSIONS: Common variation in BRCA1 may influence clinical outcomes in patients receiving RT for localized prostate cancer by modifying the response to RT. Our findings merit further follow-up studies to validate these SNPs and better understand their functional and biological significance. C1 [Sanchez, A.] Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,GRB1102, Boston, MA 02114 USA. [Schoenfeld, J. D.; Nguyen, P. L.; Chowdhury, D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Fiorentino, M.; Stampfer, M. J.; Sesso, H. D.; Giovannucci, E.; Mucci, L. A.; Shui, I. M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, M. J.; Giovannucci, E.; Mucci, L. A.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Stampfer, M. J.; Sesso, H. D.; Giovannucci, E.; Mucci, L. A.] Harvard Univ, Sch Med, Boston, MA USA. [Stampfer, M. J.; Sesso, H. D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Shui, I. M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP Sanchez, A (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,GRB1102, Boston, MA 02114 USA. EM asanchez6@partners.org FU US Army Prostate Cancer Program Idea Development Award; Department of Defense Prostate Cancer Research Program post-doctoral training award; Prostate Cancer Foundation; anonymous family foundation; [T32 CA-09001]; [CA34944]; [CA40360]; [CA097193]; [HL26490]; [HL34595]; [CA133891]; [CA141298]; [P01CA055075]; [UM1 CA167552] FX We are grateful to the participants and staff of the HPFS and PHS cohorts for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The Dana-Farber/Harvard Center Genotyping Core Facility performed the genotyping for this project. The authors assume full responsibility for analyses and interpretation of these data. This project was supported by the US Army Prostate Cancer Program Idea Development Award. IMS supported by (T32 CA-09001) and a Department of Defense Prostate Cancer Research Program post-doctoral training award. PLN was supported by a grant from an anonymous family foundation and LAM and PLN are supported by the Prostate Cancer Foundation. PHS was supported by grants CA34944, CA40360, CA097193, HL26490 and HL34595. HPFS was supported by grants CA133891, CA141298, and P01CA055075 and UM1 CA167552. NR 31 TC 0 Z9 0 U1 2 U2 5 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 JUN PY 2016 VL 19 IS 2 BP 197 EP 201 DI 10.1038/pcan.2016.4 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DL8MO UT WOS:000375896300013 PM 26926928 ER PT J AU Stark, AP Sacks, GD Rochefort, MM Donahue, TR Reber, HA Tomlinson, JS Dawson, DW Eibl, G Hines, OJ AF Stark, Alexander P. Sacks, Greg D. Rochefort, Matthew M. Donahue, Timothy R. Reber, Howard A. Tomlinson, James S. Dawson, David W. Eibl, Guido Hines, O. Joe TI Long-term survival in patients with pancreatic ductal adenocarcinoma SO SURGERY LA English DT Article ID PROGNOSTIC-FACTORS; 5-YEAR SURVIVORS; CURATIVE RESECTION; CLINICOPATHOLOGICAL ANALYSIS; PERINEURAL INVASION; SURGICAL RESECTION; TUMOR GRADE; CANCER; SURGERY; IMPACT AB Background. Long-term survival (LTS) is uncommon for patients with pancreatic ductal adenocarcinoma (PDAC). We sought to identify factors that predict 10-year, LTS after resection of PDAC. Methods. We identified all patients with PDAC who underwent resection at UCLA after 1990 and included all patients eligible for observed LTS (1/1/1990-12/31/2004). An independent pathologist reconfirmed the diagnosis of PDAC in patients with LTS. Logistic regression was used to predict LTS on the basis of patient and tumor characteristics. Results. Of 173 included patients, 53% were male, median age at diagnosis was 66 years, and median survival was 23 months. The rate of observed LTS was 12.1 % (n = 21). Age, sex, number of lymph nodes evaluated, margin status, lymphovascular invasion, and adjuvant chemotherapy and radiation were not associated with LTS. The following were associated with LTS on bivariate analysis: low AJCC stage (Ia, Ib, IIa) (P = .034), negative lymph node status (P = .034), low grade (well-, moderately-differentiated) (P = .001), and absence of perineural invasion (P = .019). Only low grade (odds ratio 7.17, P = .012) and absent perineural invasion (odds ratio 3.28, P = .036) were independently associated with increased odds of LTS. Our multivariate model demonstrated good discriminatory power for LTS, as indicated by a c-statistic of 0.7856. Conclusion. Absence of perineural invasion and low tumor grade were associated with greater likelihood of LTS. Understanding the tumor biology of LTS may provide critical insight into a disease that is typically marked by aggressive behavior and limited survival. C1 [Stark, Alexander P.; Sacks, Greg D.; Rochefort, Matthew M.; Donahue, Timothy R.; Reber, Howard A.; Tomlinson, James S.; Eibl, Guido; Hines, O. Joe] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Dawson, David W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Sacks, Greg D.; Rochefort, Matthew M.; Tomlinson, James S.] Greater Los Angeles VA Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Hines, OJ (reprint author), 10833 Le Conte Ave,72-180 CHS, Los Angeles, CA 90095 USA. EM joehines@mednet.ucla.edu OI Stark, Alexander/0000-0001-8463-5414; Dawson, Warrick/0000-0003-0050-6717 FU NCI NIH HHS [P01 CA163200]; NIDDK NIH HHS [P30 DK041301] NR 38 TC 0 Z9 0 U1 4 U2 5 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 JUN PY 2016 VL 159 IS 6 BP 1520 EP 1527 DI 10.1016/j.surg.2015.12.024 PG 8 WC Surgery SC Surgery GA DL8KH UT WOS:000375890400004 PM 26847803 ER PT J AU Romo, RD Wallhagen, MI Smith, AK AF Romo, Rafael D. Wallhagen, Margaret I. Smith, Alexander K. TI Viewing Hospice Decision Making as a Process SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Review DE hospice; end-of-life care; prognosis; communication; decision making; older adults ID END-OF-LIFE; EARLY PALLIATIVE CARE; CELL LUNG-CANCER; TREATMENT PREFERENCES; RACIAL-DIFFERENCES; SUSTAINING TREATMENT; PATIENT PREFERENCES; ADULTS PREFERENCES; SPIRITUAL SUPPORT; ADVANCED ILLNESS AB Research focused on understanding that the nature of hospice decision making has both described the characteristics of those who do and do not utilize hospice and identified many factors related to choosing hospice. However, this literature has not explored the underlying decision-making processes, limiting our understanding. We examine the extant literature and propose a framework that views hospice decisions as an evolving process, identify key factors that bear directly on this process, and discuss the contextual environment, including the idea of a decision maker triad. We end with a discussion of how this framework can be used to support clinical practice and future research. Our goal is to provide a framework from which to understand the end-of-life needs of all patients, no matter where they receive care. C1 [Romo, Rafael D.; Wallhagen, Margaret I.] Univ Calif San Francisco, Sch Nursing, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Romo, Rafael D.; Smith, Alexander K.] San Francisco Vet Affair Med Ctr, Geriatr Palliat & Extended Care, San Francisco, CA USA. [Smith, Alexander K.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. RP Romo, RD (reprint author), San Francisco VA Med Ctr, 4150 Clement St 181G, San Francisco, CA 94121 USA. EM rafael.romo@ucsf.edu FU John A. Hartford Foundation/Building Academic Geriatric Nursing Capacity scholarship FX The authors disclose receipt of the following financial support for the research, authorship and/or publication of this article: John A. Hartford Foundation/Building Academic Geriatric Nursing Capacity scholarship. NR 74 TC 1 Z9 1 U1 1 U2 5 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 JUN PY 2016 VL 33 IS 5 BP 503 EP 510 DI 10.1177/1049909115569592 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DL7RG UT WOS:000375837200014 PM 25635114 ER PT J AU Zeitels, SM AF Zeitels, Steven M. TI Glottic Cancer: A Metamorphosing Disease SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE glottic cancer; glottal cancer; smoking; vocal cord; vocal fold; HPV; KTP laser ID KTP LASER TREATMENT; CARCINOMA; ALCOHOL; TOBACCO AB Objective: Conventional wisdom is that the overwhelming majority of glottic cancer patients have a smoking history. However, in recent years observations suggested that an increasing number of glottic cancer patients had never been smokers. Therefore, an investigation was done examining the incidence of having a smoking history in a recent cohort of glottic cancer patients. Method: Retrospective review of 100 patients with glottic cancer to determine those reporting never having smoked. Results: Thirty-one of 100 did not have a smoking history. Clinical observations of those cases revealed that the disease morphology tended to be exophytic, papillary, and very vascular, often resembling recurrent respiratory papillomatosis (RRP). Remarkably, 2 of 31 were initially treated elsewhere assuming they had RRP and underwent 5 cidofovir injections. Both presented with advanced cancer, and the disease growth markedly accelerated coincident with the injections. Conclusions: Observations herein provide new insights that glottic cancer may be an evolving disease in which smoking is less exclusive, not unlike HPV-induced pharynx cancer. Similar to RRP, the angiogenic papillary disease morphology is well suited for voice-preserving angiolytic KTP laser treatment. Given the resemblance of some glottic cancers to RRP, great care should be taken when using cidofovir for papillary glottic neoplasms. C1 [Zeitels, Steven M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Zeitels, Steven M.] Massachusetts Gen Hosp, Div Laryngeal Surg, Boston, MA 02114 USA. RP Zeitels, SM (reprint author), Massachusetts Gen Hosp, Voice Ctr, One Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM zeitels.steven@mgh.harvard.edu FU Voice Health Institute; National Philanthropic Trust; Eugene B. Casey Foundation 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 by the nonprofit Voice Health Institute, National Philanthropic Trust, and the Eugene B. Casey Foundation. NR 20 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JUN PY 2016 VL 125 IS 6 BP 452 EP 456 DI 10.1177/0003489415619177 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA DL7RA UT WOS:000375836600002 PM 26611243 ER PT J AU Naunheim, MR Remenschneider, AK Scangas, GA Bunting, GW Deschler, DG AF Naunheim, Matthew R. Remenschneider, Aaron K. Scangas, George A. Bunting, Glenn W. Deschler, Daniel G. TI The Effect of Initial Tracheoesophageal Voice Prosthesis Size on Postoperative Complications and Voice Outcomes SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE total laryngectomy; tracheoesophageal puncture; voice prosthesis; voice restoration; TEP; TEVR ID TOTAL LARYNGECTOMY; VOCAL REHABILITATION; PUNCTURE; RESTORATION; EXPERIENCE; PLACEMENT; LEAKAGE; TIME AB Objectives: The optimal initial size of tracheoesophageal voice prosthesis (TEVP) for tracheoesophageal voice restoration (TEVR) remains unclear. As purported advantages exist favoring the placement of both 16F and 20F prostheses, this study compares complications and voicing outcomes after placement of 16 and 20 French (F) prostheses. Methods: All cases of TEVR at an academic medical center were retrospectively reviewed (2007-2013). Complications including dislodgement, leakage, infection, and granulation tissue were compared. Outcomes including frequency of prosthesis change, acquisition of speech, and time to fluent speech were compared. Results: Of 47 patients, 25 received 20F prostheses, and 22 received 16F. Postoperative complications were similar between groups, including leakage around the prosthesis (P = .373) and aspiration pneumonia (P = .670). There were no significant differences in timing of voicing or ability to achieve fluency. Although the 20F group appeared to undergo fewer prostheses changes per year (3.0 vs 5.3) and had a longer duration of use before first prosthesis change (76 vs 43 days), neither difference was found to be statistically significant. Conclusion: Voice restoration was successfully achieved using either 16F or 20F prostheses. Prosthesis diameter did not significantly affect complications or voicing. Both prostheses may be placed with safety and efficacy, allowing the practitioner to choose based on the potential individual benefits of either device. C1 [Naunheim, Matthew R.; Remenschneider, Aaron K.; Scangas, George A.; Bunting, Glenn W.; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Naunheim, Matthew R.; Remenschneider, Aaron K.; Scangas, George A.; Bunting, Glenn W.; Deschler, Daniel G.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Naunheim, MR (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Matthew_Naunheim@meei.harvard.edu NR 30 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JUN PY 2016 VL 125 IS 6 BP 478 EP 484 DI 10.1177/0003489415620426 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA DL7RA UT WOS:000375836600006 PM 26658068 ER PT J AU Muindi, F Kenny, JD Taylor, NE Solt, K Wilson, MA Brown, EN Van Dort, CJ AF Muindi, Fanuel Kenny, Jonathan D. Taylor, Norman E. Solt, Ken Wilson, Matthew A. Brown, Emery N. Van Dort, Christa J. TI Electrical stimulation of the parabrachial nucleus induces reanimation from isoflurane general anesthesia SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article ID THERMOSENSORY PATHWAY; EMERGENCE; NEURONS; RAT; METHYLPHENIDATE; ACTIVATION; RESPONSES; AROUSAL; SLEEP AB Clinically, emergence from general anesthesia is viewed as a passive process where anesthetics are discontinued at the end of surgery and anesthesiologists wait for the drugs to wear off. The mechanisms involved in emergence are not well understood and there are currently no drugs that can actively reverse the state of general anesthesia. An emerging hypothesis states that brain regions that control arousal become active during emergence and are a key part of the return to wakefulness. In this study, we tested the hypothesis that electrical activation of the glutamatergic parabrachial nucleus (PBN) in the brainstem is sufficient to induce reanimation (active emergence) during continuous isoflurane general anesthesia. Using c-Fos immunohistochemistry as a marker of neural activity, we first show a selective increase in active neurons in the PBN during passive emergence from isoflurane anesthesia. We then electrically stimulated the PBN to assess whether it is sufficient to induce reanimation from isoflurane general anesthesia. Stimulation induced behavioral arousal and restoration of the righting reflex during continuous isoflurane general anesthesia. In contrast, stimulation of the nearby central inferior colliculus (CIC) did not restore the righting reflex. Spectral analysis of the electroencephalogram (EEG) revealed that stimulation produced a significant decrease in EEG delta power during PBN stimulation. The results are consistent with the hypothesis that the PBN provides critical arousal input during emergence from isoflurane anesthesia. (C) 2016 Published by Elsevier B.V. C1 [Muindi, Fanuel; Kenny, Jonathan D.; Taylor, Norman E.; Solt, Ken; Wilson, Matthew A.; Brown, Emery N.; Van Dort, Christa J.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Kenny, Jonathan D.; Taylor, Norman E.; Solt, Ken; Brown, Emery N.; Van Dort, Christa J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Muindi, Fanuel; Wilson, Matthew A.; Brown, Emery N.; Van Dort, Christa J.] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Muindi, F (reprint author), MIT, 43 Vassar St, Cambridge, MA 02446 USA.; Van Dort, CJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 77 Massachusetts Ave,46-5227, Cambridge, MA 02139 USA. EM fmuindi@mit.edu; vandortc@mit.edu OI Kenny, Jonathan/0000-0003-3745-3217; Solt, Ken/0000-0001-5328-2062 FU NIH [TR01-GM104948] FX We would like to thank Daniel Zachs, Michael Nolan, Rachel Cuozzo, JunZhu Pei, Jake Bamberger, and other members of the Wilson and Brown labs for support and valuable discussions on the research project. This study was supported by NIH Grant TR01-GM104948 (to E.N.B. and M.A.W.). NR 24 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUN 1 PY 2016 VL 306 BP 20 EP 25 DI 10.1016/j.bbr.2016.03.021 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DL3DG UT WOS:000375513800004 PM 26971629 ER PT J AU Tinay, I Gelpi-Hammerschmidt, F Leow, JJ Allard, CB Rodriguez, D Wang, Y Chung, BI Chang, SL AF Tinay, Ilker Gelpi-Hammerschmidt, Francisco Leow, Jeffrey J. Allard, Christopher B. Rodriguez, Dayron Wang, Ye Chung, Benjamin I. Chang, Steven L. TI Trends in utilisation, perioperative outcomes, and costs of nephroureterectomies in the management of upper tract urothelial carcinoma: a 10-year population-based analysis SO BJU INTERNATIONAL LA English DT Article DE nephroureterectomy; upper urinary tract carcinoma; trend; utilisation; outcome ID LAPAROSCOPIC NEPHROURETERECTOMY; ONCOLOGIC OUTCOMES; CLASSIFICATION; COMPLICATIONS; DISEASE; SURGERY; PATIENT; CANCER; COHORT; STATES AB Objective To perform a population-based study to evaluate contemporary utilisation trends, morbidity, and costs associated with nephroureterectomies (NUs), as contemporary data for NUs are largely derived from single academic institution series describing the experience of high-volume surgeons and it is unclear if the same favourable results occur at a national level. Patients and Methods Using the Premier Hospital Database, we captured patients undergoing a NU with diagnoses of renal pelvis or ureteric neoplasms from 2004 to 2013. We fitted regression models, adjusting for clustering by hospitals and survey weighting to evaluate 90-day postoperative complications, operating-room time (OT), prolonged length of stay (pLOS), and direct hospital costs among open (ONU), laparoscopic (LNU) and robotic (RNU) approaches. Results After applying sampling and propensity weights, we derived a final study cohort of 17 254 ONUs, 13 317 LNUs and 3774 RNUs for upper tract urothelial carcinoma (UTUC) in the USA between 2004 and 2013. During that period, minimally invasive NU (miNU) increased from 36% to 54%, while the total number of NUs decreased by nearly 20%. No differences were noted in perioperative outcomes between the three surgical approaches, including when the analysis was restricted to the highest-volume hospitals and highest-volume surgeons. The OT was longer for LNU and RNU (P < 0.001), while the pLOS rates were decreased (P < 0.001). Adjusted 90-day median direct hospital costs were higher for LNU and RNU (P < 0.001), which disappeared when adjusting for the highest-volume groups, except for RNUs performed by high-volume surgeons. Conclusions During this contemporary 10-year study, miNU has been replacing ONU for UTUC with a recent surge in RNU, along with a concurrent reduction in total NUs performed. Despite not being associated with a clinically significant improvement in perioperative outcomes, the costs for miNUs were consistently higher. However, higher hospital volumes suggest a potential cost containment strategy when performing miNUs. C1 [Tinay, Ilker; Gelpi-Hammerschmidt, Francisco; Allard, Christopher B.; Chang, Steven L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. [Leow, Jeffrey J.; Wang, Ye; Chang, Steven L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Gelpi-Hammerschmidt, Francisco; Allard, Christopher B.; Rodriguez, Dayron] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Chung, Benjamin I.] Stanford Univ, Med Ctr, Dept Urol, Stanford, CA 94305 USA. [Tinay, Ilker] Marmara Univ, Sch Med, Dept Urol, Istanbul, Turkey. [Leow, Jeffrey J.] Tan Tock Seng Hosp, Dept Urol, Singapore, Singapore. RP Tinay, I (reprint author), Brigham & Womens Hosp, Div Urol, 45 Francis St, Boston, MA 02115 USA. EM itinay@marmara.edu.tr OI Leow, Jeffrey/0000-0002-6216-1913 NR 25 TC 2 Z9 2 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD JUN PY 2016 VL 117 IS 6 BP 954 EP 960 DI 10.1111/bju.13375 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DM0CI UT WOS:000376009800021 PM 26573216 ER PT J AU McCarthy, A Asghar, S Wilens, T Romo, S Kamin, H Jellinek, M Murphy, M AF McCarthy, Alyssa Asghar, Sunna Wilens, Timothy Romo, Stephanie Kamin, Hayley Jellinek, Michael Murphy, Michael TI Using a Brief Parent-Report Measure to Track Outcomes for Children and Teens with ADHD SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Child psychiatry; Pediatrics; Attention deficit disorder with hyperactivity; Outcome assessment ID ATTENTION-DEFICIT/HYPERACTIVITY-DISORDER; DEFICIT-HYPERACTIVITY DISORDER; ASSESSMENT SCALE CGAS; MENTAL-HEALTH; RATING-SCALE; CONTROLLED-TRIAL; FOLLOW-UP; BPRS-C; PSYCHOTHERAPY; ADOLESCENTS AB The Pediatric Symptom Checklist (PSC) is a widely used, parent-completed measure of children's emotional and behavioral functioning. Previous research has shown that the PSC and its subscales are responsive to patient progress over the course of psychiatric treatment. In this naturalistic study, parents and clinicians of 1736 patients aged 17 or younger completed standardized measures at intake and 3-month follow-up appointments. We assessed the 5-item PSC Attention Subscale (PSC-AS) as a longitudinal measure of attention-related symptoms in routine outpatient psychiatry treatment. Secondarily, we compared PSC-AS scores with clinician-reported diagnoses, psychomotor excitation symptoms, and overall functioning. Change scores on the PSC-AS were larger among patients with ADHD diagnoses than those with non-ADHD diagnoses. Comparisons between PSC-AS scores and clinician reports also showed acceptable levels of agreement. Given its effectiveness in tracking attention-related symptoms, the PSC may be particularly useful as a quality assurance or treatment outcome measure for clinicians treating ADHD. C1 [McCarthy, Alyssa] Rutgers State Univ, Dept Psychol, Piscataway, NJ USA. [Asghar, Sunna] Univ Aberdeen, Aberdeen, Scotland. [Wilens, Timothy; Murphy, Michael] Massachusetts Gen Hosp, Child Psychiat Serv, 55 Fruit St,YAW 6A, Boston, MA 02114 USA. [Wilens, Timothy; Jellinek, Michael; Murphy, Michael] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Romo, Stephanie] Shriners Hosp Children, Boston, MA USA. [Kamin, Hayley] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [Jellinek, Michael] Community Network Lahey Hlth, Burlington, MA USA. RP Murphy, M (reprint author), Massachusetts Gen Hosp, Child Psychiat Serv, 55 Fruit St,YAW 6A, Boston, MA 02114 USA.; Murphy, M (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM mmurphy6@partners.org FU Fuss Family Fund FX A portion of the planning and data analysis for this study was made possible by a Grant from the Fuss Family Fund. The support of the Fuss Family Fund is hereby gratefully acknowledged. NR 43 TC 1 Z9 1 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X EI 1573-3327 J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD JUN PY 2016 VL 47 IS 3 BP 407 EP 416 DI 10.1007/s10578-015-0575-6 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DL3WP UT WOS:000375564500006 PM 26271346 ER PT J AU Rahko, JS Vuontela, VA Carlson, S Nikkinen, J Hurtig, TM Kuusikko-Gauffin, S Mattila, ML Jussila, KK Remes, JJ Jansson-Verkasalo, EM Aronen, ET Pauls, DL Ebeling, HE Tervonen, O Moilanen, IK Kiviniemi, VJ AF Rahko, Jukka S. Vuontela, Virve A. Carlson, Synnove Nikkinen, Juha Hurtig, Tuula M. Kuusikko-Gauffin, Sanna Mattila, Marja-Leena Jussila, Katja K. Remes, Jukka J. Jansson-Verkasalo, Eira M. Aronen, Eeva T. Pauls, David L. Ebeling, Hanna E. Tervonen, Osmo Moilanen, Irma K. Kiviniemi, Vesa J. TI Attention and Working Memory in Adolescents with Autism Spectrum Disorder: A Functional MRI Study SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Autism spectrum disorder; Attention; Default mode network; Working memory; Visuospatial ID SCHOOL-AGE-CHILDREN; ASPERGER-SYNDROME; EXECUTIVE FUNCTION; BRAIN ACTIVATION; NEURAL SYSTEMS; BASE-LINE; METAANALYSIS; NETWORKS; FMRI; FACE AB The present study examined attention and memory load-dependent differences in the brain activation and deactivation patterns between adolescents with autism spectrum disorders (ASDs) and typically developing (TD) controls using functional magnetic resonance imaging. Attentional (0-back) and working memory (WM; 2-back) processing and load differences (0 vs. 2-back) were analysed. WM-related areas activated and default mode network deactivated normally in ASDs as a function of task load. ASDs performed the attentional 0-back task similarly to TD controls but showed increased deactivation in cerebellum and right temporal cortical areas and weaker activation in other cerebellar areas. Increasing task load resulted in multiple responses in ASDs compared to TD and in inadequate modulation of brain activity in right insula, primary somatosensory, motor and auditory cortices. The changes during attentional task may reflect compensatory mechanisms enabling normal behavioral performance. The inadequate memory load-dependent modulation of activity suggests diminished compensatory potential in ASD. C1 [Rahko, Jukka S.; Hurtig, Tuula M.; Kuusikko-Gauffin, Sanna; Mattila, Marja-Leena; Jussila, Katja K.; Ebeling, Hanna E.; Moilanen, Irma K.] Univ Oulu, Univ Hosp Oulu, Child Psychiat, PEDEGO Res Unit, POB 5000, Oulu 90014, Finland. [Vuontela, Virve A.; Carlson, Synnove] Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, Brain Res Unit,OV Lounasmaa Lab, Espoo, Finland. [Vuontela, Virve A.; Carlson, Synnove] Univ Helsinki, Dept Physiol, Inst Biomed Physiol, Neurosci Unit,Fac Med, Helsinki, Finland. [Nikkinen, Juha; Remes, Jukka J.; Tervonen, Osmo; Kiviniemi, Vesa J.] Univ & Univ Hosp Oulu, Dept Diagnost Radiol, POB 50, Oulu 90029, Finland. [Hurtig, Tuula M.] Univ Oulu, Univ & Univ Hosp Oulu, Clin Child Psychiat, Inst Hlth Sci, POB 5000, Oulu 90014, Finland. [Jansson-Verkasalo, Eira M.] Univ & Univ Hosp Oulu, Neurocognit Unit, Oulu, Finland. [Aronen, Eeva T.] Univ Helsinki, Cent Hosp, Childrens Hosp, Child Psychiat,Biomedicum 2, Tukholmankatu 8 C 613, FIN-00290 Helsinki, Finland. [Pauls, David L.] Harvard Univ, Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit,Sch Med, 185 Cambridge St, Boston, MA 02114 USA. [Jansson-Verkasalo, Eira M.] Univ Turku, CCN, Dept Behav Sci & Philosophy, Assistentinkatu 7, Turku 20017, Finland. RP Rahko, JS (reprint author), Univ Oulu, Univ Hosp Oulu, Child Psychiat, PEDEGO Res Unit, POB 5000, Oulu 90014, Finland. EM jrahko@me.com; vvuontel@mappi.helsinki.fi; syncarls@cc.helsinki.fi; Juha.Nikkinen@ppshp.fi; tuula.hurtig@oulu.fi; sanna.kuusikkogauffin@gmail.com; marja-leena.mattila@fimnet.fi; katja.jussila@gmail.com; jukka.remes@oulu.fi; eira.jansson-verkasalo@utu.fi; eeva.aronen@helsinki.fi; dpauls@pngu.mgh.harvard.edu; hanna.ebeling@ppshp.fi; osmo.tervonen@ppshp.fi; irma.moilanen@oulu.fi; vesa.kiviniemi@oulu.fi RI Carlson, Synnove/G-2210-2013 FU Alma and K. A. Snellman Foundation, Oulu, Finland; Emil Aaltonen Foundation, Finland; Northern Ostrobothnia Hospital District; Sigrid Juselius Foundation, Finland; Thule Institute, University of Oulu, Finland; Lundbeck Foundation, Turku, Finland; Rinnekoti Research Foundation, Espoo, Finland; Child Psychiatric Research Foundation, Finland; Academy of Finland [117111, 123772, 214412, 259752, 273147]; aivoAALTO project; Paivikki and Sakari Sohlberg Foundation; Finnish Medical Foundation; Graduate School of Circumpolar Wellbeing, Health and Adaptation; National Alliance for Autism Research FX We thank the adolescents and their parents, who graciously gave their time to participate in this study. This study received financial support from the Alma and K. A. Snellman Foundation, Oulu, Finland; the Emil Aaltonen Foundation, Finland; Northern Ostrobothnia Hospital District; the Sigrid Juselius Foundation, Finland; the Thule Institute, University of Oulu, Finland; the Lundbeck Foundation, Turku, Finland; the Rinnekoti Research Foundation, Espoo, Finland; the Child Psychiatric Research Foundation, Finland. This study was also funded by the Academy of Finland (Grants #117111, #123772, #214412, #259752, #273147)], the aivoAALTO project, the Paivikki and Sakari Sohlberg Foundation and Finnish Medical Foundation grants. The Graduate School of Circumpolar Wellbeing, Health and Adaptation is acknowledged for its support. We would also like to thank the National Alliance for Autism Research for financial support granted to David Pauls. For data collection we wish to thank Child Psychiatrist, Ph.D. Sirkka-Liisa Linna and Ph.D. Marko Kielinen. NR 100 TC 0 Z9 0 U1 9 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X EI 1573-3327 J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD JUN PY 2016 VL 47 IS 3 BP 503 EP 517 DI 10.1007/s10578-015-0583-6 PG 15 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DL3WP UT WOS:000375564500014 PM 26323584 ER PT J AU Sharma, S Place, E Lord, K Leroy, BP Falk, MJ Pradhan, M AF Sharma, Sheena Place, Emily Lord, Katherine Leroy, Bart P. Falk, Marni J. Pradhan, Madhura TI Claudin 19-based familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a sibling pair SO CLINICAL NEPHROLOGY LA English DT Article DE CLDN19; hyperinsulinism; renal transplant ID CLDN19 MUTATIONS AB Background: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare, autosomal recessive condition caused by mutations in CLDN16 or CLDN19, which encode for tight junction proteins, claudin-16 and claudin-19, respectively. This condition often has a delayed diagnosis in patients with no prior family history due to a lack of specific clinical symptoms. Description of case, diagnosis, and treatment: A 4-year, 10-month-old Caucasian boy presented with failure to thrive, developmental delay, and ocular findings consisting of horizontal nystagmus, bilateral macular staphylomas, and high myopia. Laboratory studies revealed hypercalciuria, hypomagnesemia, and renal insufficiency. Renal ultrasound showed bilateral small kidneys with medullary nephrocalcinosis. Candidate gene sequencing performed at age 7 years identified a novel, homozygous, frameshift mutation c.140_141delAT (p.Tyr47Stop) within CLDN19, confirming the molecular diagnosis of FHHNC. Due to rapid renal progression, the proband underwent renal transplant at age 10 years, 10 months. FHHNC was prenatally diagnosed in the proband's sister, who was found at birth to have ocular findings and hypomagnesemia. In addition, she had feeding intolerance and persistent hypoglycemia with hyperinsulinism that has required chronic diazoxide therapy. Conclusions: Although rare, FHHNC should be suspected in patients who present with nephrocalcinosis in the setting of congenital eye anomalies. C1 [Sharma, Sheena; Pradhan, Madhura] Childrens Hosp Philadelphia, Div Nephrol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Place, Emily; Falk, Marni J.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Lord, Katherine] Childrens Hosp Philadelphia, Div Endocrinol, Philadelphia, PA 19104 USA. [Leroy, Bart P.] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA. [Lord, Katherine; Falk, Marni J.; Pradhan, Madhura] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Leroy, Bart P.] Univ Penn, Dept Ophthalmol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Place, Emily] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Genom Inst, Boston, MA 02114 USA. [Place, Emily] Harvard Univ, Sch Med, Boston, MA USA. [Leroy, Bart P.] Univ Ghent, Dept Ophthalmol, B-9000 Ghent, Belgium. [Leroy, Bart P.] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Leroy, Bart P.] Ghent Univ Hosp, Ghent, Belgium. RP Sharma, S (reprint author), Childrens Hosp Philadelphia, Div Nephrol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM SharmaS2@email.chop.edu NR 11 TC 0 Z9 0 U1 1 U2 3 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD JUN PY 2016 VL 85 IS 6 BP 346 EP 352 DI 10.5414/CN108783 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DL6OU UT WOS:000375759300007 PM 27007868 ER PT J AU Akeju, O Song, AH Hamilos, AE Pavone, KJ Flores, FJ Brown, EN Purdon, PL AF Akeju, Oluwaseun Song, Andrew H. Hamilos, Allison E. Pavone, Kara J. Flores, Francisco J. Brown, Emery N. Purdon, Patrick L. TI Electroencephalogram signatures of ketamine anesthesia-induced unconsciousness SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE EEG; Unconsciousness; Ketamine; Anesthesia; Slow oscillations; Gamma oscillations ID PARABRACHIAL NUCLEUS; DELTA OSCILLATIONS; SEVOFLURANE; EEG; COHERENCE; PROPOFOL; HUMANS; NMDA; RAT; COMMUNICATION AB Objectives: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist commonly administered as a general anesthetic. However, neural circuit mechanisms to explain ketamine anesthesia-induced unconsciousness in humans are yet to be clearly defined. Disruption of frontal-parietal network connectivity has been proposed as a mechanism to explain this brain state. However, this mechanism was recently demonstrated at subanesthetic doses of ketamine in awake-patients. Therefore, we investigated whether there is an electroencephalogram (EEG) signature specific for ketamine anesthesia-induced unconsciousness. Methods: We retrospectively studied the EEG in 12 patients who received ketamine for the induction of general anesthesia. We analyzed the EEG dynamics using power spectral and coherence methods. Results: Following the administration of a bolus dose of ketamine to induce unconsciousness, we observed a "gamma burst" EEG pattern that consisted of alternating slow-delta (0.1-4 Hz) and gamma (similar to 27-40 Hz) oscillations. This pattern was also associated with increased theta oscillations (similar to 4-8 Hz) and decreased alpha/beta oscillations (similar to 10-24 Hz). Conclusions: Ketamine anesthesia-induced unconsciousness is associated with a gamma burst EEG pattern. Significance: The EEG signature of ketamine anesthesia-induced unconsciousness may offer new insights into NMDA circuit mechanisms for unconsciousness. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Akeju, Oluwaseun; Pavone, Kara J.; Flores, Francisco J.; Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Akeju, Oluwaseun; Hamilos, Allison E.; Flores, Francisco J.; Brown, Emery N.; Purdon, Patrick L.] Harvard Univ, Sch Med, Boston, MA USA. [Song, Andrew H.; Flores, Francisco J.; Brown, Emery N.; Purdon, Patrick L.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Hamilos, Allison E.; Brown, Emery N.] MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, Cambridge, MA 02139 USA. [Hamilos, Allison E.; Brown, Emery N.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Akeju, O (reprint author), 55 Fruit St,Jackson Bldg,Rm 460, Boston, MA 02114 USA. EM oluwaseun.akeju@mgh.harvard.edu OI Flores, Francisco/0000-0002-8974-9717 FU National Institutes of Health, Bethesda, Maryland [DP2-OD006454, DP1-OD003646, TR01-GM104948]; Foundation of Anesthesia Education and Research, Rochester, Minnesota; Massachusetts General Hospital Faculty Development Award, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA FX DP2-OD006454 (to PLP); DP1-OD003646, TR01-GM104948 (to ENB), and Ruth L. Kirchstein National Research Service Award to (AH) from the National Institutes of Health, Bethesda, Maryland; Foundation of Anesthesia Education and Research, Rochester, Minnesota (to OA); Massachusetts General Hospital Faculty Development Award, Boston, MA (to OA); Funds from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA. NR 44 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUN PY 2016 VL 127 IS 6 BP 2414 EP 2422 DI 10.1016/j.clinph.2016.03.005 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DL3YH UT WOS:000375569100017 PM 27178861 ER PT J AU Akeju, O Hamilos, AE Song, AH Pavone, KJ Purdon, PL Brown, EN AF Akeju, Oluwaseun Hamilos, Allison E. Song, Andrew H. Pavone, Kara J. Purdon, Patrick L. Brown, Emery N. TI GABAA circuit mechanisms are associated with ether anesthesia-induced unconsciousness SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE EEG; Isoflurane; Desflurane; Ketamine; Slow oscillations; Alpha oscillations ID INDUCED ELECTROENCEPHALOGRAM DYNAMICS; PROPOFOL-INDUCED UNCONSCIOUSNESS; INDUCED ALPHA-RHYTHM; GENERAL-ANESTHESIA; COHERENCE ANALYSIS; MOLECULAR TARGETS; SLOW WAVES; CONSCIOUSNESS; SEVOFLURANE; KETAMINE AB Objective: An emerging paradigm for understanding how anesthetics induce altered arousal is relating receptor targeting in specific neural circuits to electroencephalogram (EEG) activity. Enhanced gamma amino-butyric acid A (GABAA) inhibitory post-synaptic currents (IPSCs) manifest with large-amplitude slow (0.1-1 Hz) and frontally coherent alpha (8-12 Hz) EEG oscillations during general anesthesia. Therefore, we investigated the EEG signatures of modern day derivatives of ether (MDDE) anesthesia to assess the extent to which we could obtain insights into MDDE anesthetic mechanisms. Methods: We retrospectively studied cases from our database in which patients received isoflurane anesthesia vs. isoflurane/ketamine anesthesia (n = 10 each) or desflurane anesthesia vs. desflurane/ketamine anesthesia (n = 9 each). We analyzed the EEG recordings with spectral power and coherence methods. Results: Similar to known GABAA circuit level mechanisms, we found that MDDE anesthesia induced large amplitude slow and frontally coherent alpha oscillations. Additionally, MDDE anesthesia also induced frontally coherent theta (4-8 Hz) oscillations. Reduction of GABAergic IPSCs with ketamine resulted in beta/gamma (13-40 Hz) oscillations, and significantly reduced MDDE anesthesia-induced slow, theta and alpha oscillation power. Conclusions: Large amplitude slow oscillations and coherent alpha and theta oscillations are moderated by ketamine during MDDE anesthesia. Significance: These observations are consistent with the notion that GABAA circuit-level mechanisms are associated with MDDE anesthesia-induced unconsciousness. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Akeju, Oluwaseun; Pavone, Kara J.; Purdon, Patrick L.; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Akeju, Oluwaseun; Hamilos, Allison E.; Purdon, Patrick L.; Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA USA. [Song, Andrew H.; Purdon, Patrick L.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Hamilos, Allison E.; Brown, Emery N.] MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, Cambridge, MA 02139 USA. [Hamilos, Allison E.; Brown, Emery N.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Akeju, O (reprint author), 55 Fruit St,Jackson Bldg,Rm 460, Boston, MA 02114 USA. EM oluwaseun.akeju@mgh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [DP2-OD006454, DP1-OD003646, TR01-GM104948]; Foundation of Anesthesia Education and Research, Rochester, Minnesota; Massachusetts General Hospital Faculty Development Award, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA FX DP2-OD006454. (to PLP); DP1-OD003646, TR01-GM104948 (to ENB), and Ruth L. Kirchstein National Research Service Award to (AH) from the National Institutes of Health, Bethesda, Maryland; Foundation of Anesthesia Education and Research, Rochester, Minnesota (to OA); Massachusetts General Hospital Faculty Development Award, Boston, MA (to OA); Funds from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA. NR 48 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUN PY 2016 VL 127 IS 6 BP 2472 EP 2481 DI 10.1016/j.clinph.2016.02.012 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DL3YH UT WOS:000375569100023 PM 27178867 ER PT J AU Teunis, T Janssen, S Guitton, TG Ring, D Parisien, R AF Teunis, Teun Janssen, Stein Guitton, Thierry G. Ring, David Parisien, Robert TI Do Orthopaedic Surgeons Acknowledge Uncertainty? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID DOCTORS AB Much of the decision-making in orthopaedics rests on uncertain evidence. Uncertainty is therefore part of our normal daily practice, and yet physician uncertainty regarding treatment could diminish patients' health. It is not known if physician uncertainty is a function of the evidence alone or if other factors are involved. With added experience, uncertainty could be expected to diminish, but perhaps more influential are things like physician confidence, belief in the veracity of what is published, and even one's religious beliefs. In addition, it is plausible that the kind of practice a physician works in can affect the experience of uncertainty. Practicing physicians may not be immediately aware of these effects on how uncertainty is experienced in their clinical decision-making. We asked: (1) Does uncertainty and overconfidence bias decrease with years of practice? (2) What sociodemographic factors are independently associated with less recognition of uncertainty, in particular belief in God or other deity or deities, and how is atheism associated with recognition of uncertainty? (3) Do confidence bias (confidence that one's skill is greater than it actually is), degree of trust in the orthopaedic evidence, and degree of statistical sophistication correlate independently with recognition of uncertainty? We created a survey to establish an overall recognition of uncertainty score (four questions), trust in the orthopaedic evidence base (four questions), confidence bias (three questions), and statistical understanding (six questions). Seven hundred six members of the Science of Variation Group, a collaboration that aims to study variation in the definition and treatment of human illness, were approached to complete our survey. This group represents mainly orthopaedic surgeons specializing in trauma or hand and wrist surgery, practicing in Europe and North America, of whom the majority is involved in teaching. Approximately half of the group has more than 10 years of experience. Two hundred forty-two (34%) members completed the survey. We found no differences between responders and nonresponders. Each survey item measured its own trait better than any of the other traits. Recognition of uncertainty (0.70) and confidence bias (0.75) had relatively high Cronbach alpha levels, meaning that the questions making up these traits are closely related and probably measure the same construct. This was lower for statistical understanding (0.48) and trust in the orthopaedic evidence base (0.37). Subsequently, combining each trait's individual questions, we calculated a 0 to 10 score for each trait. The mean recognition of uncertainty score was 3.2 +/- 1.4. Recognition of uncertainty in daily practice did not vary by years in practice (0-5 years, 3.2 +/- 1.3; 6-10 years, 2.9 +/- 1.3; 11-20 years, 3.2 +/- 1.4; 21-30 years, 3.3 +/- 1.6 years; p = 0.51), but overconfidence bias did correlate with years in practice (0-5 years, 6.2 +/- 1.4; 6-10 years, 7.1 +/- 1.3; 11-20 years, 7.4 +/- 1.4; 21-30 years, 7.1 +/- 1.2 years; p < 0.001). Accounting for a potential interaction of variables using multivariable analysis, less recognition of uncertainty was independently but weakly associated with working in a multispecialty group compared with academic practice (beta regression coefficient, -0.53; 95% confidence interval [CI], -1.0 to -0.055; partial R-2, 0.021; p = 0.029), belief in God or any other deity/deities (beta, -0.57; 95% CI, -1.0 to -0.11; partial R-2, 0.026; p = 0.015), greater confidence bias (beta, -0.26; 95% CI, -0.37 to -0.14; partial R-2, 0.084; p < 0.001), and greater trust in the orthopaedic evidence base (beta, -0.16; 95% CI, -0.26 to -0.058; partial R-2, 0.040; p = 0.002). Better statistical understanding was independently, and more strongly, associated with greater recognition of uncertainty (beta, 0.25; 95% CI, 0.17-0.34; partial R-2, 0.13; p < 0.001). Our full model accounted for 29% of the variability in recognition of uncertainty (adjusted R-2, 0.29). The relatively low levels of uncertainty among orthopaedic surgeons and confidence bias seem inconsistent with the paucity of definitive evidence. If patients want to be informed of the areas of uncertainty and surgeon-to-surgeon variation relevant to their care, it seems possible that a low recognition of uncertainty and surgeon confidence bias might hinder adequately informing patients, informed decisions, and consent. Moreover, limited recognition of uncertainty is associated with modifiable factors such as confidence bias, trust in orthopaedic evidence base, and statistical understanding. Perhaps improved statistical teaching in residency, journal clubs to improve the critique of evidence and awareness of bias, and acknowledgment of knowledge gaps at courses and conferences might create awareness about existing uncertainties. Level 1, prognostic study. C1 [Teunis, Teun] Onze Lieve Vrouwe Gasthuis, Gen Surg, Amsterdam, Netherlands. [Janssen, Stein] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Musculoskeletal Oncol Serv, Boston, MA 02114 USA. [Guitton, Thierry G.] Univ Amsterdam, Acad Med Ctr, Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. [Parisien, Robert] Elliot Hosp, Orthopaed Surg, Manchester, NH USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu FU Wright Medical (Memphis, TN, USA); Skeletal Dynamics (Miami, FL, USA); Biomet (Warsaw, IN, USA); AO North America (Paoli, PA, USA); AO International (Dubendorf, Switzerland) FX One of the authors (DR) certifies that he, or a member of his immediate family, has or may receive payments or benefits, an amount of less than USD 10,000 during the study period from Wright Medical (Memphis, TN, USA); an amount less than USD 10,000 from Skeletal Dynamics (Miami, FL, USA); an amount less than USD 10,000 from Biomet (Warsaw, IN, USA); an amount less than USD 10,000 from AO North America (Paoli, PA, USA); and an amount less than USD 10,000 from AO International (Dubendorf, Switzerland). NR 27 TC 1 Z9 1 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUN PY 2016 VL 474 IS 6 BP 1360 EP 1369 DI 10.1007/s11999-015-4623-0 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DL4OT UT WOS:000375617800003 PM 26552806 ER PT J AU Teunis, T Janssen, S Guitton, TG Ring, D Parisien, R AF Teunis, Teun Janssen, Stein Guitton, Thierry G. Ring, David Parisien, Robert TI Do Orthopaedic Surgeons Acknowledge Uncertainty? (vol 474, pg 1360, 2016) SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Correction C1 [Teunis, Teun] Onze Lieve Vrouwe Gasthuis, Gen Surg, Amsterdam, Netherlands. [Janssen, Stein] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Musculoskeletal Oncol Serv, Boston, MA 02114 USA. [Guitton, Thierry G.] Univ Amsterdam, Acad Med Ctr, Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Ring, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. [Parisien, Robert] Elliot Hosp, Orthopaed Surg, Manchester, NH USA. RP Ring, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUN PY 2016 VL 474 IS 6 BP 1530 EP 1531 DI 10.1007/s11999-016-4733-3 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DL4OT UT WOS:000375617800032 ER PT J AU Basch, E Wood, WA Schrag, D Sima, CS Shaw, M Rogak, LJ Kris, MG Shouery, M Bennett, A Atkinson, T Pietanza, MC AF Basch, Ethan Wood, William A. Schrag, Deborah Sima, Camelia S. Shaw, Mary Rogak, Lauren J. Kris, Mark G. Shouery, Marwan Bennett, Antonia Atkinson, Thomas Pietanza, M. Catherine TI Feasibility and clinical impact of sharing patient-reported symptom toxicities and performance status with clinical investigators during a phase 2 cancer treatment trial SO CLINICAL TRIALS LA English DT Article DE Patient-reported outcome; adverse event; toxicity; drug development; clinical trial ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; OUTCOME MEASURES; CHEMOTHERAPY; CARE; COMMUNICATION; RELIABILITY; ASSESSMENTS; IMPROVEMENT; PROVIDERS AB Background: Clinicians can miss up to half of patients' symptomatic toxicities in cancer clinical trials and routine practice. Although patient-reported outcome questionnaires have been developed to capture this information, it is unclear whether clinicians will make use of patient-reported outcomes to inform their own toxicity documentation, or to prompt symptom management activities. Methods: 44 lung cancer patients that participated in a phase 2 treatment trial self-reported 13 symptomatic toxicities derived from the National Cancer Institute's Common Terminology Criteria for Adverse Events and Karnofsky Performance Status via tablet computers in waiting areas immediately preceding scheduled visits. During visits, clinicians viewed patients' self-reported toxicity and performance status ratings on a computer interface and could agree or disagree/reassign grades ("shared'' reporting). Agreement of clinicians with patient-reported grades was tabulated, and compared using weighted kappa statistics. Clinical actions in response to patient-reported severe (grade 3/4) toxicities were measured (e.g. treatment discontinuation, dose reduction, supportive medications). For comparison, 45 non-trial patients with lung cancer being treated in the same clinic by the same physicians were simultaneously enrolled in a parallel cohort study in which patients also self-reported toxicity grades but reports were not shared with clinicians ("nonshared'' reporting). Results: Toxicities and performance status were reported by patients and reviewed by clinicians at (780/782) 99.7% of study visits in the phase 2 trial which used "shared'' reporting. Clinicians agreed with patients 93% of the time with kappas 0.82-0.92. Clinical actions were taken in response to 67% of severe patient-reported toxicities. In the "non-shared'' reporting comparison group, clinicians agreed with patients 56% of the time with kappas 0.04-0.48 (significantly worse than shared reporting for all symptoms), and clinical actions were taken in response to 44% of severe patient-reported toxicities. Conclusion: Clinicians will frequently agree with patient-reported symptoms and performance status, and will use this information to guide documentation and symptom management. C1 [Basch, Ethan; Sima, Camelia S.; Shaw, Mary; Rogak, Lauren J.; Shouery, Marwan] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Basch, Ethan; Wood, William A.; Bennett, Antonia] Univ N Carolina, Lineberger Comprehens Canc Ctr, Canc Outcomes Res Program, Chapel Hill, NC 27516 USA. [Schrag, Deborah] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Kris, Mark G.; Pietanza, M. Catherine] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Thorac Oncol Serv, New York, NY 10021 USA. [Kris, Mark G.; Pietanza, M. Catherine] Weill Cornell Med Coll, New York, NY USA. [Atkinson, Thomas] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. RP Basch, E (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Canc Outcomes Res Program, Chapel Hill, NC 27516 USA. EM ebasch@med.unc.edu FU Society of Memorial Sloan Kettering Cancer Center FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this research was provided by the Society of Memorial Sloan Kettering Cancer Center. NR 25 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD JUN PY 2016 VL 13 IS 3 BP 331 EP 337 DI 10.1177/1740774515615540 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DL5PP UT WOS:000375689500012 PM 26542025 ER PT J AU Schoenfeld, DA Finkelstein, DM AF Schoenfeld, David A. Finkelstein, Dianne M. TI Assessing survival benefit when treatment delays disease progression SO CLINICAL TRIALS LA English DT Article DE Progression-free survival; piecewise exponential; interval censored; Bayesian; cancer; clinical trial; survival ID TRIALS AB Background: For a potentially lethal chronic disease like cancer, it is often infeasible to compare treatments on the basis of overall survival, so a combined outcome such as progression-free survival (which is the time from randomization to progression or death) has become an acceptable primary endpoint. The rationale of using an efficacy measure that is dominated by the time to progression is that an effective treatment will delay progression and when treatment is stopped at progression, the effect of treatment after this time is small. However, often trials that show a significant benefit for delaying progression but not on overall survival are not universally viewed as providing convincing evidence that the drug should become the standard of care. Methods: We propose that when there is a significant treatment effect of delaying progression, a Bayesian analysis of overall survival should be undertaken. We suggest using a joint piecewise exponential model, where the treatment effect on the hazard for progression and for death after progression is captured through two distinct parameters. We develop a plot of the overall survival advantage of the new therapy versus the prior distribution of the relative hazard for death after progression. This plot can augment the discussion about whether the new treatment is beneficial on survival. Results: In the example of an early breast cancer trial for which a new treatment significantly delayed disease recurrence, our Bayesian analysis showed that with very reasonable assumptions on the effects of treatment after recurrence, there is a high probability that the new treatment improves overall survival. Conclusion: For a clinical trial for which treatment delays progression, the proposed method can improve the interpretability of the survival comparison using data from the study. C1 [Finkelstein, Dianne M.] Massachusetts Gen Hosp, 50 Staniford St, Boston, MA 02114 USA. [Finkelstein, Dianne M.] Harvard Univ, Biostat Unit, 50 Staniford St, Boston, MA 02114 USA. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, 50 Staniford St, Boston, MA 02114 USA.; Finkelstein, DM (reprint author), Harvard Univ, Biostat Unit, 50 Staniford St, Boston, MA 02114 USA. EM dfinkelstein@partners.org FU Avon Foundation; NIH [CA167570, UL1RR025758, CA160233] FX This work was partially funded by grants from the Avon Foundation and from the NIH: CA167570, UL1RR025758, and CA160233. NR 9 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD JUN PY 2016 VL 13 IS 3 BP 352 EP 357 DI 10.1177/1740774515625990 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DL5PP UT WOS:000375689500015 PM 26908538 ER PT J AU Fedorov, VD Upadhyay, VA Fathi, AT AF Fedorov, Victor D. Upadhyay, Vivek A. Fathi, Amir T. TI The Approach to Acute Lymphoblastic Leukemia in Older Patients: Conventional Treatments and Emerging Therapies SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Review DE Acute lymphoblastic leukemia; CARTcells; Older patients ID ACUTE LYMPHOCYTIC-LEUKEMIA; STEM-CELL TRANSPLANTATION; TERM-FOLLOW-UP; DOSE-INTENSIVE REGIMEN; HYPER-CVAD; PHASE-II; COMPLETE REMISSION; ELDERLY-PATIENTS; ADULT PATIENTS; FREE SURVIVAL AB Acute lymphoblastic leukemia (ALL) among older adult patients presents significant clinical challenges. As opposed to pediatric populations, in whom long-term outcomes are markedly superior, those for adults remain grim. Nevertheless, younger adults with ALL have experienced a steady improvement in long-term survival in the last few decades. This is significantly different for older ALL patients, for whom long-term outcomes remain poor. Conventional chemotherapies are associated with sub-optimal outcomes and increased toxicity in this population. However, several emerging therapies, including antibody-drug conjugates, bi-specific engagers, and chimeric antigen receptor (CAR) T cells, have demonstrated much promise and are either incorporated into the existing therapeutic paradigms or being actively investigated to improve outcomes. C1 [Fedorov, Victor D.] Massachusetts Gen Hosp, Dept Med, Stanbury Serv PSP Grp, Boston, MA 02114 USA. [Upadhyay, Vivek A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Fathi, Amir T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol & Med Oncol, Zero Emerson Pl,Suite 118, Boston, MA 02114 USA. RP Fathi, AT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol & Med Oncol, Zero Emerson Pl,Suite 118, Boston, MA 02114 USA. EM afathi@partners.org NR 98 TC 1 Z9 1 U1 0 U2 3 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD JUN PY 2016 VL 11 IS 3 BP 165 EP 174 DI 10.1007/s11899-016-0316-3 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA DL5LO UT WOS:000375678800001 PM 26939921 ER PT J AU Jacobson, CA Freedman, AS AF Jacobson, Caron A. Freedman, Arnold S. TI Is There a Best Initial Treatment for a New Patient With Low Grade Follicular Lymphoma SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Review DE Follicular lymphoma; Initial therapy ID STEM-CELL TRANSPLANTATION; NON-HODGKIN-LYMPHOMA; LOW-TUMOR-BURDEN; FONDAZIONE ITALIANA LINFOMI; RANDOMIZED CONTROLLED-TRIAL; SINGLE-AGENT RITUXIMAB; DETUDE DES LYMPHOMES; CHOP PLUS RITUXIMAB; HIGH-DOSE THERAPY; ADVANCED-STAGE AB The treatment landscape for newly diagnosed follicular lymphoma (FL) has dramatically changed over the past decade, first with the advent of rituximab and then with the activity of old and new drugs, like bendamustine and lenalidomide, in this disease. The efficacy and tolerability of rituximab has led to a paradigm shift for the management of patients with low volume FL for many oncologists. Despite the lack of a survival benefit seen with this approach, many now use this single agent in patients who had historically been observed. Likewise, its use as maintenance therapy following successful front-line induction therapy of patients with symptomatic FL, with either rituximab alone or specific chemoimmunotherapy regimens, has improved remission duration and widely been adopted. As newer chemoimmunotherapy regimens, like bendamustine and rituximab, have superior outcomes with improved tolerability, upfront treatment options are redefined and questions emerge: whom do maintenance strategies benefit, and what is the optimal sequencing of therapies? Finally, as newer targeted and potentially better tolerated therapies demonstrate efficacy in the relapsed setting, their use, both in combination with and in place of chemotherapy, is being explored. The promising regimen of lenalidomide with rituximab is being compared with chemoimmunotherapy in a randomized fashion. Cure remains elusive, however, in advanced stage disease and so safety and tolerability, in addition to efficacy, remain important endpoints. C1 [Jacobson, Caron A.; Freedman, Arnold S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Hematol Malignancies,Div Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Jacobson, Caron A.; Freedman, Arnold S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. RP Jacobson, CA (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Hematol Malignancies,Div Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA.; Jacobson, CA (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. EM cajacobson@partners.org; afreedman@partners.org NR 32 TC 0 Z9 0 U1 2 U2 2 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD JUN PY 2016 VL 11 IS 3 BP 218 EP 223 DI 10.1007/s11899-016-0321-6 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA DL5LO UT WOS:000375678800006 PM 26995595 ER PT J AU Peloso, GM Rader, DJ Gabriel, S Kathiresan, S Daly, MJ Neale, BM AF Peloso, Gina M. Rader, Daniel J. Gabriel, Stacey Kathiresan, Sekar Daly, Mark J. Neale, Benjamin M. TI Phenotypic extremes in rare variant study designs SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CORONARY HEART-DISEASE; SEQUENCING ASSOCIATION; QUANTITATIVE TRAITS; STATISTICAL TESTS; COMPLEX TRAITS; POWER; CHOLESTEROL; FRAMINGHAM; MUTATIONS; RELEVANCE AB Currently, next-generation sequencing studies aim to identify rare and low-frequency variation that may contribute to disease. For a given effect size, as the allele frequency decreases, the power to detect genes or variants of interest also decreases. Although many methods have been proposed for the analysis of such data, study design and analytic issues still persist in data interpretation. In this study we present sequencing data for ABCA1 that has known rare variants associated with high-density lipoprotein cholesterol (HDL-C). We contrast empirical findings from two study designs: a phenotypic extreme sample and a population-based random sample. We found differing strengths of association with HDL-C across the two study designs (P=0.0006 with n=701 phenotypic extremes vs P=0.03 with n=1600 randomly sampled individuals). To explore this apparent difference in evidence for association, we performed a simulation study focused on the impact of phenotypic selection on power. We demonstrate that the power gain for an extreme phenotypic selection study design is much greater in rare variant studies than for studies of common variants. Our study confirms that studying phenotypic extremes is critical in rare variant studies because it boosts power in two ways: the typical increases from extreme sampling and increasing the proportion of relevant functional variants ascertained and thereby tested for association. Furthermore, we show that when combining statistical evidence through meta-analysis from an extreme-selected sample and a second separate population-based random sample, power is lower when a traditional sample size weighting is used compared with weighting by the noncentrality parameter. C1 [Peloso, Gina M.; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Gabriel, Stacey; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.] Broad Inst MIT, Program Med & Populat Genet, Cambridge, MA USA. [Peloso, Gina M.; Gabriel, Stacey; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.] Harvard Univ, Cambridge, MA USA. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Rader, Daniel J.] Univ Penn, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Daly, Mark J.; Neale, Benjamin M.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Daly, Mark J.; Neale, Benjamin M.] Harvard Univ, Sch Med, Boston, MA USA. [Daly, Mark J.; Neale, Benjamin M.] Broad Inst MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Neale, BM (reprint author), Massachusetts Gen Hosp, Dept Med, Simches Res Ctr, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA.; Neale, BM (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Simches Res Ctr, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. EM neale@atgu.mgh.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [K01HL125751] FX GMP is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125751. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 35 TC 1 Z9 1 U1 0 U2 3 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 JUN PY 2016 VL 24 IS 6 BP 924 EP 930 DI 10.1038/ejhg.2015.197 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DL5WD UT WOS:000375706800021 PM 26350511 ER PT J AU Chasseriaud, W Tearney, GJ Montaudon, M Fialon, B Coste, P Gerbaud, E AF Chasseriaud, Warren Tearney, Guillermo J. Montaudon, Michel Fialon, Benjamin Coste, Pierre Gerbaud, Edouard TI Isolated septal myocardial infarction due to spontaneous coronary artery dissection SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Acute myocardial infarction; Septal perforating coronary artery; Spontaneous coronary artery dissection; Cardiac magnetic resonance imaging; Optical coherence tomography C1 [Chasseriaud, Warren; Fialon, Benjamin; Coste, Pierre; Gerbaud, Edouard] Hop Haut Leveque, CHU Bordeaux, Soins Intensifs Cardiol Plateau Cardiol Intervent, 5 Ave Magellan, F-33604 Pessac, France. [Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tearney, Guillermo J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Tearney, Guillermo J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Montaudon, Michel] Hop Haut Leveque, CHU Bordeaux, Unite Imagerie Thorc & Cardiovasc, Pessac, France. RP Gerbaud, E (reprint author), Hop Haut Leveque, CHU Bordeaux, Soins Intensifs Cardiol Plateau Cardiol Intervent, 5 Ave Magellan, F-33604 Pessac, France. EM edouard.gerbaud@chu-bordeaux.fr NR 5 TC 1 Z9 1 U1 0 U2 1 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 JUN 1 PY 2016 VL 212 BP 259 EP 261 DI 10.1016/j.ijcard.2016.03.123 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DJ8PO UT WOS:000374474600065 PM 27057931 ER PT J AU Kamil, RJ Betz, J Powers, BB Pratt, S Kritchevsky, S Ayonayon, HN Harris, TB Helzner, E Deal, JA Martin, K Peterson, M Satterfield, S Simonsick, EM Lin, FR AF Kamil, Rebecca J. Betz, Joshua Powers, Becky Brott Pratt, Sheila Kritchevsky, Stephen Ayonayon, Hilsa N. Harris, Tammy B. Helzner, Elizabeth Deal, Jennifer A. Martin, Kathryn Peterson, Matthew Satterfield, Suzanne Simonsick, Eleanor M. Lin, Frank R. CA Hlth ABC study TI Association of Hearing Impairment With Incident Frailty and Falls in Older Adults SO JOURNAL OF AGING AND HEALTH LA English DT Article DE hearing impairment; frailty; falls; older adults; Health ABC ID RISK-FACTORS; COGNITIVE IMPAIRMENT; PHYSICAL-ACTIVITY; UNITED-STATES; OSTEOPOROTIC FRACTURES; CARDIOVASCULAR-DISEASE; FUNCTIONAL DECLINE; ELDERLY PERSONS; HEALTH; WOMEN AB Objective: We aimed to determine whether hearing impairment (HI) in older adults is associated with the development of frailty and falls. Method: Longitudinal analysis of observational data from the Health, Aging and Body Composition study of 2,000 participants aged 70 to 79 was conducted. Hearing was defined by the pure-tone-average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better hearing ear. Frailty was defined as a gait speed of <0.60 m/s and/or inability to rise from a chair without using arms. Falls were assessed annually by self-report. Results: Older adults with moderate-or-greater HI had a 63% increased risk of developing frailty (adjusted hazard ratio [HR] = 1.63, 95% confidence interval [CI] = [1.26, 2.12]) compared with normal-hearing individuals. Moderate-or-greater HI was significantly associated with a greater annual percent increase in odds of falling over time (9.7%, 95% CI = [7.0, 12.4] compared with normal hearing, 4.4%, 95% CI = [2.6, 6.2]). Discussion: HI is independently associated with the risk of frailty in older adults and with greater odds of falling over time. C1 [Kamil, Rebecca J.; Betz, Joshua; Deal, Jennifer A.; Simonsick, Eleanor M.; Lin, Frank R.] Johns Hopkins Univ, Baltimore, MD USA. [Powers, Becky Brott; Pratt, Sheila; Peterson, Matthew] US Dept Vet Affairs, Washington, DC USA. [Pratt, Sheila] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Kritchevsky, Stephen] Wake Forest Univ, Winston Salem, NC 27109 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, Tammy B.; Simonsick, Eleanor M.] NIA, Bethesda, MD 20892 USA. [Helzner, Elizabeth] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Martin, Kathryn] Univ Aberdeen, Aberdeen AB9 1FX, Scotland. [Peterson, Matthew] Duke Univ, Durham, NC USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. RP Kamil, RJ (reprint author), Johns Hopkins Univ, Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM rkamil1@jhmi.edu OI Betz, Joshua/0000-0003-4488-9799 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; National Institute of Deafness and Communication Disorders [K23DC011279]; Triological Society; American College of Surgeons Clinician Scientist Award; Eleanor Schwartz Charitable Foundation; Oticon Foundation; Geriatric Research Education and Clinical Center in the Veterans Administration Pittsburgh Healthcare System FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA Grant R01-AG028050; and NINR Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Frank Lin is supported by the National Institute of Deafness and Communication Disorders K23DC011279 Grant, Triological Society and American College of Surgeons Clinician Scientist Award, and Eleanor Schwartz Charitable Foundation. Rebecca Kamil's coursework at Bloomberg School of Public Health is supported by the Oticon Foundation. Sheila Pratt and Becky Brott Powers were supported by the Geriatric Research Education and Clinical Center in the Veterans Administration Pittsburgh Healthcare System during the development of this article. NR 55 TC 1 Z9 1 U1 4 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 EI 1552-6887 J9 J AGING HEALTH JI J. Aging Health PD JUN PY 2016 VL 28 IS 4 BP 644 EP 660 DI 10.1177/0898264315608730 PG 17 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA DL5ZC UT WOS:000375714700005 PM 26438083 ER PT J AU Wild, KV Mattek, N Austin, D Kaye, JA AF Wild, Katherine V. Mattek, Nora Austin, Daniel Kaye, Jeffrey A. TI "Are You Sure?": Lapses in Self-Reported Activities Among Healthy Older Adults Reporting Online SO JOURNAL OF APPLIED GERONTOLOGY LA English DT Article DE in-home monitoring; technology; self-report assessments ID ECOLOGICAL MOMENTARY ASSESSMENT; MILD COGNITIVE IMPAIRMENT; PHYSICAL-ACTIVITY; ACCELEROMETER; TECHNOLOGIES; ACCURACY; DIARIES; PEOPLE AB Accurate retrospective reporting of activities and symptoms has been shown to be problematic for older adults, yet standard clinical care relies on self-reports to aid in assessment and management. Our aim was to examine the relationship between self-report and sensor-based measures of activity. We administered an online activity survey to participants in our ongoing longitudinal study of in-home ubiquitous monitoring. We found a wide range of accuracies when comparing self-report with time-stamped sensor-based data. Of the 95 participants who completed the 2-hr activity log, nearly one quarter did not complete the task in a way that could potentially be compared with sensor data. Where comparisons were possible, agreement between self-reported and sensor-based activity was achieved by a minority of participants. The findings suggest that capture of real-time events with unobtrusive activity monitoring may be a more reliable approach to describing behavioral patterns and meaningful changes in older adults. C1 [Wild, Katherine V.] Oregon Hlth & Sci Univ, Layton Aging & Alzheimers Dis Ctr, Neurol & Psychiat, Portland, OR 97201 USA. [Mattek, Nora] Oregon Hlth & Sci Univ, Oregon Ctr Aging & Technol ORCATECH, Portland, OR 97201 USA. [Mattek, Nora; Kaye, Jeffrey A.] Oregon Hlth & Sci Univ, Layton Aging & Alzheimers Dis Ctr, Portland, OR 97201 USA. [Austin, Daniel] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Kaye, Jeffrey A.] Oregon Hlth & Sci Univ, Neurol & Biomed Engn, ORCATECH, Portland, OR 97201 USA. [Kaye, Jeffrey A.] Portland VA Med Ctr, Portland, OR USA. RP Wild, KV (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, CR131,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM wildk@ohsu.edu FU National Institutes of Health [P30AG024978, R01AG024059, P30AG008017] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by grants from the National Institutes of Health [P30AG024978, R01AG024059, P30AG008017]. NR 35 TC 2 Z9 2 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0733-4648 EI 1552-4523 J9 J APPL GERONTOL JI J. Appl. Gerontol. PD JUN PY 2016 VL 35 IS 6 BP 627 EP 641 DI 10.1177/0733464815570667 PG 15 WC Gerontology SC Geriatrics & Gerontology GA DL5XF UT WOS:000375709700004 PM 25669877 ER PT J AU Jeong, YJ Aldwin, CM Igarashi, H Spiro, A AF Jeong, Yu-Jin Aldwin, Carolyn M. Igarashi, Heidi Spiro, Avron, III TI Do hassles and uplifts trajectories predict mortality? Longitudinal findings from the VA Normative Aging Study SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Aging; Hassles; Longitudinal; Mortality; Uplifts ID DAILY STRESSORS; LIFE EVENTS; AFFECTIVE REACTIVITY; PHYSICAL HEALTH; POSITIVE AFFECT; OLDER MEN; PERSONALITY; DISEASE; WOMEN; RISK AB We examined whether longitudinal patterns of hassles and uplifts trajectories predicted mortality, using a sample of 1315 men from the VA Normative Aging Study (mean age = 65.31, SD = 7.6). In prior work, we identified different trajectory classes of hassles and uplifts exposure and intensity scores over a period of 16 years. In this study, we used the probabilities of these exposure and intensity class memberships to examine their ability to predict mortality. Men with higher probabilities of high hassle intensity trajectory class and high uplift intensity class had higher mortality risks. In a model combining the probabilities of hassle and uplift intensities, the probability of high intensity hassle class membership significantly increased the risk of mortality. This suggests that appraisals of hassles intensity are better predictors of mortality than simple exposure measures, and that uplifts have no independent effects. C1 [Jeong, Yu-Jin; Igarashi, Heidi] Chonbuk Natl Univ, Coll Human Ecol, Dept Child Studies, 567 Baekje Daeroh, Jeonju 561756, Jeollabuk Do, South Korea. [Aldwin, Carolyn M.] Oregon State Univ, Sch Social & Behav Hlth Sci, Program Human Dev & Family Sci, 424 Waldo Hall, Corvallis, OR 97331 USA. [Spiro, Avron, III] VA Boston Healthcare Syst, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Spiro, Avron, III] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Aldwin, CM (reprint author), Oregon State Univ, Sch Social & Behav Hlth Sci, Program Human Dev & Family Sci, 424 Waldo Hall, Corvallis, OR 97331 USA. EM yujin.jeong@jbnu.ac.kr; Carolyn.Aldwin@oregonstate.edu FU NIH [R01 AG032037, AG002287, AG018436]; CSR&D Service, US Department of Veterans Affairs; VA CSP/ERIC; Chonbuk National University FX This study was funded by NIH Grants R01 AG032037, AG002287, and AG018436, as well as a Merit Review and a Senior Research Career Scientist Award from the CSR&D Service, US Department of Veterans Affairs. The NAS is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) and is supported by VA CSP/ERIC. The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. This study was also supported by research funds of Chonbuk National University in 2014. NR 45 TC 0 Z9 0 U1 2 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 EI 1573-3521 J9 J BEHAV MED JI J. Behav. Med. PD JUN PY 2016 VL 39 IS 3 BP 408 EP 419 DI 10.1007/s10865-015-9703-9 PG 12 WC Psychology, Clinical SC Psychology GA DL3YX UT WOS:000375570700004 PM 26721518 ER PT J AU Bernard, JD Baddeley, JL Rodriguez, BF Burke, PA AF Bernard, Jared D. Baddeley, Jenna L. Rodriguez, Benjamin F. Burke, Philip A. TI Depression, Language, and Affect: An Examination of the Influence of Baseline Depression and Affect Induction on Language SO JOURNAL OF LANGUAGE AND SOCIAL PSYCHOLOGY LA English DT Article DE language; linguistic style; depression; affect; mood ID NEGATIVE AFFECT; RUMINATION; LIWC; TALK AB Literature suggests that depression influences how individuals communicate. However, no studies examine the impact of affective state on language. The current study examined the influence of depression and affective state on linguistic style. Findings suggest that depression and temporary negative moods both affect pronoun use, but depression influences use of first-person pronouns, whereas negative affect influences use of third-person pronouns. C1 [Bernard, Jared D.] So Illinois Univ, Clin Psychol, Carbondale, IL 62901 USA. [Rodriguez, Benjamin F.; Burke, Philip A.] So Illinois Univ, Dept Psychol, 1125 Lincoln Dr,LSII281 MC6502, Carbondale, IL 62901 USA. [Baddeley, Jenna L.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Baddeley, Jenna L.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Bernard, JD (reprint author), So Illinois Univ, Dept Psychol, 1125 Lincoln Dr,LSII281 MC6502, Carbondale, IL 62901 USA. EM jared.d.bernard@gmail.com NR 25 TC 0 Z9 0 U1 2 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0261-927X EI 1552-6526 J9 J LANG SOC PSYCHOL JI J. Lang. Soc. Psychol. PD JUN PY 2016 VL 35 IS 3 BP 317 EP 326 DI 10.1177/0261927X15589186 PG 10 WC Communication; Linguistics; Psychology, Social SC Communication; Linguistics; Psychology GA DL6RC UT WOS:000375765300005 ER PT J AU Madson, MB Schumacher, JA Baer, JS Martino, S AF Madson, Michael B. Schumacher, Julie A. Baer, John S. Martino, Steve TI Motivational Interviewing for Substance Use: Mapping Out the Next Generation of Research SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Editorial Material DE Motivational interviewing; Substance use; Research ID RANDOMIZED CONTROLLED-TRIAL; MANDATED COLLEGE-STUDENTS; PRIMARY-CARE SETTINGS; BRIEF INTERVENTION; DRUG-USE; CLINICAL-TRIAL; USE OUTCOMES; CHANGE TALK; METAANALYSIS; ALCOHOL C1 [Madson, Michael B.] Univ So Mississippi, Hattiesburg, MS 39406 USA. [Schumacher, Julie A.] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Baer, John S.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Martino, Steve] Yale Univ, Sch Med, VA Connecticut Healthcare Syst, New Haven, CT 06520 USA. RP Madson, MB (reprint author), Univ So Mississippi, Hattiesburg, MS 39406 USA. NR 80 TC 1 Z9 1 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUN PY 2016 VL 65 SI SI BP 1 EP 5 DI 10.1016/j.jsat.2016.02.003 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DL3DM UT WOS:000375514400001 PM 26971078 ER PT J AU Moyers, TB Rowell, LN Manuel, JK Ernst, D Houck, JM AF Moyers, Theresa B. Rowell, Lauren N. Manuel, Jennifer K. Ernst, Denise Houck, Jon M. TI The Motivational Interviewing Treatment Integrity Code (MITI 4): Rationale, Preliminary Reliability and Validity SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE MITI 4; Motivational interviewing; Treatment fidelity; Treatment integrity; Reliability; Supervision ID THERAPIST ADHERENCE; USE OUTCOMES; CHANGE TALK; INTERVENTION; ENHANCEMENT; ADOLESCENTS; COMPETENCE; FIDELITY; LANGUAGE; TRIAL AB The Motivational Interviewing Treatment Integrity code has been revised to address new evidence-based elements of motivational interviewing (MI). This new version (MITI 4) includes new global ratings to assess clinician's attention to client language, increased rigor in assessing autonomy support and client choice, and items to evaluate the use of persuasion when giving information and advice. Method: Four undergraduate, non-professional raters were trained in the MITI and used it to review 50 audiotapes of clinicians conducting MI in actual treatments sessions. Both kappa and intraclass correlation indices were calculated for all coders, for the best rater pair and for a 20% randomly selected sample from the best rater pair. Results: Reliability across raters, with the exception of Emphasize Autonomy and % Complex Reflections, were in the good to excellent range. Reliability estimates decrease when smaller samples are used and when fewer raters contribute. Conclusion: The advantages and drawbacks of this revision are discussed including implications for research and clinical applications. The MITI 4.0 represents a reliable method for assessing the integrity of MI including both the technical and relational components of the method. (C) 2016 Elsevier Inc. All rights reserved. C1 [Moyers, Theresa B.; Rowell, Lauren N.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Manuel, Jennifer K.] San Francisco VA Med Ctr, San Francisco, CA USA. [Ernst, Denise] Denise Ernst Training & Consulting, Portland, OR USA. [Houck, Jon M.] Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. RP Moyers, TB (reprint author), Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. EM tmoyers@unm.edu OI Houck, Jon/0000-0002-6565-4481 FU National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health [K01AA021431] FX JMH's effort in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award number K01AA021431. 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 5 Z9 5 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUN PY 2016 VL 65 SI SI BP 36 EP 42 DI 10.1016/j.jsat.2016.01.001 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DL3DM UT WOS:000375514400006 PM 26874558 ER PT J AU Drapkin, ML Wilbourne, P Manuel, JK Baer, J Karlin, B Raffa, S AF Drapkin, Michelle L. Wilbourne, Paula Manuel, Jennifer K. Baer, John Karlin, Bradley Raffa, Susan TI National Dissemination of Motivation Enhancement Therapy in the Veterans Health Administration: Training Program Design and Initial Outcomes SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Motivational interviewing; Dissemination; Implementation; Motivational enhancement therapy; Veterans; Competency-based; Addictions; Substance use disorders AB Motivational enhancement therapy (MET) can be defined most simply as the ".... combination of Motivational Interviewing (MI) with assessment feedback ...." (Miller & Rollnick, 2013, p. 250). MET has a clear evidence base promoting its use especially for treatment of substance use disorders (SUDS). Despite its efficacy and utility, MET is not widely used in clinical settings. In 2012, to facilitate the dissemination of MET, the Veterans Health Administration [VHA; the health care component of the U.S. Department of Veterans Affairs (VA)] launched a national training program that provided competency-based training in MET to VA staff working in SUD specialty care clinics. All VA facilities are required to implement EBP5 for SUDs, such as MET, and ensure that they are available to veterans. This paper describes the VA MET training program and examines the impact of the MET training program on participants' knowledge of MET and self-reported MET skills. We review the components of the training and consultation and discuss adaptations made from the Project MATCH MET model to a real world clinical setting. Of the 264 training participants we trained 2012-2013, 213 (81%) successfully completed all requirements of the training program, including requirements for demonstrating competency and attending at least 75% of scheduled consultation calls. After completion of the training program, approximately 85% of the clinicians reported implementing MET often (either 1-3 times per week or daily). Furthermore, we saw significant increases in MI knowledge from pretraining assessment to post-workshop and from pretraining to post-consultations. Additional training program details and revisions are discussed. Published by Elsevier Inc. C1 [Drapkin, Michelle L.; Wilbourne, Paula; Manuel, Jennifer K.; Baer, John; Karlin, Bradley; Raffa, Susan] US Dept Vet Affairs, Mental Hlth Serv, Washington, DC 20420 USA. RP Drapkin, ML (reprint author), Rutgers State Univ, 17 Senior St, New Brunswick, NJ 08901 USA. EM drapkin@rutgers.edu NR 13 TC 1 Z9 1 U1 3 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUN PY 2016 VL 65 SI SI BP 83 EP 87 DI 10.1016/j.jsat.2016.02.002 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DL3DM UT WOS:000375514400012 PM 26951921 ER PT J AU Fischer, K Meral, FC Zhang, YZ Vangel, MG Jolesz, FA Ichimura, T Bonventre, JV AF Fischer, Krisztina Meral, F. Can Zhang, Yongzhi Vangel, Mark G. Jolesz, Ferenc A. Ichimura, Takaharu Bonventre, Joseph V. TI High-resolution renal perfusion mapping using contrast-enhanced ultrasonography in ischemia-reperfusion injury monitors changes in renal microperfusion SO KIDNEY INTERNATIONAL LA English DT Article DE acute kidney injury; ischemia reperfusion; KIM-1; perfusion imaging ID ACUTE KIDNEY INJURY; OXYGENATION; PATHOGENESIS; FAILURE; DEFECT AB Alterations in renal microperfusion play an important role in the development of acute kidney injury with long-term consequences. Here we used contrast-enhanced ultrasonography as a novel method for depicting intrarenal distribution of blood flow. After infusion of microbubble contrast agent, bubbles were collapsed in the kidney and postbubble destruction refilling was measured in various regions of the kidney. Local perfusion was monitored in vivo at 15, 30, 45, 60 minutes and 24 hours after 28 minutes of bilateral ischemia in 12 mice. High-resolution, pixel-by-pixel analysis was performed on each imaging clip using customized software, yielding parametric perfusion maps of the kidney, representing relative blood volume in each pixel. These perfusion maps revealed that outer medullary perfusion decreased disproportionately to the reduction in the cortical and inner medullary perfusion after ischemia. Outer medullary perfusion was significantly decreased by 69% at 60 minutes postischemia and remained significantly less (40%) than preischemic levels at 24 hours postischemia. Thus, contrast-enhanced ultrasonography with high-resolution parametric perfusion maps can monitor changes in renal microvascular perfusion in space and time in mice. This novel technique can be translated to clinical use in man. C1 [Fischer, Krisztina; Meral, F. Can; Zhang, Yongzhi; Jolesz, Ferenc A.] Harvard Univ, Brigham & Womens Hosp, Focused Ultrasound Lab, Dept Radiol,Med Sch, Boston, MA 02115 USA. [Fischer, Krisztina; Ichimura, Takaharu; Bonventre, Joseph V.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Renal, Boston, MA 02115 USA. [Fischer, Krisztina; Ichimura, Takaharu; Bonventre, Joseph V.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Biomed Engn Div, Boston, MA 02115 USA. [Vangel, Mark G.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Bonventre, JV (reprint author), Harvard Inst Med, Brigham & Womens Hosp, Room 570,4 Blackfan Circle, Boston, MA 02115 USA. EM joseph_bonventre@hms.harvard.edu FU National Institutes of Health [DK 39773, DK 72381, R25 CA089017-06A2] FX The study was funded by National Institutes of Health grants DK 39773, DK 72381, and R25 CA089017-06A2. We thank Visual Sonics (Toronto, Ontario, Canada) for providing the MicroMarker contrast agent for this research project. We are very grateful to Fred Roberts and Dr. Sudeshna Fisch for their generous assistance during the experiments. NR 21 TC 1 Z9 1 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2016 VL 89 IS 6 BP 1388 EP 1398 DI 10.1016/j.kint.2016.02.004 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DL5QY UT WOS:000375693100027 PM 27165821 ER PT J AU Marchesan, J Jiao, YZ Schaff, RA Hao, J Morelli, T Kinney, JS Gerow, E Sheridan, R Rodrigues, V Paster, BJ Inohara, N Giannobile, WV AF Marchesan, J. Jiao, Y. Z. Schaff, R. A. Hao, J. Morelli, T. Kinney, J. S. Gerow, E. Sheridan, R. Rodrigues, V. Paster, B. J. Inohara, N. Giannobile, W. V. TI TLR4, NOD1 and NOD2 mediate immune recognition of putative newly identified periodontal pathogens SO MOLECULAR ORAL MICROBIOLOGY LA English DT Article DE anaerobes; biofilms; cell receptors; innate immunity; oral microbiology; periodontal disease ID PORPHYROMONAS-GINGIVALIS; MESOTHELIAL CELLS; DENDRITIC CELLS; BONE-RESORPTION; RECEPTOR 2; RESPONSES; ACTIVATION; DISEASE; INFECTION; MOUSE AB Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. Although the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, six being classical pathogens and four putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone-marrow-derived macrophages (BMDM) from wild-type (WT) and Toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. Campylobacter concisus, C.rectus, and S.infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs andNOD2-expressing human embryonic kidney cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2 stimulatory activity. These studies allowed us to provide important evidence on newly identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials.gov NCT01154855). C1 [Marchesan, J.; Jiao, Y. Z.; Schaff, R. A.; Hao, J.; Morelli, T.; Kinney, J. S.; Gerow, E.; Sheridan, R.; Rodrigues, V.; Giannobile, W. V.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, 1011 N Univ Ave,Rm 3397, Ann Arbor, MI 48109 USA. [Marchesan, J.; Jiao, Y. Z.; Schaff, R. A.; Hao, J.; Morelli, T.; Kinney, J. S.; Gerow, E.; Sheridan, R.; Rodrigues, V.; Giannobile, W. V.] Univ Michigan, Sch Dent, Michigan Ctr Oral Hlth Res, Ann Arbor, MI 48109 USA. [Marchesan, J.; Morelli, T.] Univ N Carolina, Dept Periodontol, Chapel Hill, NC USA. [Paster, B. J.] Forsyth Inst, Cambridge, MA USA. [Paster, B. J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Inohara, N.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. RP Giannobile, WV (reprint author), Univ Michigan, Sch Dent, Dept Periodont & Oral Med, 1011 N Univ Ave,Rm 3397, Ann Arbor, MI 48109 USA.; Inohara, N (reprint author), Univ Michigan, Sch Med, Dept Pathol, 1500 E Med Ctr Dr,MSRBI 4524, Ann Arbor, MI 48109 USA. EM ino@med.umich.edu; wgiannob@umich.edu OI Giannobile, William/0000-0002-7102-9746 FU Colgate Palmolive Co.; NIH/NCRR [UL1RR024986]; NIH [F32DE021934] FX This study was supported by Colgate Palmolive Co., NIH/NCRR UL1RR024986 (to WVG) and NIH F32DE021934 (to JTM). The authors would like to thank Dr. Gabriel Nunez (University of Michigan) for providing MyD88 and TLR2/4 double KO mice mouse BMDM and NOD2-HEK293, Drs. R. Teles (Forsyth Institute) and C. Fenno (University of Michigan) for providing bacteria, Dr. Robertson Davenport (University of Michigan) for providing filter buffy coat. The authors would like to thank Host Microbiome Initiative in University of Michigan Medical School for bacterial culture support. The authors would also thank Dr. Thomas Braun (University of Michigan School of Public Health) for the biostatistics discussion. The authors would also like to thank James Sugai, Christina Huffman, Anna Galloro, Hilye Pittman, and Amy Collins for clinical and laboratory support. All the authors declare no conflict of interest. NR 47 TC 2 Z9 2 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2041-1006 EI 2041-1014 J9 MOL ORAL MICROBIOL JI Mol. Oral Microbiol. PD JUN PY 2016 VL 31 IS 3 BP 243 EP 258 DI 10.1111/omi.12116 PG 16 WC Dentistry, Oral Surgery & Medicine; Microbiology SC Dentistry, Oral Surgery & Medicine; Microbiology GA DL6XT UT WOS:000375784100005 PM 26177212 ER PT J AU Pacold, ME Brimacombe, KR Chan, SH Rohde, JM Lewis, CA Swier, LJYM Possemato, R Chen, WW Sullivan, LB Fiske, BP Cho, S Freinkman, E Birsoy, K Abu-Remaileh, M Shaul, YD Liu, CM Zhou, M Koh, MJ Chung, H Davidson, SM Luengo, A Wang, AQ Xu, X Yasgar, A Liu, L Rai, G Westover, KD Vander Heiden, MG Shen, M Gray, NS Boxer, MB Sabatini, DM AF Pacold, Michael E. Brimacombe, Kyle R. Chan, Sze Ham Rohde, Jason M. Lewis, Caroline A. Swier, Lotteke J. Y. M. Possemato, Richard Chen, Walter W. Sullivan, Lucas B. Fiske, Brian P. Cho, Steve Freinkman, Elizaveta Birsoy, Kivanc Abu-Remaileh, Monther Shaul, Yoav D. Liu, Chieh Min Zhou, Minerva Koh, Min Jung Chung, Haeyoon Davidson, Shawn M. Luengo, Alba Wang, Amy Q. Xu, Xin Yasgar, Adam Liu, Li Rai, Ganesha Westover, Kenneth D. Vander Heiden, Matthew G. Shen, Min Gray, Nathanael S. Boxer, Matthew B. Sabatini, David M. TI A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PYRUVATE-KINASE M2; CELL LUNG-CANCER; PHOSPHOGLYCERATE DEHYDROGENASE; METABOLISM; GLYCINE; BIOSYNTHESIS; PROLIFERATION; TUMORIGENESIS; IMBALANCE; PATHWAY AB Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo. C1 [Pacold, Michael E.; Chan, Sze Ham; Swier, Lotteke J. Y. M.; Chen, Walter W.; Cho, Steve; Freinkman, Elizaveta; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Sabatini, David M.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Pacold, Michael E.; Chan, Sze Ham; Swier, Lotteke J. Y. M.; Chen, Walter W.; Cho, Steve; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Sabatini, David M.] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA USA. [Pacold, Michael E.; Chan, Sze Ham; Lewis, Caroline A.; Swier, Lotteke J. Y. M.; Chen, Walter W.; Sullivan, Lucas B.; Fiske, Brian P.; Cho, Steve; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Davidson, Shawn M.; Luengo, Alba; Vander Heiden, Matthew G.; Sabatini, David M.] Koch Inst Integrat Canc Res, Cambridge, MA USA. [Pacold, Michael E.; Chan, Sze Ham; Swier, Lotteke J. Y. M.; Chen, Walter W.; Cho, Steve; Abu-Remaileh, Monther; Liu, Chieh Min; Zhou, Minerva; Koh, Min Jung; Chung, Haeyoon; Sabatini, David M.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Pacold, Michael E.; Gray, Nathanael S.] Dana Farber Canc Inst, Longwood Ctr, Boston, MA 02115 USA. [Pacold, Michael E.; Chan, Sze Ham] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Brimacombe, Kyle R.; Rohde, Jason M.; Wang, Amy Q.; Xu, Xin; Yasgar, Adam; Liu, Li; Rai, Ganesha; Shen, Min; Boxer, Matthew B.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Possemato, Richard] NYU, Langone Med Ctr, New York, NY USA. [Birsoy, Kivanc] Rockefeller Univ, Lab Metab Regulat & Genet, 1230 York Ave, New York, NY 10021 USA. [Shaul, Yoav D.] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91010 Jerusalem, Israel. [Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Sabatini, DM (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Sabatini, DM (reprint author), MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA USA.; Sabatini, DM (reprint author), Koch Inst Integrat Canc Res, Cambridge, MA USA.; Sabatini, DM (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. EM sabatini@wi.mit.edu RI Abu-Remaileh, Monther/M-3747-2016; OI Possemato, Richard/0000-0002-2401-0030 FU Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation [DRG-112-12]; Department of Defense Breast Cancer Research Program Postdoctoral Fellowship [BC120208]; ASTRO Resident Seed Grant [RA-2011-1]; Susan G. Komen for the Cure; EMBO Long-Term Fellowship; NIH [1 R03 DA034602-01A1]; Stewart Trust FX We thank T. Wang and E. Edenberg for critical reading of the manuscript, S. Murphy for assistance with mouse experiments, and J. Pacold of the Lawrence Berkeley National Laboratory for assistance in interpreting Tm data. This research is supported by the Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG-112-12), a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC120208), and an ASTRO Resident Seed Grant (RA-2011-1) (all to M.E.P.)., by Susan G. Komen for the Cure (grant to R.L.P.), by an EMBO Long-Term Fellowship (to M.A.-R.), by the NIH (1 R03 DA034602-01A1 to D.M.S.) and by the Stewart Trust (to D.M.S.). D.M.S. is an investigator of the Howard Hughes Medical Institute. NR 36 TC 18 Z9 18 U1 8 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUN PY 2016 VL 12 IS 6 BP 452 EP U118 DI 10.1038/NCHEMBIO.2070 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM2EW UT WOS:000376160600016 PM 27110680 ER PT J AU Newton, R Priyadharshini, B Turka, LA AF Newton, Ryan Priyadharshini, Bhavana Turka, Laurence A. TI Immunometabolism of regulatory T cells SO NATURE IMMUNOLOGY LA English DT Review ID ARYL-HYDROCARBON RECEPTOR; FATTY-ACID-METABOLISM; REG CELLS; IMMUNE HOMEOSTASIS; MEMORY DEVELOPMENT; EFFECTOR FUNCTION; CIS-ELEMENT; DIFFERENTIATION; ACTIVATION; GENERATION AB The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells. C1 [Newton, Ryan; Priyadharshini, Bhavana; Turka, Laurence A.] Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA. RP Turka, LA (reprint author), Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA. EM lturka@partners.org FU US National Institutes of Health [P01-HL018646, T32-AI007529] FX We thank B. Blazar, J. Bluestone, H. Chi, J. Rathmell and members of the Turka laboratory for discussions. Supported by the US National Institutes of Health (P01-HL018646 to L.A.T. and B.P., and T32-AI007529 to R.N.). NR 86 TC 12 Z9 12 U1 11 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2016 VL 17 IS 6 BP 618 EP 625 DI 10.1038/ni.3466 PG 8 WC Immunology SC Immunology GA DM2FK UT WOS:000376162200006 PM 27196520 ER PT J AU Wu, H Wu, XJ Zhang, Y AF Wu, Hao Wu, Xiaoji Zhang, Yi TI Base-resolution profiling of active DNA demethylation using MAB-seq and caMAB-seq SO NATURE PROTOCOLS LA English DT Article ID EMBRYONIC STEM-CELLS; GENOME-WIDE ANALYSIS; TET PROTEINS; 5-METHYLCYTOSINE OXIDATION; GENE-EXPRESSION; POSTNATAL-DEVELOPMENT; MAMMALIAN DNA; SELF-RENEWAL; ES CELLS; 5-HYDROXYMETHYLCYTOSINE AB A complete understanding of the function of the ten-eleven translocation (TET) family of dioxygenase-mediated DNA demethylation requires new methods to quantitatively map oxidized 5-methylcytosine (5mC) bases at high resolution. We have recently developed a methylase-assisted bisulfite sequencing (MAB-seq) method that allows base-resolution mapping of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), two oxidized 5mC bases indicative of active DNA demethylation events. In standard bisulfite sequencing (BS-seq), unmodified C, 5fC and 5caC are read as thymine; thus 5fC and 5caC cannot be distinguished from C. In MAB-seq, unmodified C is enzymatically converted to 5mC, allowing direct mapping of rare modifications such as 5fC and 5caC. By combining MAB-seq with chemical reduction of 5fC to 5hmC, we also developed caMAB-seq, a method for direct 5caC mapping. Compared with subtraction-based mapping methods, MAB-seq and caMAB-seq require less sequencing effort and enable robust statistical calling of 5fC and/or 5caC. MAB-seq and caMAB-seq can be adapted to map 5fC/5caC at the whole-genome scale (WG-MAB-seq), within specific genomic regions enriched for enhancer-marking histone modifications (chromatin immunoprecipitation (ChIP)-MAB-seq), or at CpG-rich sequences (reduced-representation (RRRR)-MAB-seq) such as gene promoters. The full protocol, including DNA preparation, enzymatic treatment, library preparation and sequencing, can be completed within 6-8 d. C1 [Wu, Hao; Wu, Xiaoji; Zhang, Yi] Howard Hughes Med Inst, Boston, MA 02115 USA. [Wu, Hao; Wu, Xiaoji; Zhang, Yi] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Wu, Hao; Wu, Xiaoji; Zhang, Yi] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Wu, Hao; Wu, Xiaoji; Zhang, Yi] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. [Wu, Hao] Univ Penn, Epigenet Program, Dept Genet, Philadelphia, PA 19104 USA. RP Zhang, Y (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA.; Zhang, Y (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA.; Zhang, Y (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.; Zhang, Y (reprint author), Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. EM yzhang@genetics.med.harvard.edu FU Jane Coffin Childs Memorial Fund for Medical Research; National Human Genome Research Institute [R00HG007982]; China Scholarship Council FX H.W. was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research and is currently supported by the National Human Genome Research Institute (R00HG007982). X.W. was supported by the China Scholarship Council. Y.Z. is an investigator of the Howard Hughes Medical Institute. NR 67 TC 1 Z9 1 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD JUN PY 2016 VL 11 IS 6 BP 1081 EP 1100 DI 10.1038/nprot.2016.069 PG 20 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DL5PQ UT WOS:000375689600005 PM 27172168 ER PT J AU de Leeuw, CA Neale, BM Heskes, T Posthuma, D AF de Leeuw, Christiaan A. Neale, Benjamin M. Heskes, Tom Posthuma, Danielle TI The statistical properties of gene-set analysis SO NATURE REVIEWS GENETICS LA English DT Review ID GENOME-WIDE ASSOCIATION; PATHWAY ANALYSIS; BIOLOGICAL PATHWAYS; BIPOLAR DISORDER; DISEASE; IDENTIFICATION; VARIANTS; INSIGHTS; LOCI AB The rapid increase in loci discovered in genome-wide association studies has created a need to understand the biological implications of these results. Gene-set analysis provides a means of gaining such understanding, but the statistical properties of gene-set analysis are not well understood, which compromises our ability to interpret its results. In this Analysis article, we provide an extensive statistical evaluation of the core structure that is inherent to all gene-set analyses and we examine current implementations in available tools. We show which factors affect valid and successful detection of gene sets and which provide a solid foundation for performing and interpreting gene-set analysis. C1 [de Leeuw, Christiaan A.; Posthuma, Danielle] Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogen & Cognit Res, NL-1081 HV Amsterdam, Netherlands. [de Leeuw, Christiaan A.; Heskes, Tom] Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 EC Nijmegen, Netherlands. [Neale, Benjamin M.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Posthuma, Danielle] VU Univ Med Ctr Amsterdam, Dept Clin Genet, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands. RP de Leeuw, CA; Posthuma, D (reprint author), Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogen & Cognit Res, NL-1081 HV Amsterdam, Netherlands.; de Leeuw, CA (reprint author), Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 EC Nijmegen, Netherlands.; Posthuma, D (reprint author), VU Univ Med Ctr Amsterdam, Dept Clin Genet, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands. EM c.a.de.leeuw@vu.nl; d.posthuma@vu.nl RI Heskes, Tom/A-1443-2010 OI Heskes, Tom/0000-0002-3398-5235 FU Wellcome Trust [076113, 085475]; Netherlands Organization for Scientific Research [NWO VICI 453-14-005, 645-000-003] FX This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. This work was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005, 645-000-003). NR 43 TC 6 Z9 6 U1 13 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD JUN PY 2016 VL 17 IS 6 BP 353 EP 364 DI 10.1038/nrg.2016.29 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DM2FY UT WOS:000376163600010 PM 27070863 ER PT J AU Feraco, AM Brand, SR Mack, JW Kesselheim, JC Block, SD Wolfe, J AF Feraco, Angela M. Brand, Sarah R. Mack, Jennifer W. Kesselheim, Jennifer C. Block, Susan D. Wolfe, Joanne TI Communication Skills Training in Pediatric Oncology: Moving Beyond Role Modeling SO PEDIATRIC BLOOD & CANCER LA English DT Review DE childhood cancer; communication skills; communication skills training; fellowship training; graduate medical education; medical education; pediatric oncology ID DOCTOR-PATIENT COMMUNICATION; RANDOMIZED CONTROLLED-TRIAL; OF-LIFE CARE; PALLIATIVE CARE; ADVANCED CANCER; INFORMED-CONSENT; DIFFICULT CONVERSATIONS; TEACHING COMMUNICATION; HEMATOLOGY-ONCOLOGY; IMPROVING COMMUNICATION AB Communication is central to pediatric oncology care. Pediatric oncologists disclose life-threatening diagnoses, explain complicated treatment options, and endeavor to give honest prognoses, to maintain hope, to describe treatment complications, and to support families in difficult circumstances ranging from loss of function and fertility to treatment-related or disease-related death. However, parents, patients, and providers report substantial communication deficits. Poor communication outcomes may stem, in part, from insufficient communication skills training, overreliance on role modeling, and failure to utilize best practices. This review summarizes evidence for existing methods to enhance communication skills and calls for revitalizing communication skills training within pediatric oncology. C1 [Feraco, Angela M.; Mack, Jennifer W.; Kesselheim, Jennifer C.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Feraco, Angela M.; Mack, Jennifer W.; Kesselheim, Jennifer C.; Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Feraco, Angela M.; Block, Susan D.] Brigham & Womens Hosp, Ariadne Labs, 75 Francis St, Boston, MA 02115 USA. [Feraco, Angela M.; Block, Susan D.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Brand, Sarah R.; Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Mack, Jennifer W.; Kesselheim, Jennifer C.] Dana Farber Canc Inst, Ctr Populat Sci, Boston, MA 02115 USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Block, Susan D.] Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA USA. RP Feraco, AM (reprint author), 450 Brookline Ave,Dana 3, Boston, MA 02215 USA. EM Angela_Feraco@dfci.harvard.edu FU NHLBI NIH HHS [T32 HL007574] NR 86 TC 3 Z9 3 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 IS 6 BP 966 EP 972 DI 10.1002/pbc.25918 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FR UT WOS:000374306400003 PM 26822066 ER PT J AU Bona, K Blonquist, TM Neuberg, DS Silverman, LB Wolfe, J AF Bona, Kira Blonquist, Traci M. Neuberg, Donna S. Silverman, Lewis B. Wolfe, Joanne TI Impact of Socioeconomic Status on Timing of Relapse and Overall Survival for Children Treated on Dana-Farber Cancer Institute ALL Consortium Protocols (2000-2010) SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute lymphoblastic leukemia; disparities; poverty; socioeconomic status ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ONCOLOGY GROUP; MULTISITE SURVEILLANCE; FOOD SECURITY; UNITED-STATES; DISPARITIES; MORTALITY; HEALTH; INCOME; NEIGHBORHOOD AB BackgroundPopulation-based evidence suggests that lower socioeconomic status (SES) negatively impacts the overall survival (OS) of children with leukemia; however, the relationships between SES and treatment-related mortality, relapse, and timing of relapse remain unclear. ProcedureWe examined OS, event-free survival (EFS) and cumulative incidence (CI) and timing of relapse by community-level poverty for 575 children aged 1-18 years with newly diagnosed acute lymphoblastic leukemia (ALL) treated on consecutive phase III multicenter Dana-Farber Cancer Institute ALL Consortium Protocols between 2000 and 2010. Children were categorized into high- and low-poverty areas for the analysis using aggregate U.S. Census data linked to zip code. ResultsChildren living in high-poverty areas experienced a 5-year OS of 85% as compared with 92% for those in low-poverty areas (P = 0.02); poverty remained marginally significant (P = 0.07) after adjustment for immunophenotype, age, and white blood cell count. There were no differences detected in EFS or CI relapse by poverty area. However, 92% of the relapses observed in children from high-poverty areas occurred <36 months from complete remission, compared to 48% of those in children from low-poverty areas (P = 0.008). ConclusionsU.S. children with ALL living in high-poverty areas have a higher risk of early relapse when compared with those living in low-poverty areas despite uniform treatment. This may in part explain decreased OS observed in these children. This finding highlights disparities in childhood cancer outcomes by SES despite uniform treatment. Further investigations of the mechanistic pathways underlying this finding are needed. C1 [Bona, Kira; Silverman, Lewis B.; Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Bona, Kira; Silverman, Lewis B.; Wolfe, Joanne] Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, Boston, MA USA. [Bona, Kira; Silverman, Lewis B.; Wolfe, Joanne] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bona, Kira; Wolfe, Joanne] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Blonquist, Traci M.; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Bona, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM kira.bona@childrens.harvard.edu FU St. Baldrick's Foundation; National Palliative Care Research Center; Pablove Foundation; NIH [5PO1CA068484] FX Grant sponsor: St. Baldrick's Foundation; Grant sponsor: National Palliative Care Research Center; Grant sponsor: Pablove Foundation; Grant sponsor: NIH P01; Grant number: 5PO1CA068484. NR 41 TC 4 Z9 4 U1 9 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 IS 6 BP 1012 EP 1018 DI 10.1002/pbc.25928 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FR UT WOS:000374306400009 PM 26913850 ER PT J AU Hamrahian, AH Yuen, KCJ Gordon, MB Pulaski-Liebert, KJ Bena, J Biller, BMK AF Hamrahian, Amir H. Yuen, Kevin C. J. Gordon, Murray B. Pulaski-Liebert, Karen J. Bena, James Biller, Beverly M. K. TI Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study SO PITUITARY LA English DT Article DE Glucagon stimulation test; Adult growth hormone deficiency; Diagnosis; Adrenal insufficiency; Weight based ID GROWTH-HORMONE DEFICIENCY; CLINICAL-PRACTICE GUIDELINE; ENDOCRINE-SOCIETY; SUBCUTANEOUS GLUCAGON; DIAGNOSTIC UTILITY; ACTH; SECRETION; RESPONSES; ASSAYS; REQUIRE AB Context Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic-pituitary-adrenal (HPA) axes using weight-based dosing for the GST. Objective To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5 mg in patients >90 kg) with weight-based dosing (WB: 0.03 mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of >= 3 ng/ml and >= 18 mu g/dL, respectively. Design 28 Patients with hypothalamic-pituitary disease and 1-2 (n = 14) or >= 3 (n = 14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order. Results Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92 % sensitivity, 100 % specificity) and 2.0 ng/mL (96 % sensitivity and 100 % specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r = -0.32, P = 0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8 mu g/dL (92 % sensitivity, 100 % specificity) and 11.2 mu g/dL (92 % sensitivity and 100 % specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST. Conclusion The GST correctly classified GHD using GH cut-points of 1 ng/ml for FD-GST and 2 ng/ml for WB-GST, hence using 3 ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9 mu g/dL for FD-GST and 11 mu g/dL for WB-GST. C1 [Hamrahian, Amir H.] Cleveland Clin, Dept Endocrinol Diabet & Metab, Cleveland, OH 44022 USA. [Hamrahian, Amir H.] Cleveland Clin Abu Dhabi, Med Subspecialty Inst, Dept Endocrinol, 7th Floor,POB 112412, Abu Dhabi, U Arab Emirates. [Yuen, Kevin C. J.] Swedish Neurosci Inst, Swedish Pituitary Ctr, Seattle, WA 98122 USA. [Gordon, Murray B.] Allegheny Gen Hosp, Allegheny Neuroendocrinol Ctr, Dept Med & Neurosurg, Pittsburgh, PA 15212 USA. [Pulaski-Liebert, Karen J.; Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Bena, James] Lerner Res Inst, Quantitatve Hlth Sci, Cleveland, OH 44195 USA. RP Hamrahian, AH (reprint author), Cleveland Clin, Dept Endocrinol Diabet & Metab, Cleveland, OH 44022 USA.; Hamrahian, AH (reprint author), Cleveland Clin Abu Dhabi, Med Subspecialty Inst, Dept Endocrinol, 7th Floor,POB 112412, Abu Dhabi, U Arab Emirates. EM hamraha@clevelandclinicabudhabi.ae FU Novo Nordisk FX This study was partially supported by a Grant from Novo Nordisk. NR 35 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X EI 1573-7403 J9 PITUITARY JI Pituitary PD JUN PY 2016 VL 19 IS 3 BP 332 EP 341 DI 10.1007/s11102-016-0712-7 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DL5IA UT WOS:000375669400012 PM 26897383 ER PT J AU Pasternak, O Kubicki, M Shenton, ME AF Pasternak, Ofer Kubicki, Marek Shenton, Martha E. TI In vivo imaging of neuroinflammation in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Review DE Neuroinflammation; Schizophrenia; MRI; PET; Neuroimaging; Diffusion MRI; DTI; Free-water; Magnetization transfer ID POSITRON-EMISSION-TOMOGRAPHY; TRAUMATIC BRAIN-INJURY; MAGNETIC-RESONANCE-SPECTROSCOPY; PULSED-FIELD GRADIENT; WHITE-MATTER INJURY; RELAXATION-TIME ABNORMALITIES; PROTON MR SPECTROSCOPY; FREE-WATER ELIMINATION; MULTIPLE-SCLEROSIS; DIFFUSION MRI AB In recent years evidence has accumulated to suggest that neuroinflammation might be an early pathology of schizophrenia that later leads to neurodegeneration, yet the exact role in the etiology, as well as the source of neuroinflammation, are still not known. The hypothesis of neuroinflammation involvement in schizophrenia is quickly gaining popularity, and thus it is imperative that we have reliable and reproducible tools and measures that are both sensitive, and, most importantly, specific to neuroinflammation. The development and use of appropriate human in vivo imaging methods can help in our understanding of the location and extent of neuroinflammation in different stages of the disorder, its natural time-course, and its relation to neurodegeneration. Thus far, there is little in vivo evidence derived from neuroimaging methods. This is likely the case because the methods that are specific and sensitive to neuroinflammation are relatively new or only just being developed. This paper provides a methodological review of both existing and emerging positron emission tomography and magnetic resonance imaging techniques that identify and characterize neuroinflammation. We describe\how these methods have been used in schizophrenia research. We also outline the shortcomings of existing methods, and we highlight promising future techniques that will likely improve state-of-the-art neuroimaging as a more refined approach for investigating neuroinflammation in schizophrenia. (C) 2015 Elsevier B.V. All rights reserved. C1 [Pasternak, Ofer; Kubicki, Marek; Shenton, Martha E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02215 USA. [Pasternak, Ofer; Kubicki, Marek; Shenton, Martha E.] Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp, Boston, MA 02215 USA. [Pasternak, Ofer] Tel Aviv Univ, Dept Appl Math, IL-69978 Tel Aviv, Israel. [Kubicki, Marek] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02215 USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Brockton, MA USA. RP Pasternak, O (reprint author), Harvard Univ, Neurosci Image Comp, Brigham & Womens Hosp, Sch Med, 1249 Boylston St, Boston, MA 02215 USA. EM ofer@bwh.harvard.edu FU NIH [R01MH102377-01, R01MH074794, P41RR013218, P41EB015902]; VA Merit Award; NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator grant from the Brain & Behavior Research Foundation FX This work was partially funded by grants from the NIH (nos. R01MH102377-01, R01MH074794, P41RR013218, and P41EB015902) and by a VA Merit Award (MES). OP was partially supported by a NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator grant from the Brain & Behavior Research Foundation. NR 177 TC 4 Z9 4 U1 7 U2 14 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 JUN PY 2016 VL 173 IS 3 BP 200 EP 212 DI 10.1016/j.schres.2015.05.034 PG 13 WC Psychiatry SC Psychiatry GA DL7VE UT WOS:000375847400012 PM 26048294 ER PT J AU Schorr, M Dichtel, LE Gerweck, AV Torriani, M Miller, KK Bredella, MA AF Schorr, Melanie Dichtel, Laura E. Gerweck, Anu V. Torriani, Martin Miller, Karen K. Bredella, Miriam A. TI Body composition predictors of skeletal integrity in obesity SO SKELETAL RADIOLOGY LA English DT Article DE Obesity; DXA; Trabecular bone score; Hip structural analysis; Visceral adipose tissue; Lean mass ID X-RAY ABSORPTIOMETRY; BONE-MINERAL DENSITY; FEMORAL-NECK STRENGTH; OSTEOPOROTIC FRACTURES; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; HIP FRACTURE; FAT MASS; ABDOMINAL FAT; YOUNG-ADULTS AB Objective To determine body composition predictors of skeletal integrity in overweight/obese subjects using dual energy X-ray absorptiometry (DXA). We hypothesized that visceral adiposity would be negatively, and lean mass positively, associated with DXA measures of skeletal integrity in obesity. Materials and methods Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant and written informed consent was obtained. We studied 82 overweight or obese, but otherwise healthy premenopausal women and men of similar age who were part of a clinical trial (mean age: 37 +/- 10 years, mean BMI: 34 +/- 7 kg/m(2)). All subjects underwent DXA of the spine and hip for assessment of bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA), and of the whole body for the assessment of body composition, including estimated visceral adipose tissue (VAT). Results Sixty-three subjects (77 %) had normal BMD and 19 subjects (23 %) had osteopenia. There were strong age-, sex-, and BMD-independent positive associations between lean mass and HSA parameters (r = 0.50 to r = 0.81, p < 0.0001), whereas there was no association with TBS. There were strong age-, sex- and BMD-independent inverse associations between total fat and VAT mass and TBS (r = -0.60 and r = -0.72, p < 0.0001 for both correlations), whereas there were no associations with HSA parameters. Conclusion Lean mass is a positive predictor of hip geometry, whereas fat and VAT mass are negative predictors of trabecular microarchitecture in overweight/obese subjects. C1 [Schorr, Melanie; Dichtel, Laura E.; Gerweck, Anu V.; Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B,55 Fruit St, Boston, MA 02114 USA. [Schorr, Melanie; Dichtel, Laura E.; Gerweck, Anu V.; Miller, Karen K.] Harvard Univ, Sch Med, Bulfinch 457B,55 Fruit St, Boston, MA 02114 USA. [Torriani, Martin; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Torriani, Martin; Bredella, Miriam A.] Harvard Univ, Sch Med, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA.; Bredella, MA (reprint author), Harvard Univ, Sch Med, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@mgh.harvard.edu FU NIH [R01 DK095792, K24 HL092902, UL1 RR-025758] FX This study was supported by NIH grants R01 DK095792, K24 HL092902 and UL1 RR-025758. NR 51 TC 1 Z9 1 U1 1 U2 3 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 JUN PY 2016 VL 45 IS 6 BP 813 EP 819 DI 10.1007/s00256-016-2363-1 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DJ8QD UT WOS:000374476200008 PM 26984471 ER PT J AU Handforth, A AF Handforth, Adrian TI Linking Essential Tremor to the Cerebellum-Animal Model Evidence SO CEREBELLUM LA English DT Review DE Tremor; Harmaline; Inferior olive; Cerebellum; Animal model ID PURKINJE-CELL DEGENERATION; HARMALINE-INDUCED TREMOR; COMPLEX SPIKE SYNCHRONY; LEANER MUTANT MICE; INFERIOR OLIVARY NEURONS; KNOCKOUT MICE; OLIVOCEREBELLAR CIRCUIT; PARVALBUMIN EXPRESSION; MORPHOLOGICAL-CHANGES; MOTOR COORDINATION AB In this review, we hope to stimulate interest in animal models as opportunities to understand tremor mechanisms within the cerebellar system. We begin by considering the harmaline model of essential tremor (ET), which has ET-like anatomy and pharmacology. Harmaline induces the inferior olive (IO) to burst fire rhythmically, recruiting rhythmic activity in Purkinje cells (PCs) and deep cerebellar nuclei (DCN). This model has fostered the IO hypothesis of ET, which postulates that factors that promote excess IO, and hence PC complex spike synchrony, also promote tremor. In contrast, the PC hypothesis postulates that partial PC cell loss underlies tremor of ET. We describe models in which chronic partial PC loss is associated with tremor, such as the Weaver mouse, and others with PC loss that do not show tremor, such as the Purkinje cell degeneration mouse. We postulate that partial PC loss with tremor is associated with terminal axonal sprouting. We then discuss tremor that occurs with large lesions of the cerebellum in primates. This tremor has variable frequency and is an ataxic tremor not related to ET. Another tremor type that is not likely related to ET is tremor in mice with mutations that cause prolonged synaptic GABA action. This tremor is probably due to mistiming within cerebellar circuitry. In the final section, we catalog tremor models involving neurotransmitter and ion channel perturbations. Some appear to be related to the IO hypothesis of ET, while in others tremor may be ataxic or due to mistiming. In summary, we offer a tentative framework for classifying animal action tremor, such that various models may be considered potentially relevant to ET, subscribing to IO or PC hypotheses, or not likely relevant, as with mistiming or ataxic tremor. Considerable further research is needed to elucidate the mechanisms of tremor in animal models. C1 [Handforth, Adrian] Vet Affairs Greater Los Angeles Healthcare Syst, Neurol Serv, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Handforth, A (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Neurol Serv, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM charles.handforth@va.gov FU Veterans Affairs; Cyberonics Inc.; Medtronic; UCB Pharma; Ortho-McNeil; Forest Laboratories; Sonexa; Eisai FX We are grateful to Nicholas Franich, Ph.D. for the assistance with figure. The author was supported by Veterans Affairs. The author has received clinical research funding from Cyberonics Inc., Medtronic, UCB Pharma, Ortho-McNeil, Forest Laboratories, Sonexa, and Eisai. NR 106 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD JUN PY 2016 VL 15 IS 3 SI SI BP 285 EP 298 DI 10.1007/s12311-015-0750-0 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DK7EL UT WOS:000375087600007 PM 26660708 ER PT J AU Bodranghien, F Bastian, A Casali, C Hallett, M Louis, E Manto, M Marien, P Nowak, DA Schmahmann, JD Serrao, M Steiner, KM Strupp, M Tilikete, C Timmann, D van Dun, K AF Bodranghien, Florian Bastian, Amy Casali, Carlo Hallett, Mark Louis, Elan D. Manto, Mario Marien, Peter Nowak, Dennis A. Schmahmann, Jeremy D. Serrao, Mariano Steiner, Katharina Marie Strupp, Michael Tilikete, Caroline Timmann, Dagmar van Dun, Kim TI Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome SO CEREBELLUM LA English DT Article DE Cerebellum; Ataxia; Eye movements; Dysmetria; Tremor; A- or Dysdiadochokinesia; Hypotonia; Speech; Dysarthria; Language; Cognition; Affect; Loops; Functional topography; Cerebellar syndrome ID COGNITIVE-AFFECTIVE SYNDROME; ATAXIA RATING-SCALE; ESSENTIAL TREMOR; SPINOCEREBELLAR ATAXIA; SPEECH PRODUCTION; ARM MOVEMENTS; MOTOR CONTROL; FUNCTIONAL TOPOGRAPHY; DOWNBEAT NYSTAGMUS; ALZHEIMERS-DISEASE AB The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops. C1 [Bodranghien, Florian; Manto, Mario] FNRS ULB Erasme, Unite Etude Mouvement, 808 Route Lennik, B-1070 Brussels, Belgium. [Strupp, Michael] Univ Munich, Munich, Germany. [Tilikete, Caroline] Team ImpAct, CNRS UMR5292, CRNL INSERM U1028, F-69676 Bron, France. [Tilikete, Caroline] Univ Lyon 1, F-69373 Lyon, France. [Tilikete, Caroline] Hop Neurol Pierre Wertheimer, Hosp Civils Lyon, Neuroophthalmol & Neurol D, F-69677 Bron, France. [Hallett, Mark] NINDS, Human Motor Control Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Timmann, Dagmar] Univ Clin Essen, Dept Neurol, Hufelandstr 55, D-45147 Essen, Germany. [Steiner, Katharina Marie; Timmann, Dagmar] Univ Duisburg Essen, Dept Neurol, Hufelandstr 55, D-45147 Essen, Germany. [Louis, Elan D.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT USA. [Nowak, Dennis A.] Helios Klin Kipfenberg, Kindingerstr 13, D-85110 Kipfenberg, Germany. [Nowak, Dennis A.] Univ Marburg, Neurol Univ Klin, Baldingerstr, D-35043 Marburg, Germany. [Bastian, Amy] Kennedy Krieger Inst, 707 N Broadway, Baltimore, MD 21205 USA. [Casali, Carlo; Serrao, Mariano] Univ Rome La Sapienza, Dept Med & Surg Sci & Biotechnol, Rome, Italy. [Serrao, Mariano] Policlin Italia, Rehabil Ctr, Movement Anal LAB, Rome, Italy. [Schmahmann, Jeremy D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Cognit Behav Neurol Unit,Ataxia Unit, Dept Neurol,Lab Neuroanat & Cerebellar Neurobiol, Boston, MA 02114 USA. [Marien, Peter] Vrije Univ Brussel, CLIN, Clin & Expt Neurolinguist, Pleinlaan 2, B-1050 Brussels, Belgium. [van Dun, Kim] ZNA Middelheim Gen Hosp, Dept Neurol, Antwerp, Belgium. [van Dun, Kim] ZNA Middelheim Gen Hosp, Memory Clin, Antwerp, Belgium. RP Manto, M (reprint author), FNRS ULB Erasme, Unite Etude Mouvement, 808 Route Lennik, B-1070 Brussels, Belgium. EM fbodrang@ulb.ac.be; bastian@kennedykrieger.org; carlo.casali@uniroma1.it; hallettm@ninds.nih.gov; elan.louis@yale.edu; mmanto@ulb.ac.be; peter.marien5@telenet.be; dennis.nowak@neurologie-kipfenberg.de; JSCHMAHMANN@mgh.harvard.edu; mariano.serrao@uniroma1.it; KatharinaMarie.Steiner@uk-essen.de; Michael.Strupp@med.uni-muenchen.de; caroline.tilikete@inserm.fr; dagmar.timmann-braun@uni-duisburg-essen.de; kimvandun@gmail.com NR 185 TC 9 Z9 9 U1 8 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD JUN PY 2016 VL 15 IS 3 SI SI BP 369 EP 391 DI 10.1007/s12311-015-0687-3 PG 23 WC Neurosciences SC Neurosciences & Neurology GA DK7EL UT WOS:000375087600015 PM 26105056 ER PT J AU Lerrigo, R Beste, LA Leipertz, SL Green, PK Lok, ASF Kogut, MJ Ioannou, GN AF Lerrigo, Robert Beste, Lauren A. Leipertz, Steven L. Green, Pamela K. Lok, Anna S. F. Kogut, Matthew J. Ioannou, George N. TI Characteristics and outcomes of transjugular intrahepatic portosystemic shunt recipients in the VA Healthcare System SO EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Article ID STAGE LIVER-DISEASE; HEPATORENAL-SYNDROME; REFRACTORY ASCITES; HEPATOCELLULAR-CARCINOMA; ADMINISTRATIVE DATABASES; HEPATIC HYDROTHORAX; MELD SCORE; CHILD-PUGH; SURVIVAL; VETERANS AB complications of portal hypertension. We aimed to describe post-TIPS mortality and its predictors in the modern era of covered stents. Patients and methods We identified patients with cirrhosis who underwent TIPS insertion at Veterans Affairs Healthcare facilities nationally from 2004 to 2014 (n=703), most of which (95%) were performed as elective procedures. We followed patients until the date of death, transplantation, or the end of the observation period. Results TIPS recipients had a mean age of 59.3 years (SD 8) and 97% were men. The mean Model for End Stage Liver Disease (MELD) score was 13 (SD 4.8); 47% had hepatitis C virus (HCV) infection, 48% had variceal hemorrhage, and 40% had ascites. During a mean follow-up of 1.72 years (SD 1.9), 57.5% of TIPS recipients died (n=404) and only 5.3% underwent liver transplantation (n=37). The median survival after TIPS was 1.74 years (interquartile range 0.3-4.7). Thirty-day mortality after TIPS was 11.6% [95% confidence interval (CI) 9.4-14.2], 1-year mortality was 40.3% (95% CI 36.7-44.2), and 3-year mortality was 61.9% (95% CI 57.9-66.0). Independent predictors of post-TIPS mortality included medical comorbidity burden, low albumin, HCV infection, and high MELD score (or high international normalized ratio and bilirubin when the components of the MELD score were analyzed individually). TIPS revision was performed at least once in 27.3% of TIPS recipients. Conclusion TIPS should not be considered simply as a bridge to transplantation. Burden of extra-hepatic comorbidities, HCV infection, and low serum albumin strongly predict post-TIPS mortality in addition to the MELD score. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Lerrigo, Robert; Beste, Lauren A.] Vet Affairs Puget Sound Healthcare Syst, Primary Care Serv, Seattle, WA USA. [Beste, Lauren A.; Leipertz, Steven L.; Green, Pamela K.] Vet Affairs Puget Sound Healthcare Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Kogut, Matthew J.] Vet Affairs Puget Sound Healthcare Syst, Dept Radiol, Seattle, WA USA. [Ioannou, George N.] Vet Affairs Puget Sound Healthcare Syst, Hosp & Specialty Med Serv, Seattle, WA USA. [Lerrigo, Robert; Beste, Lauren A.] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Kogut, Matthew J.] Univ Washington, Div Intervent Radiol, Seattle, WA 98195 USA. [Ioannou, George N.] Univ Washington, Div Gastroenterol, Seattle, WA 98195 USA. [Lok, Anna S. F.] Univ Michigan, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Healthcare Syst, Gastroenterol, S-111 Gastro,1660 S Columbian Way, Seattle, WA 98108 USA. EM georgei@medicine.washington.edu FU VA Puget Sound HealthCare System (Seattle, Washington); Clinical Science Research and Development, Office of Research and Development, Veterans Affairs [CX000320]; VA Office of Public Health and Human Health Pathogens FX This work was supported by resources from the VA Puget Sound HealthCare System (Seattle, Washington). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.; The study was funded by a Merit Review grant (CX000320), Clinical Science Research and Development, Office of Research and Development, Veterans Affairs (GNI), and by the VA Office of Public Health and Human Health Pathogens (LAB). NR 31 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 0954-691X EI 1473-5687 J9 EUR J GASTROEN HEPAT JI Eur. J. Gastroenterol. Hepatol. PD JUN PY 2016 VL 28 IS 6 BP 667 EP 675 DI 10.1097/MEG.0000000000000604 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK7ZX UT WOS:000375147100010 PM 26886386 ER PT J AU Karel, MJ Mulligan, EA Walder, A Martin, LA Moye, J Naik, AD AF Karel, Michele J. Mulligan, Elizabeth A. Walder, Annette Martin, Lindsey A. Moye, Jennifer Naik, Aanand D. TI Valued life abilities among veteran cancer survivors SO HEALTH EXPECTATIONS LA English DT Article DE cancer survivors; goal oriented care; older adults; patient centered care; quality of life; values clarification ID MEDICAL DECISION-MAKING; RESPONSE SHIFT THEORY; QUALITY-OF-LIFE; ADVANCE DIRECTIVES; OLDER PATIENTS; FIT INDEXES; CARE; END; CLARIFICATION; PREFERENCES AB BackgroundWhen patients have multiple chronic illnesses, it is not feasible to provide disease-based care when treatments for one condition adversely affect another. Instead, health-care delivery requires a broader person-centred treatment plan based on collaborative, patient-oriented values and goals. ObjectiveWe examined the individual variability, thematic content, and sociodemographic correlates of valued life abilities and activities among multimorbid veterans diagnosed with life-altering cancer. Setting and participantsParticipants were 144 veterans in the Vet-Cares' study who completed a health-care values and goals scale 12months after diagnosis of head and neck, gastro-oesophageal, or colorectal cancer. They had mean age of 65years and one quarter identified as Hispanic and/or African American. DesignAt twelve months post-diagnosis, participants rated 16 life abilities/activities in their importance to quality of life on a 10-point Likert scale, during an in-person interview. Scale themes were validated via exploratory factor analysis and examining associations with sociodemographic variables. ResultsParticipants rated most life abilities/activities as extremely important. Variability in responses was sufficient to identify three underlying values themes in exploratory factor analysis: self-sufficiency, enjoyment/comfort, and connection to family, friends and spirituality. Veterans with a spouse/partner rated self-sufficiency as less important. African American veterans rated connection as more important than did White veterans. ConclusionsIt is feasible yet challenging to ask older, multimorbid patients to rate relative importance of values associated with life abilities/activities. Themes related to self-sufficiency, enjoyment/comfort in daily life and connection are salient and logically consistent with sociodemographic traits. Future studies should explore their role in goal-directed health care. C1 [Karel, Michele J.; Mulligan, Elizabeth A.; Moye, Jennifer] VA Boston Healthcare Syst, Mental Hlth Serv, Boston, MA USA. [Karel, Michele J.; Mulligan, Elizabeth A.; Moye, Jennifer] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Walder, Annette; Martin, Lindsey A.; Naik, Aanand D.] Michael E DeBakey VA Med Ctr, Houston VA Hlth Serv Res & Dev Ctr Excellence, Houston, TX USA. [Walder, Annette; Martin, Lindsey A.; Naik, Aanand D.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Karel, MJ (reprint author), Cent Off, Mental Hlth Serv 10P4M, Dept Vet Affairs, 810 Vermont Ave, Washington, DC 20420 USA. EM Michele.Karel@va.gov RI Moye, Jennifer/F-2240-2017; OI Moye, Jennifer/0000-0002-3434-347X; Naik, Aanand/0000-0001-6936-7984 FU Department of Veterans Affairs Rehabilitation Research and Development Service [5I01RX00 0104] FX Funding for this study was provided by the Department of Veterans Affairs Rehabilitation Research and Development Service (5I01RX00 0104; PI: Moye). NR 41 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1369-6513 EI 1369-7625 J9 HEALTH EXPECT JI Health Expect. PD JUN PY 2016 VL 19 IS 3 BP 679 EP 690 DI 10.1111/hex.12343 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DK8DT UT WOS:000375158100016 PM 25645124 ER PT J AU Shen, LS Diroma, MA Gonzalez, M Navarro-Gomez, D Leipzig, J Lott, MT van Oven, M Wallace, DC Muraresku, CC Zolkipli-Cunningham, Z Chinnery, PF Attimonelli, M Zuchner, S Falk, MJ Gai, XW AF Shen, Lishuang Diroma, Maria Angela Gonzalez, Michael Navarro-Gomez, Daniel Leipzig, Jeremy Lott, Marie T. van Oven, Mannis Wallace, Douglas C. Muraresku, Colleen Clarke Zolkipli-Cunningham, Zarazuela Chinnery, Patrick F. Attimonelli, Marcella Zuchner, Stephan Falk, Marni J. Gai, Xiaowu TI MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease SO HUMAN MUTATION LA English DT Article DE mitochondria; genetics; informatics; database ID SEQUENCE VARIATION; HUMAN PHENOTYPE; MUTATIONS; VARIANTS; DATABASE; CONSEQUENCES; ANNOTATION; GUIDELINES; DISORDERS; BIOLOGY AB MSeqDR is the Mitochondrial Disease Sequence Data Resource, a centralized and comprehensive genome and phenome bioinformatics resource built by the mitochondrial disease community to facilitate clinical diagnosis and research investigations of individual patient phenotypes, genomes, genes, and variants. A central Web portal () integrates community knowledge from expert-curated databases with genomic and phenotype data shared by clinicians and researchers. MSeqDR also functions as a centralized application server for Web-based tools to analyze data across both mitochondrial and nuclear DNA, including investigator-driven whole exome or genome dataset analyses through MSeqDR-Genesis. MSeqDR-GBrowse genome browser supports interactive genomic data exploration and visualization with custom tracks relevant to mtDNA variation and mitochondrial disease. MSeqDR-LSDB is a locus-specific database that currently manages 178 mitochondrial diseases, 1,363 genes associated with mitochondrial biology or disease, and 3,711 pathogenic variants in those genes. MSeqDR Disease Portal allows hierarchical tree-style disease exploration to evaluate their unique descriptions, phenotypes, and causative variants. Automated genomic data submission tools are provided that capture ClinVar compliant variant annotations. PhenoTips will be used for phenotypic data submission on deidentified patients using human phenotype ontology terminology. The development of a dynamic informed patient consent process to guide data access is underway to realize the full potential of these resources. (C) 2016 Wiley Periodicals, Inc. C1 [Shen, Lishuang; Gai, Xiaowu] Childrens Hosp Los Angeles, Ctr Personalized Med, Los Angeles, CA 90027 USA. [Shen, Lishuang; Navarro-Gomez, Daniel; Gai, Xiaowu] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Diroma, Maria Angela; Attimonelli, Marcella] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, Italy. [Diroma, Maria Angela] CEINGE Biotecnol Avanzate, Naples, Italy. [Gonzalez, Michael; Zuchner, Stephan] Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA. [Gonzalez, Michael; Zuchner, Stephan] Genesis Project, Miami, FL USA. [Leipzig, Jeremy] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Lott, Marie T.; Wallace, Douglas C.] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [van Oven, Mannis] Erasmus MC Univ Med Ctr Rotterdam, Dept Forens Mol Biol, Rotterdam, Netherlands. [Wallace, Douglas C.] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA. [Wallace, Douglas C.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Muraresku, Colleen Clarke; Falk, Marni J.] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Zolkipli-Cunningham, Zarazuela] Childrens Hosp Philadelphia, Dept Pediat, Div Neurol, Philadelphia, PA 19104 USA. [Chinnery, Patrick F.] Univ Cambridge, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge, England. [Falk, Marni J.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. RP Falk, MJ (reprint author), ARC 1002c,3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Gai, XW (reprint author), 2100 W 3rd St,Suite 300, Los Angeles, CA 90057 USA. EM falkm@email.chop.edu; xgai@chla.usc.edu RI Shen, Lishuang/B-3040-2013; OI van Oven, Mannis/0000-0003-0026-7998; Diroma, Maria Angela/0000-0003-1427-8946 FU United Mitochondrial Disease Foundation; National Institutes of Health [U54-NS078059, U41-HG006834]; Netherlands Genomic Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) FX Contract grant sponsors: United Mitochondrial Disease Foundation; National Institutes of Health (U54-NS078059 and U41-HG006834); Netherlands Genomic Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). NR 38 TC 6 Z9 6 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2016 VL 37 IS 6 SI SI BP 540 EP 548 DI 10.1002/humu.22974 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DK8DL UT WOS:000375157300007 PM 26919060 ER PT J AU Prashanth, R Roy, SD Mandal, PK Ghosh, S AF Prashanth, R. Roy, Sumantra Dutta Mandal, Pravat K. Ghosh, Shantanu TI High-Accuracy Detection of Early Parkinson's Disease through Multimodal Features and Machine Learning SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE Parkinson's disease; non-motor features; cerebrospinal fluid markers; dopaminergic imaging; Computer-aided diagnosis; pattern classification ID SLEEP BEHAVIOR DISORDER; SCREENING QUESTIONNAIRE; LOGISTIC-REGRESSION; CEREBROSPINAL-FLUID; DIAGNOSIS; SMELL; SPECT; CLASSIFICATION; DYSFUNCTION; PROGRESSION AB Early (or preclinical) diagnosis of Parkinson's disease (PD) is crucial for its early management as by the time manifestation of clinical symptoms occur, more than 60% of the dopaminergic neurons have already been lost. It is now established that there exists a premotor stage, before the start of these classic motor symptoms, characterized by a constellation of clinical features, mostly non-motor in nature such as Rapid Eye Movement (REM) sleep Behaviour Disorder (RBD) and olfactory loss. In this paper, we use the non motor features of RBD and olfactory loss, along with other significant biomarkers such as Cerebrospinal fluid (CSF) measurements and dopaminergic imaging markers from 183 healthy normal and 401 early PD subjects, as obtained from the Parkinson's Progression Markers Initiative (PPMI) database, to classify early PD subjects from normal using Naive Bayes, Support Vector Machine (SVM), Boosted Trees and Random Forests classifiers. We observe that SVM classifier gave the best performance (96.40% accuracy, 97.03% sensitivity, 95.01% specificity, and 98.88% area under ROC). We infer from the study that a combination of non-motor, CSF and imaging markers may aid in the preclinical diagnosis of PD. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Prashanth, R.; Roy, Sumantra Dutta] Indian Inst Technol, Dept Elect Engn, Delhi, India. [Mandal, Pravat K.] Natl Brain Res Ctr, Neuroimaging & Neurospect Lab, Bangalore, Karnataka, India. [Mandal, Pravat K.] Johns Hopkins Med, Dept Radiol, Baltimore, MD USA. [Ghosh, Shantanu] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Ghosh, Shantanu] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Prashanth, R (reprint author), Azoi Mobile Technol Pvt Ltd, Ahmadabad 380009, Gujarat, India. EM prashanth.r.itd@gmail.com FU Michael J. Fox Foundation for Parkinson's Research; Abbott Laboratories; Avid Radiopharmaceuticals; Biogen Idec; Bristol-Myers Squibb; Covance; Elan; GE Healthcare; Genentech; GlaxoSmithKline; Eli Lilly and Company; Merck Co.; Meso Scale Discovery; Pfizer; Hoffmann-La Roche; UCB (Union Chimique Beige); Piramal FX PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbott Laboratories, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Elan, GE Healthcare, Genentech, GlaxoSmithKline, Eli Lilly and Company, Merck & Co., Meso Scale Discovery, Pfizer, Hoffmann-La Roche, UCB (Union Chimique Beige), and Piramal. NR 37 TC 3 Z9 3 U1 5 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 EI 1872-8243 J9 INT J MED INFORM JI Int. J. Med. Inform. PD JUN PY 2016 VL 90 BP 13 EP 21 DI 10.1016/j.ijmedinf/2016.03.001 PG 9 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA DK8CQ UT WOS:000375155200003 PM 27103193 ER PT J AU Joshi, G Wozniak, J Faraone, SV Fried, R Chan, J Furtak, S Grimsley, E Conroy, K Kilcullen, JR Woodworth, KY Biederman, J AF Joshi, Gagan Wozniak, Janet Faraone, Stephen V. Fried, Ronna Chan, James Furtak, Stephannie Grimsley, Emily Conroy, Kristina Kilcullen, J. Ryan Woodworth, K. Yvonne Biederman, Joseph TI A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE autism spectrum disorder; memantine; adults; treatment; psychopharmacology ID PERVASIVE DEVELOPMENTAL DISORDERS; PLACEBO-CONTROLLED TRIAL; RATING-SCALE; PSYCHIATRIC COMORBIDITY; REFERRED POPULATION; DOUBLE-BLIND; CHILDREN; VALIDITY; LINKAGE; GENE AB This prospective 12-week open-label trial evaluates the tolerability and efficacy of memantine hydrochloride for the treatment of core social and cognitive deficits in adults with high-functioning autism spectrum disorder (ASD). Measures for assessment of therapeutic response included the Social Responsiveness Scale-Adult Research Version (SRS-A), disorder-specific Clinical Global Impression scales, Behavior Rating Inventory of Executive Functioning-Adult Self-Report, Diagnostic Analysis of Nonverbal Accuracy Scale, and Cambridge Neuropsychological Test Automated Battery. Eighteen adults (mean age, 28 +/- 9.5 years) with high-functioning ASD (SRS-A raw score, 99 +/- 17) were treated with memantine (mean dose, 19.7 +/- 1.2 mg/d; range, 15-20 mg), and 17 (94%) completed the trial. Treatment with memantine was associated with significant reduction on informant-rated (SRS-A, -28 +/- 25; P < 0.001) and clinician-rated (Clinical Global Impression-Improvement subscale <= 2, 83%) measures of autism severity. In addition, memantine treatment was associated with significant improvement in ADHD and anxiety symptom severity. Significant improvement was noted in nonverbal communication on the Diagnostic Analysis of Nonverbal Accuracy Scale test and in executive function per self-report (Behavior Rating Inventory of Executive Functioning-Adult Self-Report Global Executive Composite, -6 +/- 8.8; P < 0.015) and neuropsychological assessments (Cambridge Neuropsychological Test Automated Battery). Memantine treatment was generally well tolerated and was not associated with any serious adverse events. Treatment with memantine appears to be beneficial for the treatment of ASD and associated psychopathology and cognitive dysfunction in intellectually capable adults. Future placebo-controlled trials are warranted. C1 [Joshi, Gagan; Wozniak, Janet; Fried, Ronna; Chan, James; Furtak, Stephannie; Grimsley, Emily; Conroy, Kristina; Kilcullen, J. Ryan; Woodworth, K. Yvonne; Biederman, Joseph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin & Res Program Pediat Psychopharmacol, Boston, MA USA. [Joshi, Gagan; Wozniak, Janet; Fried, Ronna; Biederman, Joseph] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Faraone, Stephen V.] Univ Bergen, Dept Biomed, KG Jebsen Ctr Psychiat Disorders, Bergen, Norway. RP Joshi, G (reprint author), Massachusetts Gen Hosp, Alan & Lorraine Bressler Clin & Res Program Autis, 55 Fruit St,WRN 625, Boston, MA 02114 USA. EM joshi.gagan@mgh.harvard.edu FU Norma Fine Pediatric Psychopharmacology Fellowship Fund; National Institute of Mental Health of the National Institutes of Health [K23MH100450]; Merck/Schering-Plough; Cantor Colburn; UCB; Xenoport; UCB Pharma; GSK; Impax; K. G. Jebsen Centre for Research on Neuropsychiatric Disorders; University of Bergen, Bergen, Norway; European Community [602805]; National Institute of Mental Health [R13MH059126, R01MH094469]; Pfizer; Ironshore; Shire; Akili Interactive Labs; CogCubed; Alcobra; VAYA Pharma; Neurovance; NeuroLifeSciences; Otsuka; McNeil; Janssen; Novartis; Eli Lilly; National Institutes of Health; Department of Defense; Food and Drug Administration, Ironshore, Lundbeck; Magceutics Inc; Merck; PamLab; Shire Pharmaceuticals Inc; SPRITES; Sunovion; Vaya Pharma/Enzymotec; AACAP; Forest Research Institute; Shire Pharmaceuticals. Inc; Ingenix; Prophase; Bracket Global; Theravance; MGH Psychiatry Academy; APSARD; ElMindA FX This work was supported by the Norma Fine Pediatric Psychopharmacology Fellowship Fund and the members of the MGH Pediatric Psychopharmacology Council. Dr Gagan Joshi is supported by the National Institute of Mental Health of the National Institutes of Health under award number K23MH100450.; In 2013 to 2014, Dr Janet Wozniak has received research support from Merck/Schering-Plough. She is the author of the book Is Your Child Bipolar published May 2008, Bantam Books. In 2013 to 2014, her spouse John Winkelman MD, PhD, received royalties from Cambridge University Press and UptoDate. He has received consultation fees from Cantor Colburn, UCB, and Xenoport. He has received research support from UCB Pharma, GSK, and Impax.; Dr Stephen V. Faraone is supported by the K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 602805 and National Institute of Mental Health grants R13MH059126 and R01MH094469. He has received income, travel expenses, and/or research support from, and/or has been on an advisory board for, and/or participated in continuing medical education programs sponsored by the following: Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Neurovance, Impax, NeuroLifeSciences, Otsuka, McNeil, Janssen, Novartis, Eli Lilly, and the National Institutes of Health. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He receives royalties from books published by Guilford Press, Straight Talk About Your Child's Mental Health; Oxford University Press, Schizophrenia: The Facts; and Elsevier, ADHD: Non-Pharmacologic Treatments.; Dr Joseph Biederman is currently receiving research support from the following sources: The Department of Defense, Food and Drug Administration, Ironshore, Lundbeck, Magceutics Inc, Merck, PamLab, Pfizer, Shire Pharmaceuticals Inc, SPRITES, Sunovion, Vaya Pharma/Enzymotec, and National Institutes of Health. In 2015, he has a US patent application pending (provisional number 61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse. In 2014, he received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He received research support from AACAP, Alcobra, Forest Research Institute, and Shire Pharmaceuticals. Inc, Dr Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. In 2013, he received an honorarium from the MGH Psychiatry Academy for a tuition-funded CME course. He received research support from APSARD, ElMindA, McNeil, and Shire. Dr Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Shire and Sunovion; these royalties were paid to the Department of Psychiatry at MGH. NR 42 TC 2 Z9 2 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD JUN PY 2016 VL 36 IS 3 BP 262 EP 271 DI 10.1097/JCP.0000000000000499 PG 10 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA DK7FH UT WOS:000375089900012 PM 27043118 ER PT J AU Dale, SK Bogart, LM Galvan, FH Wagner, GJ Pantalone, DW Klein, DJ AF Dale, Sannisha K. Bogart, Laura M. Galvan, Frank H. Wagner, Glenn J. Pantalone, David W. Klein, David J. TI Discrimination and Hate Crimes in the Context of Neighborhood Poverty and Stressors Among HIV-Positive African-American Men Who Have Sex with Men SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE African-American men; HIV; Neighborhood; Perceived discrimination; Stigma ID US METROPOLITAN-AREAS; PERCEIVED DISCRIMINATION; MULTILEVEL ANALYSIS; BLACK-WHITE; DRUG-USERS; HEALTH; DISPARITIES; STIGMA; INTERSECTIONALITY; STRATIFICATION AB In a sample of HIV-positive African-American men who have sex with men (MSM), we examined neighborhood factors that may contextualize perceived discrimination from three intersecting stigmatized characteristics: race, HIV status, and sexual orientation. HIV-positive African-American MSM (N = 162, mean age = 44, SD = 8) provided information on neighborhood-related stressors and discrimination experiences related to being Black, HIV-positive, or perceived as gay. Residential ZIP codes and US Census data were used to determine neighborhood poverty rates. Regressions, controlling for socio-demographics, indicated that (1) higher neighborhood poverty was significantly related to more frequent experiences with hate crimes (Gay-related: b = 1.15, SE = .43, p < .008); and (2) higher neighborhood-related stressors were significantly related to more frequent discrimination (Black-related: b = .91, SE = .28, p = .001; gay-related: b = .71, SE = .29, p = .01; and HIV-related: b = .65, SE = .28, p = .02) and hate crimes (Gay-related: b = .48, SE = .13, p = .001; and Black-related: b = .28, SE = .14, p = .04). For HIV-positive African-American MSM, higher neighborhood poverty and related stressors are associated with experiencing more discrimination and hate crimes. Interventions for this group should promote individual- and neighborhood-level socioeconomic empowerment and stigma reduction. C1 [Dale, Sannisha K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dale, Sannisha K.] Harvard Univ, Sch Med, Boston, MA USA. [Bogart, Laura M.; Wagner, Glenn J.] RAND Corp, Hlth Unit, Santa Monica, CA USA. [Galvan, Frank H.] Bienestar Human Serv Inc, Los Angeles, CA USA. [Pantalone, David W.] Univ Massachusetts, Boston, MA 02125 USA. [Pantalone, David W.] Fenway Inst Fenway Hlth, Boston, MA USA. [Klein, David J.] RAND Corp, Santa Monica, CA USA. RP Dale, SK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Dale, SK (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM skdale@mgh.harvard.edu FU National Institute of Mental Health [R01MH072351, 1K23MH108439-01]; OASIS FX This research was funded by the National Institute of Mental Health [R01MH072351, PI: Laura M. Bogart]. Some of Sannisha K. Dale's time was covered by 1K23MH108439-01 from the National Institute of Mental Health. We would like to express gratitude to Charisma Acey, Denedria Banks, E. Michael Speltie, and Kellii Trombacco for their assistance; Charles Hilliard, Ph.D, and the staff and clients of SPECTRUM at the Charles Drew University of Medicine and Science for their contribution to the project; as well as the staff of AIDS Project Los Angeles, Minority AIDS Project, and OASIS for their support. NR 50 TC 0 Z9 0 U1 5 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD JUN PY 2016 VL 41 IS 3 BP 574 EP 583 DI 10.1007/s10900-015-0132-z PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DK3TB UT WOS:000374839200017 PM 26696119 ER PT J AU Gupta, ND Etcoff, NL Jaeger, MM AF Gupta, Nabanita Datta Etcoff, Nancy L. Jaeger, Mads M. TI Beauty in Mind: The Effects of Physical Attractiveness on Psychological Well-Being and Distress SO JOURNAL OF HAPPINESS STUDIES LA English DT Article DE Physical attractiveness; Psychological well-being; Distress; Longitudinal survey; Random effects; Sibling differences ID GENDER-DIFFERENCES; POSITIVE EMOTION; LIFE; EXPRESSIONS; PERSONALITY; DEPRESSION; HAPPINESS; OUTCOMES; MATTERS; PEOPLE AB Attractive people enjoy many social and economic advantages. Most studies find effects of attractiveness on happiness or life satisfaction, but based on traditional cross-sectional approaches. We use a large longitudinal survey consisting of a sample of male and female high school graduates from Wisconsin followed from their late teens to their mid-1960s. The panel construction of the data and the fact that interviews of the siblings of the respondents are available allow us to analyze the effects of physical appearance on psychological well-being (human flourishing) and ill-being (distress and depression) conditioning on unobserved individual heterogeneity via random effects. We find a significant positive relationship between measures of physical attractiveness (greater facial attractiveness at high school, and lower BMI and greater height in middle age) and a measure of psychological well-being, and a significant negative relationship between measures of physical attractiveness and distress/depression. These effects are slightly smaller when we adjust for demographics and mental ability but, with the exception of height, remain significant. Our results suggest that attractiveness impacts psychological well-being and depression directly as well as through its effects on other life outcomes. C1 [Gupta, Nabanita Datta] Aarhus Univ, Dept Econ & Business Econ, Fuglesangs Alle 4, DK-8210 Aarhus V, Denmark. [Etcoff, Nancy L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, CNY 149,13th St, Charlestown, MA 02138 USA. [Jaeger, Mads M.] Univ Copenhagen, Dept Sociol, Oster Farimagsgade 5,Bldg 16, DK-1014 Copenhagen K, Denmark. [Jaeger, Mads M.] Danish Natl Ctr Social Res, Herluf Trolles Gade 11, DK-1052 Copenhagen K, Denmark. RP Gupta, ND (reprint author), Aarhus Univ, Dept Econ & Business Econ, Fuglesangs Alle 4, DK-8210 Aarhus V, Denmark. EM ndg@econ.au.dk; netcoff@mgh.harvard.edu; mmj@soc.ku.dk FU National Institute on Aging [AG-9775 AG-21079, AG-033285]; Vilas Estate Trust; National Science Foundation; Spencer Foundation; Graduate School of the University of Wisconsin-Madison FX We use data from the WLS of the University of Wisconsin-Madison. Since 1991, the WLS has been supported by the National Institute on Aging (AG-9775 AG-21079 and AG-033285), with additional support from the Vilas Estate Trust, the National Science Foundation, the Spencer Foundation, and the Graduate School of the University of Wisconsin-Madison. A public use file of data is available from the WLS, University of Wisconsin-Madison, 1180 Observatory Drive, Madison, Wisconsin 53706 and at http://www.ssc.wisc.edu/wlsresearch/data/. We thank Danielle Barry and Lauren Haley for assistance. NR 42 TC 0 Z9 0 U1 12 U2 22 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-4978 EI 1573-7780 J9 J HAPPINESS STUD JI J. Happiness Stud. PD JUN PY 2016 VL 17 IS 3 BP 1313 EP 1325 DI 10.1007/s10902-015-9644-6 PG 13 WC Psychology, Multidisciplinary; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA DK7AR UT WOS:000375077700022 ER PT J AU Huffman, JC Boehm, JK Beach, SR Beale, EE DuBois, CM Healy, BC AF Huffman, Jeff C. Boehm, Julia K. Beach, Scott R. Beale, Eleanor E. DuBois, Christina M. Healy, Brian C. TI Relationship of optimism and suicidal ideation in three groups of patients at varying levels of suicide risk SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Depression; Optimism; Risk assessment; Suicidal ideation; Suicide ID CORONARY-HEART-DISEASE; LIFE ORIENTATION TEST; BASE-LINE DATA; REPORT QIDS-SR; MYOCARDIAL-INFARCTION; DEPRESSIVE SYMPTOMATOLOGY; PSYCHOMETRIC EVALUATION; GRATITUDE RESEARCH; PHYSICAL ILLNESS; MAJOR DEPRESSION AB Optimism has been associated with reduced suicidal ideation, but there have been few studies in patients at high suicide risk. We analyzed data from three study populations (total N = 319) with elevated risk of suicide: (1) patients with a recent acute cardiovascular event, (2) patients hospitalized for heart disease who had depression or an anxiety disorder, and (3) patients psychiatrically hospitalized for suicidal ideation or following a suicide attempt. For each study we analyzed the association between optimism (measured by the Life Orientation Test-Revised) and suicidal ideation, and then completed an exploratory random effects meta-analysis of the findings to synthesize this data. The meta-analysis of the three studies showed that higher levels of self-reported optimism were associated with a lower likelihood of suicidal ideation (odds ratio [OR]=.89, 95% confidence interval [CI] = .85-.95, z = 3.94, p < .001), independent of age, gender, and depressive symptoms. This association held when using the subscales of the Life Orientation Test-Revised scale that measured higher optimism (OR = .84, 95% CI = .76-.92, z = 3.57, p < .001) and lower pessimism (OR = .83, 95% CI = .75-.92], z = 3.61, p < .001). These results also held when suicidal ideation was analyzed as an ordinal variable. Our findings suggest that optimism may be associated with a lower risk of suicidal ideation, above and beyond the effects of depressive symptoms, for a wide range of patients with clinical conditions that place them at elevated risk for suicide. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Huffman, Jeff C.; Beach, Scott R.; Beale, Eleanor E.; DuBois, Christina M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Huffman, Jeff C.; Beach, Scott R.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Boehm, Julia K.] Chapman Univ, Dept Psychol, Orange, CA USA. [Healy, Brian C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, 55 Fruit St Blake 11, Boston, MA 02114 USA. EM jhuffman@partners.org FU American Heart Association [10GRNT3450015]; Expanding the Science and Practice of Gratitude Project by UC Berkeley's Greater Good Science Center; UC Davis; John Templeton Foundation [15627]; National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL113272] FX This research and analysis time were funded by an American Heart Association Grant-in-Aid 10GRNT3450015, the Expanding the Science and Practice of Gratitude Project run by UC Berkeley's Greater Good Science Center in partnership with UC Davis with funding from the John Templeton Foundation (grant ID 15627), and the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL113272, all to JH. The content is solely the responsibility of the authors and does not represent the official views of the funders. NR 69 TC 1 Z9 1 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUN PY 2016 VL 77 BP 76 EP 84 DI 10.1016/j.jpsychires.2016.02.020 PG 9 WC Psychiatry SC Psychiatry GA DK3GI UT WOS:000374804700011 PM 26994340 ER PT J AU Harshman, LC Wang, X Nakabayashi, M Xie, W Valenca, L Werner, L Yu, Y Kantoff, AM Sweeney, CJ Mucci, LA Pomerantz, M Lee, GS Kantoff, PW AF Harshman, L. C. Wang, X. Nakabayashi, M. Xie, W. Valenca, L. Werner, L. Yu, Y. Kantoff, A. M. Sweeney, C. J. Mucci, L. A. Pomerantz, M. Lee, G. S. Kantoff, P. W. TI Re: Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients with Hormone-Sensitive Prostate Cancer Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Harshman, L. C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Gelb Ctr Translat Oncol,Lank Ctr Genitourinary On, 44 Binney St, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, 44 Binney St, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Apple Tree Partners, New York, NY USA. Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Urol, Shanghai 200030, Peoples R China. RP Harshman, LC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Gelb Ctr Translat Oncol,Lank Ctr Genitourinary On, 44 Binney St, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUN PY 2016 VL 195 IS 6 BP 1780 EP 1781 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DL1DZ UT WOS:000375373700048 ER PT J AU Rieckmann, A Van Dijk, KRA Sperling, RA Johnson, KA Buckner, RL Hedden, T AF Rieckmann, Anna Van Dijk, Koene R. A. Sperling, Reisa A. Johnson, Keith A. Buckner, Randy L. Hedden, Trey TI Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; Amyloid; Diffusion tensor imaging; Longitudinal; White matter ID MILD COGNITIVE IMPAIRMENT; NORMAL OLDER-ADULTS; TENSOR IMAGING DETECTS; APOE EPSILON-4 ALLELE; PITTSBURGH COMPOUND-B; AMYLOID BURDEN; SPATIAL STATISTICS; HEALTHY-ADULTS; IN-VIVO; FUNCTIONAL CONNECTIVITY AB Prior studies have identified white matter abnormalities in Alzheimer's disease (AD). Yet, cross-sectional studies in normal older individuals show little evidence for an association between markers of AD risk (APOE4 genotype and amyloid deposition), and white matter integrity. Here, 108 normal older adults (age, 66-87) with assessments of apolipoprotein e4 (APOE4) genotype and assessment of amyloid burden by positron emission tomography underwent diffusion tensor imaging scans for measuring white matter integrity at 2 time points, on average 2.6 years apart. Linear mixed-effects models showed that amyloid burden at baseline was associated with steeper decline in fractional anisotropy in the parahippocampal cingulum (p < 0.05). This association was not significant between baseline measures suggesting that longitudinal analyses can provide novel insights that are not detectable in cross-sectional designs. Amyloid-related changes in hippocampus volume did not explain the association between amyloid burden and change in fractional anisotropy. The results suggest that accumulation of cortical amyloid and white matter changes in parahippocampal cingulum are not independent processes in individuals at increased risk for AD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Rieckmann, Anna; Van Dijk, Koene R. A.; Sperling, Reisa A.; Buckner, Randy L.; Hedden, Trey] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Rieckmann, Anna] Umea Univ, Dept Radiat Sci, Diagnost Radiol, Umea, Sweden. [Van Dijk, Koene R. A.; Buckner, Randy L.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Van Dijk, Koene R. A.; Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Sperling, Reisa A.] Harvard Univ, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol,Med Sch, Boston, MA 02115 USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Dept Radiol, Div Nucl Med & Mol Imaging,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Johnson, Keith A.; Buckner, Randy L.; Hedden, Trey] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Buckner, Randy L.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Hedden, T (reprint author), Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM hedden@nmr.mgh.harvard.edu RI Van Dijk, Koene/G-3317-2012 OI Van Dijk, Koene/0000-0001-6137-4282 FU National Institute on Aging [P01 AG036694, P50 AG005134, R01 AG034556, R01 AG027435, K01 AG040197]; Alzheimer's Association [ZEN-10-174210]; Howard Hughes Medical Institute; European Commission; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health [P41 EB015896]; NIH [S10RR023401, S10RR019307, S10RR019254, S10RR023043] FX This work was supported by National Institute on Aging grants (P01 AG036694, P50 AG005134, R01 AG034556, R01 AG027435, and K01 AG040197), the Alzheimer's Association grant (ZEN-10-174210), and by the Howard Hughes Medical Institute. Anna Rieckmann is supported by a Marie Curie International Outgoing Fellowship from the European Commission. This research was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (P41 EB015896). This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program (specifically S10RR023401, S10RR019307, S10RR019254, and S10RR023043). The authors are grateful for the help of all research assistants involved in the Harvard Aging Brain study (http://www.martinos.org/harvardagingbrain/Acknowledgements.html). They thank Elizabeth Mormino, David Salat, and Christian Wachinger for helpful discussions and advise on statistical analyses. NR 77 TC 3 Z9 3 U1 4 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2016 VL 42 BP 177 EP 188 DI 10.1016/j.neurobiolaging.2016.03.016 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DK7TV UT WOS:000375129500019 PM 27143434 ER PT J AU Alexander-Bloch, AF McDougle, CJ Ullman, Z Sweetser, DA AF Alexander-Bloch, Aaron F. McDougle, Christopher J. Ullman, Zhanna Sweetser, David A. TI IQSEC2 and X-linked syndromal intellectual disability SO PSYCHIATRIC GENETICS LA English DT Review DE autism spectrum disorder; intellectual disability; IQSEC2; Rett syndrome; syndromal intellectual disability ID NUCLEOTIDE EXCHANGE FACTOR; DE-NOVO MUTATIONS; MENTAL-RETARDATION; RETT-SYNDROME; POSTSYNAPTIC DENSITY; EXCITATORY SYNAPSES; CHINESE PATIENTS; GENE; SPECTRUM; EXPRESSION AB Despite the recent acceleration in the discovery of genetic risk factors for intellectual disability (ID), the genetic etiology of ID is unknown in approximately half of cases and remains a major frontier of genetics in medicine and psychiatry. The distinction between syndromal and nonsyndromal forms of ID is of great clinical importance, but the boundary between these clinical entities is difficult to ascertain for many genes of interest. ID is more common in men than in women, but the genetic explanation of this sex asymmetry is incompletely understood. This Review systematically examines the reported cases of X-linked ID caused by de novo loss-of-function mutations in the gene IQSEC2. This gene is largely known as a cause of X-linked nonsyndromal ID in male patients. However, depending on the severity of the mutation, the phenotypic spectrum of IQSEC2-related ID can range from the classic X-linked nonsyndromal form of the disease to a severe syndrome that has been reported in the context of de novo mutations only, in both male and female patients. Bioinformatics analysis suggests that truncation of the longer of the two protein isoforms of the gene can be sufficient to lead to the syndrome, which may be caused by the disruption of cell signaling and signal transduction pathways. The clinical features of the syndrome converge on a pattern of global developmental delay, deficits in social communication, stereotypical hand movements, and hypotonia. In addition, many if not all of these patients have seizures, microcephaly, and language regression in addition to delay. We argue that it is clinically appropriate to test for IQSEC2 mutations in male and female patients with this symptom profile but without a known genetic mutation. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Alexander-Bloch, Aaron F.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [McDougle, Christopher J.] Massachusetts Gen Hosp, Lurie Ctr Autism, Boston, MA 02114 USA. [Ullman, Zhanna; Sweetser, David A.] MassGen Hosp Children, Div Med Genet & Metab, Boston, MA 02114 USA. RP Sweetser, DA (reprint author), MassGen Hosp Children, Dept Pediat, 175 Cambridge St, Boston, MA 02114 USA. EM dsweetser@mgh.harvard.edu NR 45 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 0955-8829 EI 1473-5873 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD JUN PY 2016 VL 26 IS 3 BP 101 EP 108 DI 10.1097/YPG.0000000000000128 PG 8 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DK8BR UT WOS:000375152500001 PM 27010919 ER PT J AU Bos, D Allard, CB Dason, S Ruzhynsky, V Kapoor, A Shayegan, B AF Bos, Derek Allard, Christopher B. Dason, Shawn Ruzhynsky, Vladimir Kapoor, Anil Shayegan, Bobby TI Impact of resident involvement in endoscopic bladder cancer surgery on pathological outcomes SO SCANDINAVIAN JOURNAL OF UROLOGY LA English DT Article DE Bladder cancer; cystectomy; education; endoscopy ID TRANSURETHRAL RESECTION; RISK; EXPERIENCE; RECURRENCE; CYSTECTOMY; PROSTATE; QUALITY; MUSCLE; TUMOR AB Objective: Transurethral resection of bladder tumor (TURBT) pathology specimens which lack muscle are associated with clinical upstaging and may necessitate repeat resections, potentially delaying curative treatment. This study evaluated whether resident involvement in TURBT is associated with suboptimal perioperative outcomes. Materials and methods: All TURBTs performed at a Canadian healthcare institution from November 2011 to June 2014 were reviewed. Multivariable logistic regression models assessed associations between intraoperative resident involvement and TURBT muscle presence. Among high-risk patients (high grade, >= T1 or carcinoma in situ) who underwent cystectomy, time from TURBT to cystectomy was compared between resident and attending urologists with the log-rank test. Results: In total, 463 TURBTs were identified. In multivariable analyses, residents were less likely to obtain muscle in specimens for all TURBTs [adjusted odds ratio (aOR) 0.59, p = 0.03] and the subset of 275 high-risk TURBTs (aOR 0.41, p = 0.006). Among patients who underwent cystectomy, time to cystectomy was delayed by a median of 23 days when residents were involved in the initial high-risk TURBT compared with attending urologists only (p = 0.024). Conclusions: In this single academic center series, intraoperative resident involvement was associated with a decreased rate of muscle presence in TURBT specimens and a prolonged time to cystectomy. C1 [Bos, Derek; Allard, Christopher B.; Dason, Shawn; Ruzhynsky, Vladimir; Kapoor, Anil; Shayegan, Bobby] McMaster Univ, Hamilton, ON, Canada. [Allard, Christopher B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Allard, Christopher B.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Bos, D (reprint author), 43 Charlton Ave East, Hamilton, ON, Canada. EM derek.bos@medportal.ca NR 20 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2168-1805 EI 2168-1813 J9 SCAND J UROL JI Scand. J. Urol. PD JUN PY 2016 VL 50 IS 3 BP 234 EP 238 DI 10.3109/21681805.2016.1163616 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA DK6NC UT WOS:000375039800018 PM 27045233 ER PT J AU Zecha, JAEM Raber-Durlacher, JE Nair, RG Epstein, JB Sonis, ST Elad, S Hamblin, MR Barasch, A Migliorati, CA Milstein, DMJ Genot, MT Lansaat, L van der Brink, R Arnabat-Dominguez, J van der Molen, L Jacobi, I van Diessen, J de Lange, J Smeele, LE Schubert, MM Bensadoun, RJ AF Zecha, Judith A. E. M. Raber-Durlacher, Judith E. Nair, Raj G. Epstein, Joel B. Sonis, Stephen T. Elad, Sharon Hamblin, Michael R. Barasch, Andrei Migliorati, Cesar A. Milstein, Dan M. J. Genot, Marie-Therese Lansaat, Liset van der Brink, Ron Arnabat-Dominguez, Josep van der Molen, Lisette Jacobi, Irene van Diessen, Judi de lange, Jan Smeele, Ludi E. Schubert, Mark M. Bensadoun, Rene-Jean TI Low level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considerations SO SUPPORTIVE CARE IN CANCER LA English DT Review DE Low level laser therapy; Low level light therapy; Photobiomodulation; Mucositis; Orofacial complications; Chemotherapy; Radiation therapy; Head and neck cancer; Safety; LLLT and PBM ID TISSUES HARBORING CANCER; SQUAMOUS-CELL CARCINOMA; BIPHASIC DOSE-RESPONSE; CYTOCHROME-C-OXIDASE; IN-VITRO; LIGHT THERAPY; ORAL MUCOSITIS; TUMOR-CELLS; TGF-BETA; FIBROBLAST PROLIFERATION AB Purpose There is a large body of evidence supporting the efficacy of low level laser therapy (LLLT), more recently termed photobiomodulation (PBM), for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved, may expand the applications for PBM in the management of other complications associated with HNC treatment. This article (part 1) describes PBM mechanisms of action, dosimetry, and safety aspects and, in doing so, provides a basis for a companion paper (part 2) which describes the potential breadth of potential applications of PBM in the management of side-effects of (chemo)radiation therapy in patients being treated for HNC and proposes PBM parameters. Methods This study is a narrative non-systematic review. Results We review PBM mechanisms of action and dosimetric considerations. Virtually, all conditions modulated by PBM (e.g., ulceration, inflammation, lymphedema, pain, fibrosis, neurological and muscular injury) are thought to be involved in the pathogenesis of (chemo)radiation therapy-induced complications in patients treated for HNC. The impact of PBM on tumor behavior and tumor response to treatment has been insufficiently studied. In vitro studies assessing the effect of PBM on tumor cells report conflicting results, perhaps attributable to inconsistencies of PBM power and dose. Nonetheless, the biological bases for the broad clinical activities ascribed to PBM have also been noted to be similar to those activities and pathways associated with negative tumor behaviors and impeded response to treatment. While there are no anecdotal descriptions of poor tumor outcomes in patients treated with PBM, confirming its neutrality with respect to cancer responsiveness is a critical priority. Conclusion Based on its therapeutic effects, PBM may have utility in a broad range of oral, oropharyngeal, facial, and neck complications of HNC treatment. Although evidence suggests that PBM using LLLT is safe in HNC patients, more research is imperative and vigilance remains warranted to detect any potential adverse effects of PBM on cancer treatment outcomes and survival. C1 [Zecha, Judith A. E. M.; Raber-Durlacher, Judith E.; Milstein, Dan M. J.; de lange, Jan; Smeele, Ludi E.] Univ Amsterdam, Acad Med Ctr, Dept Oral & Maxillofacial Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Univ Amsterdam, Acad Ctr Dent Amsterdam ACTA, Dept Med Dent Interact, POB 22660, NL-1100 DD Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Univ Amsterdam, Acad Ctr Dent Amsterdam ACTA, Dept Periodontol, POB 22660, NL-1100 DD Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Vrije Univ Amsterdam, POB 22660, NL-1100 DD Amsterdam, Netherlands. Menzies Hlth Inst Queensland, Oral Med Oral Pathol & Human Dis, Gold Coast, Qld, Australia. [Nair, Raj G.] Gold Coast Univ Hosp, Queensland Hlth, Dept Haematol & Oncol Canc Serv, Gold Coast, Qld, Australia. [Epstein, Joel B.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Epstein, Joel B.] City Hope Natl Med Ctr, Div Otolaryngol & Head & Neck Surg, Duarte, CA 91010 USA. [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, Boston, MA 02115 USA. [Elad, Sharon] Univ Rochester, Med Ctr, Eastman Inst Oral Hlth, Div Oral Med, Rochester, NY 14620 USA. [Elad, Sharon] Univ Rochester, Med Ctr, Wilmot Canc Ctr, Rochester, NY 14620 USA. [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. [Barasch, Andrei] Weill Cornell Med Ctr, Div Oncol, New York, NY USA. [Migliorati, Cesar A.] Univ Tennessee, Hlth Sci Ctr, Coll Dent, Dept Diagnost Sci & Oral Med, 875 Union Ave Suite N231, Memphis, TN 38163 USA. [Genot, Marie-Therese] Univ Libre Bruxelles, Ctr Tumeurs, Inst Jules Bordet, Laser Therapy Unit, Brussels, Belgium. [Lansaat, Liset; van der Molen, Lisette; Jacobi, Irene; Smeele, Ludi E.] Netherlands Canc Inst, Antoni van Leeuwenhoek Dept Head & Neck Oncol & S, Amsterdam, Netherlands. [van der Brink, Ron] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Arnabat-Dominguez, Josep] Univ Barcelona, Fac Dent, Dept Oral Surg, Barcelona, Spain. [van Diessen, Judi] Netherlands Canc Inst, Antoni van Leeuwenhoek Dept Radiat Oncol Amsterda, Amsterdam, Netherlands. [Schubert, Mark M.; Bensadoun, Rene-Jean] SCCA, 825 Eastlake Ave Ste G6900, Seattle, WA 98109 USA. [Bensadoun, Rene-Jean] CHE, WALT Sci Secretary, 10 Bd Pasteur, F-06000 Nice, France. RP Bensadoun, RJ (reprint author), CHE, WALT Sci Secretary, 10 Bd Pasteur, F-06000 Nice, France. EM j.zecha@amc.uva.nl; j.e.raberdurlacher@amc.uva.nl; r.nair@griffith.edu.au; joel.epstein@cshs.org; ssonis@partners.org; SElad@URMC.Rochester.edu; hamblin@helix.mgh.harvard.edu; barasaff@cs.com; migliorati@uthsc.edu; D.M.Milstein@amc.uva.nl; mtgenot@skynet.be; l.lansaat@nki.nl; RVanderbrink@coh.org; joseparnabat@ub.edu; l.vd.molen@nki.nl; i.jacobi@nki.nl; j.v.diessen@nki.nl; j.delange@amc.uva.nl; l.smeele@nki.nl; mschuber@seattlecca.org; renejean.bensadoun@che-nice.com FU US NIH grant [R01AI050875] FX Judith E. Raber-Durlacher, Raj G. Nair, Joel B. Epstein, Ron van der Brink, Josep Arnabat Dominguez, and Rene-Jean Bensadoun have received travel expenses and hotel accommodation from THOR Photomedicine Ltd. UK. Raj Nair has received an honorarium from THOR, UK. Michael R Hamblin was supported by US NIH grant R01AI050875. All the other authors declare that they have no conflict of interest. NR 100 TC 4 Z9 4 U1 7 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUN PY 2016 VL 24 IS 6 BP 2781 EP 2792 DI 10.1007/s00520-016-3152-z PG 12 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DK5TL UT WOS:000374983300046 PM 26984240 ER PT J AU Zecha, JAEM Raber-Durlacher, JE Nair, RG Epstein, JB Elad, S Hamblin, MR Barasch, A Migliorati, CA Milstein, DMJ Genot, MT Lansaat, L van der Brink, R Arnabat-Dominguez, J van der Molen, L Jacobi, I van Diessen, J de Lange, J Smeele, LE Schubert, MM Bensadoun, RJ AF Zecha, Judith A. E. M. Raber-Durlacher, Judith E. Nair, Raj G. Epstein, Joel B. Elad, Sharon Hamblin, Michael R. Barasch, Andrei Migliorati, Cesar A. Milstein, Dan M. J. Genot, Marie-Therese Lansaat, Liset van der Brink, Ron Arnabat-Dominguez, Josep van der Molen, Lisette Jacobi, Irene van Diessen, Judi de lange, Jan Smeele, Ludi E. Schubert, Mark M. Bensadoun, Rene-Jean TI Low-level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols SO SUPPORTIVE CARE IN CANCER LA English DT Review DE Low-level laser therapy; Low-level light therapy; Photobiomodulation; Mucositis; Orofacial complications; Chemotherapy; Radiation therapy; Head and neck cancer; LLLT; PBM ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; BISPHOSPHONATE-INDUCED OSTEONECROSIS; CLINICAL-PRACTICE GUIDELINES; SALIVARY-GLAND HYPOFUNCTION; INDUCED ORAL MUCOSITIS; SWALLOWING DYSFUNCTION; BREAST-CANCER; RADIATION DERMATITIS; CONCURRENT CHEMORADIOTHERAPY AB Purpose There is a large body of evidence supporting the efficacy of low-level laser therapy (LLLT), more recently termed photobiomodulation (PBM) for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved and dosimetric parameters may lead to the management of a broader range of complications associated with HNC treatment. This could enhance patient adherence to cancer therapy, and improve quality of life and treatment outcomes. The mechanisms of action, dosimetric, and safety considerations for PBM have been reviewed in part 1. Part 2 discusses the head and neck treatment side effects for which PBM may prove to be effective. In addition, PBM parameters for each of these complications are suggested and future research directions are discussed. Methods Narrative review and presentation of PBM parameters are based on current evidence and expert opinion. Results PBM may have potential applications in the management of a broad range of side effects of (chemo)radiation therapy (CRT) in patients being treated for HNC. For OM management, optimal PBM parameters identified were as follows: wavelength, typically between 633 and 685 nm or 780-830 nm; energy density, laser or light-emitting diode (LED) output between 10 and 150 mW; dose, 2-3 J (J/cm(2)), and no more than 6 J/cm(2) on the tissue surface treated; treatment schedule, two to three times a week up to daily; emission type, pulsed (< 100 Hz); and route of delivery, intraorally and/or transcutaneously. To facilitate further studies, we propose potentially effective PBM parameters for prophylactic and therapeutic use in supportive care for dermatitis, dysphagia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, and voice/speech alterations. Conclusion PBM may have a role in supportive care for a broad range of complications associated with the treatment of HNC with CRT. The suggested PBM irradiation and dosimetric parameters, which are potentially effective for these complications, are intended to provide guidance for well-designed future studies. It is imperative that such studies include elucidating the effects of PBM on oncology treatment outcomes. C1 [Zecha, Judith A. E. M.; Raber-Durlacher, Judith E.; Milstein, Dan M. J.; de lange, Jan; Smeele, Ludi E.] Univ Amsterdam, Acad Med Ctr, Dept Oral & Maxillofacial Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Univ Amsterdam, Acad Ctr Dent Amsterdam ACTA, Dept Med Dent Interact, POB 22660, NL-1100 DD Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Univ Amsterdam, Acad Ctr Dent Amsterdam ACTA, Dept Periodontol, POB 22660, NL-1100 DD Amsterdam, Netherlands. [Raber-Durlacher, Judith E.] Vrije Univ Amsterdam, POB 22660, NL-1100 DD Amsterdam, Netherlands. [Nair, Raj G.] Gold Coast Univ Hosp, Queensland Hlth, Dept Haematol & Oncol Canc Serv,Oral Med Oral Pat, Menzies Hlth Inst Queensland & Oral Med Consultan, Brisbane, Qld, Australia. [Epstein, Joel B.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Epstein, Joel B.; van der Brink, Ron] City Hope Natl Med Ctr, Div Otolaryngol & Head & Neck Surg, Duarte, CA 91010 USA. [Elad, Sharon] Univ Rochester, Med Ctr, Eastman Inst Oral Hlth, Div Oral Med, Rochester, NY 14620 USA. [Elad, Sharon] Univ Rochester, Med Ctr, Wilmot Canc Ctr, Rochester, NY 14620 USA. [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 Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Barasch, Andrei] Weill Cornell Med Ctr, Div Oncol, New York, NY USA. [Migliorati, Cesar A.] Univ Tennessee, Hlth Sci Ctr, Coll Dent, Dept Diagnost Sci & Oral Med, 875 Union Ave Suite N231, Memphis, TN 38163 USA. [Migliorati, Cesar A.] Univ Tennessee, Hlth Sci Ctr, Coll Dent, Oral Med, 875 Union Ave Suite N231, Memphis, TN 38163 USA. [Genot, Marie-Therese] Univ Libre Bruxelles, Ctr Tumeurs, Inst Jules Bordet, Laser Therapy Unit, Brussels, Belgium. [Lansaat, Liset; van der Molen, Lisette; Jacobi, Irene; Smeele, Ludi E.] Netherlands Canc Inst, Antoni van Leeuwenhoek Dept Head & Neck Oncol & S, Amsterdam, Netherlands. [van Diessen, Judi] Netherlands Canc Inst, Antoni van Leeuwenhoek Dept Radiat Oncol, Amsterdam, Netherlands. [Arnabat-Dominguez, Josep] Univ Barcelona, Fac Dent, Dept Oral Surg, Barcelona, Spain. [Schubert, Mark M.] SCCA, Oral Med, 825 Eastlake Ave E Ste G6900, Seattle, WA 98109 USA. [Bensadoun, Rene-Jean] CHE, WALT Sci Secretary, 10 Bd Pasteur, F-06000 Nice, France. RP Bensadoun, RJ (reprint author), CHE, WALT Sci Secretary, 10 Bd Pasteur, F-06000 Nice, France. EM j.zecha@amc.uva.nl; j.e.raberdurlacher@amc.uva.nl; r.nair@griffith.edu.au; joel.epstein@cshs.org; SElad@URMC.Rochester.edu; hamblin@helix.mgh.harvard.edu; barasaff@cs.com; migliorati@uthsc.edu; D.M.Milstein@amc.uva.nl; mtgenot@skynet.be; l.lansaat@nki.nl; RVanderbrink@coh.org; joseparnabat@ub.edu; l.vd.molen@nki.nl; i.jacobi@nki.nl; j.v.diessen@nki.nl; j.delange@amc.uva.nl; l.smeele@nki.nl; mschuber@seattlecca.org; renejean.bensadoun@che-nice.com FU US NIH grant [R01AI050875] FX Judith E. Raber-Durlacher, Raj G. Nair, Joel B. Epstein, Ron van der Brink, Josep Arnabat Dominguez, and Rene-Jean Bensadoun have received travel expenses and hotel accommodation for the founding meeting of iGLOB from THOR Photomedicine Ltd., UK. Raj Nair has received an honorarium from THOR, UK. Michael R Hamblin was supported by US NIH grant R01AI050875. NR 123 TC 7 Z9 7 U1 11 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUN PY 2016 VL 24 IS 6 BP 2793 EP 2805 DI 10.1007/s00520-016-3153-y PG 13 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DK5TL UT WOS:000374983300047 PM 26984249 ER PT J AU Manterola, M Sicinski, P Wolgemuth, DJ AF Manterola, Marcia Sicinski, Piotr Wolgemuth, Debra J. TI E-type cyclins modulate telomere integrity in mammalian male meiosis SO CHROMOSOMA LA English DT Article DE Meiosis; E-type cyclins; Cyclin E1; Cyclin E2; Meiosis control; Telomere; Telomere integrity; Shelterin complex; TRF1; TRF2 ID MEIOTIC TELOMERES; PROTEIN; MOUSE; RECOMBINATION; SHELTERIN; BINDING; MICE; REPLICATION; ATTACHMENT; CENTROMERE AB We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/-E2-/-) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of gamma-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis. C1 [Manterola, Marcia; Wolgemuth, Debra J.] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA. [Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Wolgemuth, Debra J.] Columbia Univ, Med Ctr, Obstet & Gynecol, New York, NY 10032 USA. [Wolgemuth, Debra J.] Columbia Univ, Med Ctr, Inst Human Nutr, New York, NY 10032 USA. RP Wolgemuth, DJ (reprint author), Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA.; Wolgemuth, DJ (reprint author), Columbia Univ, Med Ctr, Obstet & Gynecol, New York, NY 10032 USA.; Wolgemuth, DJ (reprint author), Columbia Univ, Med Ctr, Inst Human Nutr, New York, NY 10032 USA. EM djw3@columbia.edu RI Manterola, Marcia/H-9420-2016 FU NIH [R01 HD034915, R01 CA083688]; Lalor Foundation FX The authors would like to thank Dr. Titia de Lange for kindly providing the anti-TRF1 and RAP1 antibodies and Dr. Manfred Alsheimer for providing the anti-LAP2 antibody. This work was supported in part by grants from the NIH, R01 HD034915 (DJW) and R01 CA083688 (PS), and the Lalor Foundation (MM). NR 40 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 EI 1432-0886 J9 CHROMOSOMA JI Chromosoma PD JUN PY 2016 VL 125 IS 2 SI SI BP 253 EP 264 DI 10.1007/s00412-015-0564-3 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DJ6EW UT WOS:000374304000008 PM 26712234 ER PT J AU Shi, Y Shu, ZJ Xue, XL Yeh, CK Katz, MS Kamat, A AF Shi, Yun Shu, Zhen-Ju Xue, Xiaoling Yeh, Chih-Ko Katz, Michael S. Kamat, Amrita TI beta(2)-Adrenergic receptor ablation modulates hepatic lipid accumulation and glucose tolerance in aging mice SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Lipid; Hepatocytes; Cide; Triglycerides; Metabolism; Nonalcoholic fatty liver disease ID FATTY LIVER-DISEASE; SYMPATHETIC-NERVOUS-SYSTEM; BETA-ADRENERGIC-RECEPTORS; INSULIN-RESISTANCE; RAT-LIVER; ADENYLATE-CYCLASE; METABOLISM; EXPRESSION; GLYCOGENOLYSIS; EPINEPHRINE AB Catecholamines acting through beta-adrenergic receptors (beta(1)-, beta(2)-, beta(3)-AR subtypes) modulate important biological responses in various tissues. Our previous studies suggest a role for increased hepatic beta-AR-mediated signaling during aging as a mediator of hepatic steatosis, liver glucose output, and insulin resistance in rodents. In the current study, we have utilized beta(2)-AR knockout (KO) and wildtype (WT) control mice to define further the role of beta(2)-AR signaling during aging on lipid and glucose metabolism. Our results demonstrate for the first time that age-related increases in hepatic triglyceride accumulation and body weight are attenuated upon beta(2)-AR ablation. Although no differences in plasma triglyceride, non-esterified fatty acids or insulin levels were detected between old WT and KO animals, an age-associated increase in hepatic expression of lipid homeostasis regulator Cidea was significantly reduced in old KO mice. Interestingly, we also observed a shift from reduced glucose tolerance in young adult KO animals to significantly improved glucose tolerance in old KO when compared to age-matched WT mice. These results provide evidence for an important role played by beta(2)-ARs in the regulation of lipid and glucose metabolism during aging. The effect of beta(2)-AR ablation on caloric intake during aging is currently not known and requires investigation. Future studies are also warranted to delineate the beta(2)-AR-mediated mechanisms involved in the control of lipid and glucose homeostasis, especially in the context of a growing aging population. Published by Elsevier Inc. C1 [Shi, Yun; Shu, Zhen-Ju; Xue, Xiaoling; Yeh, Chih-Ko; Katz, Michael S.; Kamat, Amrita] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Audie L Murphy Div, San Antonio, TX 78229 USA. [Shi, Yun; Shu, Zhen-Ju; Xue, Xiaoling; Katz, Michael S.; Kamat, Amrita] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Yeh, Chih-Ko; Katz, Michael S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Comprehens Dent, San Antonio, TX 78229 USA. [Yeh, Chih-Ko; Kamat, Amrita] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. RP Kamat, A (reprint author), South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr 182, Audie L Murphy Div, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM shiy@uthscsa.edu; shuz2@uthscsa.edu; xue@uthscsa.edu; yeh@uthscsa.edu; katz@uthscsa.edu; Amrita.Kamat@va.gov FU VA Merit Review Award [1I01BX001744-01]; Kronos Longevity Research Institute Award FX This work was supported by VA Merit Review Award (1I01BX001744-01 to AK) and Kronos Longevity Research Institute Award (to MSK). NR 50 TC 0 Z9 0 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD JUN 1 PY 2016 VL 78 BP 32 EP 38 DI 10.1016/j.exger.2016.03.005 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DJ6OR UT WOS:000374333300004 PM 26952573 ER PT J AU Vardjan, N Horvat, A Anderson, JE Yu, D Croom, D Zeng, X Luznik, Z Kreft, M Teng, YD Kirov, SA Zorec, R AF Vardjan, Nina Horvat, Anemari Anderson, Jamie E. Yu, Dou Croom, Deborah Zeng, Xiang Luznik, Zala Kreft, Marko Teng, Yang D. Kirov, Sergei A. Zorec, Robert TI Adrenergic Activation Attenuates Astrocyte Swelling Induced by Hypotonicity and Neurotrauma SO GLIA LA English DT Article DE astrocytes; contusion trauma; cerebral cortex; spinal cord; cytotoxic edema; epinephrine ID SPINAL-CORD-INJURY; BRAIN EDEMA; CELL-VOLUME; IN-VIVO; SPREADING DEPOLARIZATIONS; CULTURED ASTROCYTES; FUNCTIONAL DEFICITS; WATER-INTOXICATION; DENDRITIC INJURY; ISCHEMIC-STROKE AB Edema in the central nervous system can rapidly result in life-threatening complications. Vasogenic edema is clinically manageable, but there is no established medical treatment for cytotoxic edema, which affects astrocytes and is a primary trigger of acute post-traumatic neuronal death. To test the hypothesis that adrenergic receptor agonists, including the stress stimulus epinephrine protects neural parenchyma from damage, we characterized its effects on hypotonicity-induced cellular edema in cortical astrocytes by in vivo and in vitro imaging. After epinephrine administration, hypotonicity-induced swelling of astrocytes was markedly reduced and cytosolic 3'-5'-cyclic adenosine monophosphate (cAMP) was increased, as shown by a fluorescence resonance energy transfer nanosensor. Although, the kinetics of epinephrine-induced cAMP signaling was slowed in primary cortical astrocytes exposed to hypotonicity, the swelling reduction by epinephrine was associated with an attenuated hypotonicity-induced cytosolic Ca2+ excitability, which may be the key to prevent astrocyte swelling. Furthermore, in a rat model of spinal cord injury, epinephrine applied locally markedly reduced neural edema around the contusion epicenter. These findings reveal new targets for the treatment of cellular edema in the central nervous system. C1 [Vardjan, Nina; Kreft, Marko; Zorec, Robert] BIOMEDICAL, Celica, Tehnol Pk 24, Ljubljana 1000, Slovenia. [Vardjan, Nina; Horvat, Anemari; Luznik, Zala; Kreft, Marko; Zorec, Robert] Univ Ljubljana, Fac Med, Inst Pathophysiol, Lab Neuroendocrinol Mol Cell Physiol, Zaloska 4, Ljubljana 1000, Slovenia. [Anderson, Jamie E.; Yu, Dou; Zeng, Xiang; Teng, Yang D.] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Anderson, Jamie E.; Yu, Dou; Zeng, Xiang; Teng, Yang D.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Croom, Deborah; Kirov, Sergei A.] Med Coll Georgia, Brain & Behav Discovery Inst, Augusta, GA 30912 USA. [Croom, Deborah; Kirov, Sergei A.] Med Coll Georgia, Dept Neurosurg, Augusta, GA 30912 USA. [Kreft, Marko] Univ Ljubljana, Biotech Fac, Dept Biol, Vecna Pot 111, Ljubljana 1000, Slovenia. [Teng, Yang D.] VA Boston Healthcare Syst, Div SCI Res, Boston, MA USA. RP Zorec, R (reprint author), BIOMEDICAL, Celica, Tehnol Pk 24, Ljubljana 1000, Slovenia.; Zorec, R (reprint author), Univ Ljubljana, Fac Med, Inst Pathophysiol, Lab Neuroendocrinol Mol Cell Physiol, Zaloska 4, Ljubljana 1000, Slovenia.; Teng, YD (reprint author), Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA.; Teng, YD (reprint author), Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA.; Kirov, SA (reprint author), Med Coll Georgia, Brain & Behav Discovery Inst, Augusta, GA 30912 USA.; Kirov, SA (reprint author), Med Coll Georgia, Dept Neurosurg, Augusta, GA 30912 USA.; Teng, YD (reprint author), VA Boston Healthcare Syst, Div SCI Res, Boston, MA USA. EM yang_teng@hms.harvard.edu; skirov13@gmail.com; robert.zorec@mf.uni-lj.si FU Slovenian Research Agency [P3 310, J3 4051, J3 3632, J3 6790, J3 4146]; Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins; COST Action [BM1002]; EduGlia ITN EU grant; National Institute of Health [NS083858]; American Heart Association [12GRNT16570006]; US Department of Veterans Affairs Rehabilitation Research and Development [B7076R]; US Department of Defense-Center for Integration of Medicine & Innovative Technology grants FX We thank Dr. Martin Lohse and Dr. Viacheslav Olegowitsch Nikolaev (University of Wurzburg, Wurzburg, Germany) for providing the Epac1-camps FRET plasmid construct. We also thank Ursa Gubensek for assistance with the experiments. This work was supported by the Slovenian Research Agency (P3 310 to R.Z., J3 4051 to R.Z., J3 3632 to R.Z., J3 6790 to R.Z., J3 4146 to M.K.), the Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins to R.Z., the COST Action BM1002 to R.Z., the EduGlia ITN EU grant to R.Z., the National Institute of Health (NS083858 to S.A.K.), the American Heart Association (12GRNT16570006 to S.A.K.), the US Department of Veterans Affairs Rehabilitation Research and Development (B7076R to Y.D.T.), and the US Department of Defense-Center for Integration of Medicine & Innovative Technology grants to Y.D.T. NR 69 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD JUN PY 2016 VL 64 IS 6 BP 1034 EP 1049 DI 10.1002/glia.22981 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DJ6ME UT WOS:000374326600012 PM 27018061 ER PT J AU Ni, MY Jiang, CQ Cheng, KK Zhang, WS Gilman, SE Lam, TH Leung, GM Schooling, CM AF Ni, Michael Y. Jiang, Chaoqiang Cheng, Kar Keung Zhang, Weisen Gilman, Stephen E. Lam, Tai Hing Leung, Gabriel M. Schooling, C. Mary TI Stress across the life course and depression in a rapidly developing population: the Guangzhou Biobank Cohort Study SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE depression; childhood adversity; life change events; life stress ID CHILDHOOD ADVERSITY; RETROSPECTIVE REPORTS; PSYCHIATRIC-DISORDER; MAJOR DEPRESSION; HONG-KONG; RISK; IDENTIFICATION; CHILDREN; EVENTS; ONSET AB ObjectiveThe objective of this study was to examine the role of stress across the life course in the development of depression among older adults in a non-Western developing setting. MethodsMultivariable linear and multinomial logistic regression were used in cross-sectional analyses of 9729 Chinese participants (mean age 60.2years) from phase 3 of the Guangzhou Biobank Cohort Study (2006-2008) to investigate the association of childhood adversities and adulthood stressors with depression. ResultsChildhood adversities were associated with mild depression (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.58, 2.02) and moderate-to-severe depression (OR 2.30, 95% CI 1.68, 3.15), adjusted for age, sex, education and childhood socio-economic status. Past-year adulthood stressors were also associated with mild depression (OR 1.96, 95% CI 1.54, 2.02) and moderate-to-severe depression (OR 3.55, 95% CI 2.21, 5.68), adjusting additionally for occupation and income. Adulthood stressors were more strongly associated with depressive symptoms among individuals with a history of childhood adversities. ConclusionsChildhood adversities and adulthood stressors were independently associated with an increased risk of depression among older ambulatory adults, although adulthood stressors were more strongly associated with depression following exposure to childhood adversities. This is consistent with evidence from Western settings in which the social context of risk and protective factors for depression may differ and implies that the role of stress in the aetiology of depression is not context specific. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Ni, Michael Y.; Lam, Tai Hing; Leung, Gabriel M.; Schooling, C. Mary] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. [Jiang, Chaoqiang; Zhang, Weisen] Guangzhou 12 Hosp, Guangzhou, Guangdong, Peoples R China. [Cheng, Kar Keung] Univ Birmingham, Dept Publ Hlth & Epidemiol, Birmingham, W Midlands, England. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, Rockville, MD USA. [Schooling, C. Mary] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. [Schooling, C. Mary] CUNY, New York, NY 10021 USA. RP Lam, TH (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. EM hrmrlth@hku.hk OI Ni, Michael/0000-0002-1217-5858; Cheng, Kar/0000-0002-1516-1857; Gilman, Stephen/0000-0002-8331-6419 FU University of Hong Kong Foundation for Development and Research; University of Hong Kong University Research Committee Strategic Research Theme Public Health, Hong Kong; Guangzhou Public Health Bureau; Guangzhou Science and Technology Bureau, Guangzhou, China; University of Birmingham, UK; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA FX This work was supported by The University of Hong Kong Foundation for Development and Research and The University of Hong Kong University Research Committee Strategic Research Theme Public Health, Hong Kong; Guangzhou Public Health Bureau and Guangzhou Science and Technology Bureau, Guangzhou, China; and The University of Birmingham, UK; and in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. The funding sources had no role in any of the following: study design; the collection, analysis and interpretation of data; the writing of the report; and the decision to submit the paper for publication. NR 61 TC 0 Z9 0 U1 5 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD JUN PY 2016 VL 31 IS 6 BP 629 EP 637 DI 10.1002/gps.4370 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DK1UM UT WOS:000374700000010 PM 26452069 ER PT J AU Wu, CA Mulder, AL Zai, AH Hu, YS Costa, M Tishler, LW Saltzman, JR Ellner, AL Bitton, A AF Wu, Charlotte A. Mulder, Amara L. Zai, Adrian H. Hu, Yuanshan Costa, Manuela Tishler, Lori Wiviott Saltzman, John R. Ellner, Andrew L. Bitton, Asaf TI A population management system for improving colorectal cancer screening in a primary care setting SO JOURNAL OF EVALUATION IN CLINICAL PRACTICE LA English DT Article DE care redesign; health information technology; population management; preventive colorectal cancer screening; primary care ID RANDOMIZED-CONTROLLED-TRIAL; PAID MALPRACTICE CLAIMS; PATIENT; COLONOSCOPY; NAVIGATION; SUPPORT AB RationaleProvision of colorectal cancer (CRC) screening in primary care is suboptimal; failure to observe screening guidelines poses unnecessary risks to patients and doctors. Aims and objectivesImplement a population management system for CRC screening; evaluate impact on compliance with evidence-based guidelines. Methods DesignA quasi-experimental, prospective quality improvement study design using pre-post-analyses with concurrent controls. SettingSix suites within an academic primary care practice. Participants5320 adults eligible for CRC screening treated by 70 doctors. InterventionIn three intervention suites, doctors reviewed real-time rosters of patients due for CRC screening and chose practice delegate outreach or default reminder letter. Delegates tracked overdue patients, made outreach calls, facilitated test ordering, obtained records and documented patient deferral, exclusion or decline. In three control suites, doctors followed usual preventive care practices. Main outcome measuresCRC screening compliance (including documented decline, deferral or exclusion) and CRC screening completion rates over 5 months. ResultsAt baseline, there was no significant difference in CRC screening compliance (I: 80.4% and C: 79.6%, P=0.439) and CRC screening completion rates (I: 78.3% and C: 77.3%, P=0.398) between intervention and control groups. Post-intervention, compliance rates (I: 88.1% and C: 80.5%, P < 0.01) and completion rates (I: 81.0% and C: 78.1%, P < 0.05) were significantly higher in the intervention group. ConclusionsA population management system using closed-loop communication may improve CRC screening compliance and completion rates within academic primary care practices. Team-based care using well-designed IT systems can enable sharing of patient care responsibilities and improve patient outcomes. C1 [Wu, Charlotte A.] Boston Med Ctr, Gen Internal Med, 725 Albany St,Shapiro 6C, Boston, MA 02118 USA. [Mulder, Amara L.] South Shore Med Ctr, Norwell, MA 02061 USA. [Hu, Yuanshan] Brigham & Womens Hosp, Populat Hlth, Boston, MA 02115 USA. [Tishler, Lori Wiviott; Ellner, Andrew L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bitton, Asaf] Brigham & Womens Hosp, Dept Med, Adv Primary Care Associates, 75 Francis St, Boston, MA 02115 USA. [Zai, Adrian H.] Massachusetts Gen Hosp, Comp Sci Lab, Populat Informat, Boston, MA 02114 USA. [Saltzman, John R.] Brigham & Womens Hosp, Dept Med, Div Gastroenterol Hepatol & Endoscopy, Endoscopy, 75 Francis St, Boston, MA 02115 USA. [Ellner, Andrew L.] Harvard Univ, Sch Ctr Primary Care, Cambridge, MA 02138 USA. [Bitton, Asaf] Harvard Univ, Sch Med, Boston, MA USA. RP Wu, CA (reprint author), Boston Med Ctr, Gen Internal Med, 725 Albany St,Shapiro 6C, Boston, MA 02118 USA. EM charlotte.wu@bmc.org FU CRICO/Risk Management Foundation of the Harvard Medical Institutions, Inc. (RMF) FX The authors wish to thank Jennifer Luttrell, Steven Wong, Lauren Murphy, Wrene Robyn from the Laboratory of Computer Science at the Massachusetts General Hospital, and Janice Dolan, Katrina Harris, the Orange and the Red Teams from the Jen Center for Primary Care at Brigham and Women's Hospital for their invaluable assistance in making this project possible. This study was supported by a grant from CRICO/Risk Management Foundation of the Harvard Medical Institutions, Inc. (RMF). No funding source had a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. The authors 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 35 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1356-1294 EI 1365-2753 J9 J EVAL CLIN PRACT JI J. Eval. Clin. Pract. PD JUN PY 2016 VL 22 IS 3 BP 319 EP 328 DI 10.1111/jep.12427 PG 10 WC Health Care Sciences & Services; Medical Informatics; Medicine, General & Internal SC Health Care Sciences & Services; Medical Informatics; General & Internal Medicine GA DK1BN UT WOS:000374647100003 PM 26259696 ER PT J AU Feraco, A Gagne, J Brand, S Block, S Wolfe, J AF Feraco, Angela Gagne, Joshua Brand, Sarah Block, Susan Wolfe, Joanne TI SPEAKING TO THE "NEW NORMAL": WOULD FAMILIES VALUE A DAY 100 TALK IN THE FIRST SIX MONTHS OF CANCER CARE? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Feraco, Angela; Gagne, Joshua; Brand, Sarah; Block, Susan; Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 570 BP S31 EP S32 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900098 ER PT J AU Koegel, A Blonquist, T Silverman, L Vrooman, L AF Koegel, Ashley Blonquist, Traci Silverman, Lewis Vrooman, Lynda TI INDUCTION TOXICITIES AND DELAY IN THE START OF PLANNED POST-INDUCTION THERAPY IN CHILDHOOD ALL: A REPORT FROM DANA FARBER CANCER INSTITUTE ALL CONSORTIUM PROTOCOL 05-001 SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Koegel, Ashley; Blonquist, Traci; Silverman, Lewis; Vrooman, Lynda] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 506 BP S15 EP S15 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900035 ER PT J AU Sheu, J Hawryluk, E London, W Guo, DJ Sridharan, M Rea, C Lehmann, L Duncan, C Huang, JT AF Sheu, Johanna Hawryluk, Elena London, Wendy Guo, Dongjing Sridharan, Madhumitha Rea, Corinna Lehmann, Leslie Duncan, Christine Huang, Jennifer T. TI LATE EFFECTS OF THE SKIN IN CHILDREN AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Sheu, Johanna; Hawryluk, Elena; London, Wendy; Guo, Dongjing; Sridharan, Madhumitha; Rea, Corinna; Lehmann, Leslie; Duncan, Christine; Huang, Jennifer T.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 5014 BP S94 EP S95 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900344 ER PT J AU Zerillo, J Santacroce, E Zimmerman, MA Freeman, M Greenberg, TL Nguyen, P Chi, S Bandopadhayay, P Lane, S Szabatura, A Houlahan, K Billett, A AF Zerillo, Jessica Santacroce, Erin Zimmerman, Mary Ann Freeman, Melissa Greenberg, Teresa Lau Phuong Nguyen Chi, Susan Bandopadhayay, Pratiti Lane, Sharon Szabatura, Audrea Houlahan, Kathleen Billett, Amy TI BUILDING A NEW PROCESS: NURSING VERIFICATION OF PEDIATRIC ORAL CHEMOTHERAPY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Zerillo, Jessica; Santacroce, Erin; Zimmerman, Mary Ann; Freeman, Melissa; Greenberg, Teresa Lau; Phuong Nguyen; Chi, Susan; Bandopadhayay, Pratiti; Lane, Sharon; Szabatura, Audrea; Houlahan, Kathleen; Billett, Amy] Dana Farber Boston Childrens Canc & Blood Disorde, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2016 VL 63 SU 1 MA 584 BP S35 EP S35 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DJ6FW UT WOS:000374306900112 ER PT J AU Farschtschi, S Merker, VL Wolf, D Schuhmann, M Blakeley, J Plotkin, SR Hagel, C Mautner, VF AF Farschtschi, S. Merker, V. L. Wolf, D. Schuhmann, M. Blakeley, J. Plotkin, S. R. Hagel, C. Mautner, V. F. TI Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2 SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Editorial Material DE neurofibromatosis; ependymoma; bevacizumab; neurofibromatosis type 2; vascular endothelial growth factor ID VESTIBULAR-SCHWANNOMA; RECURRENT EPENDYMOMA; GLIOMAS AB BackgroundNeurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). AimsThe aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas MethodsWe conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. ResultsEight patients with NF2 and symptomatic ependymoma were treated with bevacizumab. All patients had subjective clinical improvement with bevacizumab, although only five of eight patients evaluated had radiographic response. All tumors expressed VEGF-R2. Four of five evaluated ependymomas expressed VEGF-R1; one without VEGF-R1 expression was from a patient who showed clinical but not radiographic response. ConclusionsTreatment using bevacizumab improved symptoms related to NF2-associated ependymomas, often without concurrent radiographic response. This treatment effect may be related to VEGF-R1 expression in NF2-associated ependymoma. C1 [Farschtschi, S.; Mautner, V. F.] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Merker, V. L.; Plotkin, S. R.] Massachusetts Gen Hosp, Pappas Ctr Neuro Oncol, Boston, MA 02114 USA. [Wolf, D.; Blakeley, J.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Schuhmann, M.] Univ Med Ctr Tubingen, Dept Neurosurg, Tubingen, Germany. [Hagel, C.] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany. RP Farschtschi, S (reprint author), Martinistr 52, D-20246 Hamburg, Germany. EM s.farschtschi@uke.de OI Merker, Vanessa/0000-0002-4542-5227 NR 15 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-6314 EI 1600-0404 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD JUN PY 2016 VL 133 IS 6 BP 475 EP 480 DI 10.1111/ane.12490 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DJ2OM UT WOS:000374044400010 PM 26369495 ER PT J AU Peteet, JR Rodriguez, VB Herschkopf, MD McCarthy, A Betts, J Romo, S Murphy, JM AF Peteet, John R. Rodriguez, Vithya B. Herschkopf, Marta D. McCarthy, Alyssa Betts, Jennifer Romo, Stephanie Murphy, J. Michael TI Does a Therapist's World View Matter? SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Spiritual; Religious; World view; Psychotherapy ID CLINICAL-PRACTICE; PSYCHIATRY; PHYSICIANS; AUTONOMY; RELIGION AB While past research indicates that mental health professionals are less religious than the public they serve, little is known about the implications of therapists' world views for their practice. In this study, approximately 50 therapists completed surveys that assessed self-identification in relation to spirituality, religion, and/or world view; how relevant they considered their patients' and their own world views; and responses to clinical vignettes involving issues arising in treatment. While a minority considered themselves religious, a majority indicated that they considered themselves moderately or very spiritual. When asked how they would respond to a series of clinical vignettes involving topics such as assisted suicide and encouraging the use of spiritual resources, responses varied significantly by world view. Respondents endorsed several factors limiting the integration of religion/spiritualities/world views into their clinical work. These data raise questions about how to further explore the clinical relevance of the therapist's world view. C1 [Peteet, John R.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Rodriguez, Vithya B.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Herschkopf, Marta D.; Murphy, J. Michael] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [McCarthy, Alyssa] Rutgers State Univ, Dept Psychol, Piscataway, NJ USA. [Betts, Jennifer] McLean Hosp, Behav Psychopharmacol Lab, 115 Mill St, Belmont, MA 02178 USA. [Romo, Stephanie] Shriners Hosp Children, Dept Clin Res, Boston, MA USA. RP Peteet, JR (reprint author), Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. EM John_Peteet@dfci.harvard.edu NR 32 TC 1 Z9 1 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 EI 1573-6571 J9 J RELIG HEALTH JI J. Relig. Health PD JUN PY 2016 VL 55 IS 3 BP 1097 EP 1106 DI 10.1007/s10943-016-0208-9 PG 10 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA DI2UY UT WOS:000373355600030 PM 26922750 ER PT J AU Lynch, HT Kosoko-Lasaki, O Leslie, SW Rendell, M Shaw, T Snyder, C D'Amico, AV Buxbaum, S Isaacs, WB Loeb, S Moul, JW Powell, I AF Lynch, Henry T. Kosoko-Lasaki, Omofolasade Leslie, Stephen W. Rendell, Marc Shaw, Trudy Snyder, Carrie D'Amico, Anthony V. Buxbaum, Sarah Isaacs, William B. Loeb, Stacy Moul, Judd W. Powell, Isaac TI Screening for familial and hereditary prostate cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE prostate cancer; genome wide association studies; prostate specific antigen; BRCA2; HOXB13 ID GENOME-WIDE ASSOCIATION; 5 GENETIC-VARIANTS; RISK-ASSOCIATED LOCI; SUSCEPTIBILITY LOCI; LINKAGE ANALYSIS; AGGRESSIVENESS LOCI; GERMLINE MUTATIONS; SEQUENCE VARIANTS; LYNCH SYNDROME; MULTIPLE LOCI AB Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man (R) Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate chromosomes. Genome-wide association studies have added many more markers to the set derived from linkage investigations. A subset of the alleles is associated with early onset and aggressive cancer. Due to the great heterogeneity, the OR for any one allele predicting future development of this malignancy is low. The strongest predictors are the BRCA2 mutations, and the highly penetrant G84E mutation in HOXB13. The presence of multiple risk alleles is more highly predictive than a single allele. Technical limitations on screening large panels of alleles are being overcome. It is appropriate to begin supplementing prostate specific antigen testing with alleles, such as BRCA2 and HOXB13, disclosed by targeted genomic analysis in families with an unfavorable family cancer history. Future population studies of PC should include genomic sequencing protocols, particularly in families with a history of PC and other malignancies. C1 [Lynch, Henry T.; Shaw, Trudy; Snyder, Carrie] Creighton Univ, Hereditary Canc Ctr, 2500 Calif Plaza, Omaha, NE 68178 USA. [Lynch, Henry T.; Kosoko-Lasaki, Omofolasade; Shaw, Trudy; Snyder, Carrie] Creighton Univ, Dept Prevent Med, 2500 Calif Plaza, Omaha, NE 68178 USA. [Kosoko-Lasaki, Omofolasade] Creighton Univ, Dept Surg, 2500 Calif Plaza, Omaha, NE USA. [Kosoko-Lasaki, Omofolasade] Creighton Univ, Dept Publ Hlth, 2500 Calif Plaza, Omaha, NE USA. [Leslie, Stephen W.] Creighton Univ, Dept Urol Surg, Med Ctr, 601 North 30th St,Suite 3700, Omaha, NE 68178 USA. [Rendell, Marc] Creighton Univ, Dept Internal Med, Med Ctr, 601 North 30th St,Suite 3700, Omaha, NE 68178 USA. [D'Amico, Anthony V.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA USA. [D'Amico, Anthony V.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Buxbaum, Sarah] Jackson State Univ, Sch Hlth Sci, 350 W Woodrow Wilson Dr, Jackson, MS USA. [Isaacs, William B.] Johns Hopkins Univ, Sch Med, Dept Urol, Johns Hopkins Hosp, Marburg 115,600 N Wolfe St, Baltimore, MD 21205 USA. [Isaacs, William B.] Johns Hopkins Univ, Sch Med, Dept Oncol, Johns Hopkins Hosp, Marburg 115,600 N Wolfe St, Baltimore, MD 21205 USA. [Loeb, Stacy] NYU, Dept Urol & Populat Hlth, 550 1st Ave VZ30 612, New York, NY USA. [Moul, Judd W.] Duke Univ, Med Ctr, Duke Prostate Ctr, Div Urol Surg, DUMC 3707 Room 1562 Duke South, Durham, NC USA. [Powell, Isaac] Wayne State Univ, Dept Urol, Karmanos Canc Inst, Univ Hlth Ctr 7-C, Detroit, MI USA. RP Rendell, M (reprint author), Creighton Univ, Dept Internal Med, Med Ctr, 601 North 30th St,Suite 3700, Omaha, NE 68178 USA. EM rendell@asndi.com RI Buxbaum, Sarah/E-1970-2013 OI Buxbaum, Sarah/0000-0002-4886-3564 FU Nebraska Department of Health and Human Services [LL595]; Cancer Research at Creighton University; Health Disparity Research Award - "Prostate Cancer Genetics in African Americans" (Lynch) Department of Defense Prostate Cancer Research Program of Office of Congressionally Directed Medical Research Programs (CDMRP) [PC101953]; Kicks for a Cure; Jackson State University from the National Institute of Minority Health [P20MD006899]; Health Disparities (NIMHD) of National Institutes of Health; Laura & Isaac Perlmutter NYU Cancer Center; Louis Feil Charitable Lead Trust FX Grant sponsors: Nebraska Department of Health and Human Services (Nebraska cigarette taxes awarded under LL595; to H.T.L.), Cancer Research at Creighton University (HTL), Health Disparity Research Award PC101953 - "Prostate Cancer Genetics in African Americans" (Lynch) Department of Defense Prostate Cancer Research Program of the Office of the Congressionally Directed Medical Research Programs (CDMRP), and Kicks for a Cure; Grant sponsor: Jackson State University from the National Institute of Minority Health (to S.G.B.); Grant number: P20MD006899; Grant sponsor: Health Disparities (NIMHD) of the National Institutes of Health and PC101953; Grant sponsor: Laura & Isaac Perlmutter NYU Cancer Center and the Louis Feil Charitable Lead Trust (to S.L.). NR 145 TC 4 Z9 4 U1 2 U2 26 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 JUN 1 PY 2016 VL 138 IS 11 BP 2579 EP 2591 DI 10.1002/ijc.29949 PG 13 WC Oncology SC Oncology GA DH6PN UT WOS:000372913400004 PM 26638190 ER PT J AU Wang, YR Liu, HL Ready, NE Su, L Wei, YY Christiani, DC Wei, QY AF Wang, Yanru Liu, Hongliang Ready, Neal E. Su, Li Wei, Yongyue Christiani, David C. Wei, Qingyi TI Genetic variants in ABCG1 are associated with survival of nonsmall-cell lung cancer patients SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lung cancer; drug transporters; overall survival; single-nucleotide polymorphism; ABCG1 ID GENOME-WIDE ASSOCIATION; ATP-BINDING CASSETTE; MULTIDRUG-RESISTANCE; FUNCTIONAL VARIATION; RANDOMIZED PROSTATE; SCREENING TRIAL; TRANSPORTERS; FAMILY; COPPER; ADENOCARCINOMA AB Cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of nonsmall-cell lung cancer (NSCLC) patients by reanalyzing two datasets from published genome-wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single-nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR <= 0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP-binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r(2) > 0.8 for linkage disequilibrium with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G>A [adjusted hazards ratio (HR) = 1.12, 95% confidence interval (CI) 51.03-1.20, P-trend = 4.6 x 10(-3)] and rs225390 A>G (adjusted HR = 1.16, 95% CI = 1.07-1.25, P-trend = 3.8 x 10(-4)). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients. C1 [Wang, Yanru; Liu, Hongliang; Ready, Neal E.; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, 905 S LaSalle St, Durham, NC 27710 USA. [Wang, Yanru; Liu, Hongliang; Ready, Neal E.; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Wei, QY (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, 905 S LaSalle St, Durham, NC 27710 USA. EM qingyi.wei@duke.edu FU Duke Cancer Institute, Duke University Medical Center; Duke Cancer Institute as part of the National Institutes of Health (NIH)-National Cancer Institute (NCI) P30 Cancer Center Support Grant [NIH-NCI CA014236]; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University; NIH-NCI [NIH-NCI CA092824, CA074386, CA090578] FX Grant sponsor: Duke Cancer Institute, Duke University Medical Center and support from the Duke Cancer Institute as part of the National Institutes of Health (NIH)-National Cancer Institute (NCI) P30 Cancer Center Support Grant (to Q. W.); Grant number: NIH-NCI CA014236; Grant sponsor: Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University (to Y. W.); Grant sponsor: NIH-NCI (to D. C. C.); Grant numbers: NIH-NCI CA092824, CA074386 and CA090578 NR 46 TC 1 Z9 1 U1 1 U2 12 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 JUN 1 PY 2016 VL 138 IS 11 BP 2592 EP 2601 DI 10.1002/ijc.29991 PG 10 WC Oncology SC Oncology GA DH6PN UT WOS:000372913400005 PM 26757251 ER PT J AU Mikse, OR Tchaicha, JH Akbay, EA Chen, L Bronson, RT Hammerman, PS Wong, KK AF Mikse, Oliver R. Tchaicha, Jeremy H. Akbay, Esra A. Chen, Liang Bronson, Roderick T. Hammerman, Peter S. Wong, Kwok-Kin TI The impact of the MYB-NFIB fusion protooncogene in vivo SO ONCOTARGET LA English DT Article DE MYB-NFIB; adenoid cystic carcinoma; breast; salivary; GEMM ID ADENOID CYSTIC CARCINOMA; GENE FUSION; BREAST; ONCOGENE; CANCER; CELLS; NECK; HEAD AB Recurrent fusion of the v-myb avian myelobastosis viral oncogene homolog (MYB) and nuclear factor I/B (NFIB) generates the MYB-NFIB transcription factor, which has been detected in a high percentage of individuals with adenoid cystic carcinoma (ACC). To understand the functional role of this fusion protein in carcinogenesis, we generated a conditional mutant transgenic mouse that expresses MYB-NFIB along with p53 mutation in tissues that give rise to ACC: mammary tissue, salivary glands, or systemically in the whole body. Expression of the oncogene in mammary tissue resulted in hyperplastic glands that developed into adenocarcinoma in 27.3% of animals. Systemic expression of the MYB-NFIB fusion caused more rapid development of this breast phenotype, but mice died due to abnormal proliferation in the glomerular compartment of the kidney, which led to development of glomerulonephritis. These findings suggest the MYB-NFIB fusion is oncogenic and treatments targeting this transcription factor may lead to therapeutic responses in ACC patients. C1 [Mikse, Oliver R.; Tchaicha, Jeremy H.; Akbay, Esra A.; Chen, Liang; Hammerman, Peter S.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Mikse, Oliver R.; Tchaicha, Jeremy H.; Akbay, Esra A.; Chen, Liang; Hammerman, Peter S.; Wong, Kwok-Kin] Harvard Univ, Sch Med, Boston, MA USA. [Mikse, Oliver R.; Tchaicha, Jeremy H.; Akbay, Esra A.; Chen, Liang; Wong, Kwok-Kin] Ludwig Inst Canc, Cambridge, MA USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA USA. [Hammerman, Peter S.] Broad Inst, Cambridge, MA USA. [Wong, Kwok-Kin] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA USA. RP Wong, KK (reprint author), Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA.; Wong, KK (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Wong, KK (reprint author), Ludwig Inst Canc, Cambridge, MA USA.; Wong, KK (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA USA. EM kwong1@partners.org FU Adeno-Cystic Carcinoma Foundation; NIH/NCI [P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10, 5R01CA166480-04]; Gross-Loh Family Fund for Lung Cancer Research; Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute; Stand Up To Cancer (SU2C) - American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2CAACR-DT17-15] FX This study was funded by the Adeno-Cystic Carcinoma Foundation. K. K. Wong is supported by NIH/NCI P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10, and 5R01CA166480-04 grants and the Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute. P. S. Hammerman and K. K. Wong are supported by a Stand Up To Cancer (SU2C) - American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2CAACR-DT17-15). SU2C is a program of the Entertainment Industry Foundation, and research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. NR 16 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 31 PY 2016 VL 7 IS 22 BP 31681 EP 31688 DI 10.18632/oncotarget.9426 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4JP UT WOS:000377748500006 PM 27213588 ER PT J AU Liu, XC Wang, AL Liang, XF Chen, C Liu, JJ Zhao, Z Wu, H Deng, YX Wang, L Wang, BL Wu, JX Liu, FY Fernandes, SM Adamia, S Stone, RM Galinsky, IA Brown, JR Griffin, JD Zhang, SC Loh, TP Zhang, X Wang, WC Weisberg, EL Liu, J Liu, QS AF Liu, Xiaochuan Wang, Aoli Liang, Xiaofei Chen, Cheng Liu, Juanjuan Zhao, Zheng Wu, Hong Deng, Yuanxin Wang, Li Wang, Beilei Wu, Jiaxin Liu, Feiyang Fernandes, Stacey M. Adamia, Sophia Stone, Richard M. Galinsky, Ilene A. Brown, Jennifer R. Griffin, James D. Zhang, Shanchun Loh, Teckpeng Zhang, Xin Wang, Wenchao Weisberg, Ellen L. Liu, Jing Liu, Qingsong TI Characterization of selective and potent PI3K delta inhibitor (PI3KD-IN-015) for B-Cell malignances SO ONCOTARGET LA English DT Article DE PI3K delta; leukemia; B-cell malignances; PI3K; kinase inhibitors ID CHRONIC LYMPHOCYTIC-LEUKEMIA; PI3K; P110-DELTA; IDELALISIB; 3-KINASES; SURVIVAL; ISOFORM; CANCER AB PI3K delta is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3K delta inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KD-IN-015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate antiproliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies. C1 [Liu, Xiaochuan; Loh, Teckpeng] Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China. [Liu, Xiaochuan; Wang, Aoli; Liang, Xiaofei; Chen, Cheng; Liu, Juanjuan; Zhao, Zheng; Wu, Hong; Deng, Yuanxin; Wang, Li; Wang, Beilei; Wu, Jiaxin; Liu, Feiyang; Zhang, Xin; Wang, Wenchao; Liu, Jing; Liu, Qingsong] Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China. [Wang, Aoli; Liu, Juanjuan; Wu, Hong; Deng, Yuanxin; Wu, Jiaxin; Liu, Feiyang] Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China. [Liang, Xiaofei; Chen, Cheng; Zhao, Zheng; Wang, Li; Wang, Beilei; Zhang, Shanchun; Wang, Wenchao; Liu, Jing; Liu, Qingsong] CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China. [Fernandes, Stacey M.; Adamia, Sophia; Stone, Richard M.; Galinsky, Ilene A.; Brown, Jennifer R.; Griffin, James D.; Weisberg, Ellen L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Zhang, Shanchun] Hefei Cosource Med Technol Co LTD, Hefei 230031, Anhui, Peoples R China. [Liu, Qingsong] Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. RP Wang, WC; Liu, J; Liu, QS (reprint author), Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China.; Wang, WC; Liu, J; Liu, QS (reprint author), CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China.; Weisberg, EL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA.; Liu, QS (reprint author), Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. EM wwcbox@hmfl.cas.cn; Ellen_weisberg@dfci.harvard.edu; jingliu@hmfl.ac.cn; qsliu97@hmfl.ac.cn FU Chinese Academy of Sciences; Anhui Province Natural Science Foundation Annual Key Program [1301023011]; China "Thousand Talents Program"; "Hundred Talents Program" of The Chinese Academy of Sciences; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC) [2015SRG-HSC022]; CAS/SAFEA international partnership program for creative research teams FX W. Wang, J. Liu and Q. Liu are supported by the grant of"Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014-2016)' from Chinese Academy of Sciences. Z. Zhao is supported by Anhui Province Natural Science Foundation Annual Key Program (grant number: 1301023011). We want to thank China "Thousand Talents Program" support for Prof. Q. Liu and "Hundred Talents Program" of The Chinese Academy of Sciences support for Prof. J. Liu, and W. Wang. Prof. Q. Liu is also supported by Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC # 2015SRG-HSC022) and CAS/SAFEA international partnership program for creative research teams. NR 15 TC 0 Z9 0 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 MAY 31 PY 2016 VL 7 IS 22 BP 32641 EP 32651 DI 10.18632/oncotarget.8702 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4JP UT WOS:000377748500078 PM 27081697 ER PT J AU Derks, S Liao, XY Chiaravalli, AM Xu, XS Camargo, MC Solcia, E Sessa, F Fleitas, T Freeman, GJ Rodig, SJ Rabkin, CS Bass, AJ AF Derks, Sarah Liao, Xiaoyun Chiaravalli, Anna M. Xu, Xinsen Camargo, M. Constanza Solcia, Enrico Sessa, Fausto Fleitas, Tania Freeman, Gordon J. Rodig, Scott J. Rabkin, Charles S. Bass, Adam J. TI Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers SO ONCOTARGET LA English DT Article DE EBV-infected gastric cancers; MSI gastric cancer; PD-L1; PD-1 inhibitors ID T-CELLS; BLOCKADE; RECEPTOR; ACTIVATION; LYMPHOMAS; TUMORS; EBV AB Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV) + GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-gamma driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors. C1 [Derks, Sarah; Liao, Xiaoyun; Xu, Xinsen; Fleitas, Tania; Freeman, Gordon J.; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Derks, Sarah] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Liao, Xiaoyun; Rodig, Scott J.] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02115 USA. [Chiaravalli, Anna M.; Sessa, Fausto] Osped Circolo Varese, Dept Pathol, Varese, Italy. [Camargo, M. Constanza; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Solcia, Enrico] Univ Pavia, Dept Mol Med, Via Palestro 3, I-27100 Pavia, Italy. [Solcia, Enrico] Policlin San Matteo, Pavia, Italy. [Fleitas, Tania] Hosp Clin Univ Valencia, Dept Med Oncol, Valencia, Spain. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Bass, Adam J.] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bass, AJ (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA. EM adam_bass@dfci.harvard.edu RI Camargo, M. Constanza/R-9891-2016 FU Dutch Cancer Society [VU 2012-535]; Center of Immune Oncology at Dana-Farber Cancer Institute [R01AI089955]; Target Cancer Foundation; Schottenstein Fund for Stomach Cancer Research FX The project described was supported by the Dutch Cancer Society (VU 2012-535) (SD), the Center of Immune Oncology at Dana-Farber Cancer Institute (XL and SJR), R01AI089955 (GJF) and Target Cancer Foundation and The Schottenstein Fund for Stomach Cancer Research (to AJB). NR 24 TC 5 Z9 5 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 MAY 31 PY 2016 VL 7 IS 22 BP 32925 EP 32932 DI 10.18632/oncotarget.9076 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4JP UT WOS:000377748500101 PM 27147580 ER PT J AU Phuah, CL Raffeld, MR Ayres, AM Viswanathan, A Greenberg, SM Biffi, A Rosand, J Anderson, CD AF Phuah, Chia-Ling Raffeld, Miriam R. Ayres, Alison M. Viswanathan, Anand Greenberg, Steven M. Biffi, Alessandro Rosand, Jonathan Anderson, Christopher D. TI Subacute decline in serum lipids precedes the occurrence of primary intracerebral hemorrhage SO NEUROLOGY LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; CEREBROVASCULAR-DISEASE; UNITED-STATES; RISK-FACTOR; STROKE; LEVEL; INFLAMMATION; ASSOCIATION; MORTALITY; PROGRAM AB Objective:We aimed to describe the temporal variation in circulating lipid levels among patients with intracerebral hemorrhage (ICH) and investigate their association with ICH risk.Methods:This was a single-center, retrospective, longitudinal, case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a hospital-based clinical data registry. Piecewise linear mixed-effect random coefficient models were used to determine the significance of changes in serum lipid trends on ICH risk.Results:Two hundred twelve ICH cases and 301 control individuals were analyzed. Overall trends in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels differed between ICH cases and non-ICH controls (p = 0.00001 and p = 0.0092, respectively). Patients with ICH experience accelerated decline in serum TC and LDL levels during 6 months immediately preceding ICH, compared with levels between 6 and 24 months pre-ICH (TC: -29.25 mg/dL, p = 0.001; LDL: -21.48 mg/dL, p = 0.0038), which was not observed in non-ICH controls. Subgroup analysis confirmed that this phenomenon cannot be attributed to statin or alcohol exposure. Serum triglycerides and high-density lipoprotein trends did not differ between groups.Conclusions:Longitudinal lipid levels differ between ICH cases and non-ICH controls, most notably for a decline in serum TC and LDL levels within 6 months preceding primary ICH, independent of statin or alcohol use. These changes in serum TC and LDL trends suggest a biological pathway that precipitates ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury. C1 [Phuah, Chia-Ling; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Phuah, Chia-Ling; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ayres, Alison M.; Viswanathan, Anand; Greenberg, Steven M.; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Ayres, Alison M.; Viswanathan, Anand; Greenberg, Steven M.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Phuah, Chia-Ling; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA.; Anderson, CD (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Anderson, CD (reprint author), Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA.; Anderson, CD (reprint author), Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA.; Anderson, CD (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. EM cdanderson@mgh.harvard.edu OI Anderson, Christopher/0000-0002-0053-2002 FU National Institute for Neurologic Disorders and Stroke [R01 NS059727, K23 NS086873] FX This work was supported by funding from the National Institute for Neurologic Disorders and Stroke (R01 NS059727 and K23 NS086873). All funding entities had no involvement in study design, data collection, analysis, interpretation, writing of the report, and in the decision to submit the paper for publication. NR 35 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 31 PY 2016 VL 86 IS 22 BP 2034 EP 2041 DI 10.1212/WNL.0000000000002716 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DN9WM UT WOS:000377431400008 PM 27164693 ER PT J AU Robinson, MT Vickrey, BG Holloway, RG Chong, K Williams, LS Brook, RH Leng, M Parikh, P Zingmond, DS AF Robinson, Maisha T. Vickrey, Barbara G. Holloway, Robert G. Chong, Kelly Williams, Linda S. Brook, Robert H. Leng, Mei Parikh, Punam Zingmond, David S. TI The lack of documentation of preferences in a cohort of adults who died after ischemic stroke SO NEUROLOGY LA English DT Article ID OF-LIFE CARE; 30-DAY MORTALITY; PALLIATIVE CARE; INPATIENT; QUALITY; SCALE; END; HOSPITALS; ACCURACY; ICD-9-CM AB Objective:To measure the extent and timing of physicians' documentation of communication with patients and families regarding limitations on life-sustaining interventions, in a population cohort of adults who died within 30 days after hospitalization for ischemic stroke.Methods:We used the California Office of Statewide Health Planning and Development Patient Discharge Database to identify a retrospective cohort of adults with ischemic strokes at all California acute care hospitals from December 2006 to November 2007. Of 326 eligible hospitals, a representative sample of 39 was selected, stratified by stroke volume and mortality. Medical records of 981 admissions were abstracted, oversampled on mortality and tissue plasminogen activator receipt. Among 198 patients who died by 30 days postadmission, overall proportions and timing of documented preferences were calculated; factors associated with documentation were explored.Results:Of the 198 decedents, mean age was 80 years, 78% were admitted from home, 19% had mild strokes, 11% received tissue plasminogen activator, and 42% died during the index hospitalization. Preferences about at least one life-sustaining intervention were recorded on 39% of patients: cardiopulmonary resuscitation 34%, mechanical ventilation 23%, nasogastric tube feeding 10%, and percutaneous enteral feeding 6%. Most discussions occurred within 5 days of death. Greater stroke severity was associated with increased in-hospital documentation of preferences (p < 0.05).Conclusions:Documented discussions about limitations on life-sustaining interventions during hospitalization were low, even though this cohort died within 30 days poststroke. Improving the documentation of preferences may be difficult given the 2015 Centers for Medicare and Medicaid 30-day stroke mortality hospital performance measure that is unadjusted for patient preferences regarding life-sustaining interventions. C1 [Robinson, Maisha T.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Vickrey, Barbara G.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Brook, Robert H.] Univ Calif Los Angeles, David Geffen UCLA Sch Med, Los Angeles, CA 90024 USA. [Leng, Mei; Parikh, Punam; Zingmond, David S.] Univ Calif Los Angeles, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90024 USA. [Vickrey, Barbara G.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Holloway, Robert G.] Univ Rochester, Dept Neurol, New York, NY USA. [Chong, Kelly] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Williams, Linda S.] Vet Affairs HSR&D Ctr Hlth Informat & Commun, Seattle, WA USA. [Williams, Linda S.] Indiana Univ, Dept Neurol, Bloomington, IN 47405 USA. [Williams, Linda S.] Regenstrief Inst Inc, Seattle, WA USA. [Brook, Robert H.] RAND Corp, Santa Monica, CA 90406 USA. [Brook, Robert H.] Jonathan & Karin Fielding Sch Publ Hlth, Los Angeles, CA USA. [Zingmond, David S.] Vet Affairs Greater Los Angeles Healthcare Syst, San Francisco, CA USA. RP Robinson, MT (reprint author), Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. EM robinson.maisha@mayo.edu FU Office of Statewide Health Planning and Development (OSHPD) [08-9079]; Robert Wood Johnson Clinical Scholars Program at the University of California, Los Angeles FX This study was funded by the Office of Statewide Health Planning and Development (OSHPD), contract 08-9079, awarded to the University of California, Los Angeles. OSHPD approved the original stroke outcomes validation study as contracted work. After completion of the original contracted work and creation of the deidentified research database, OSHPD and the state of California institutional review board gave us permission to pursue the research protocol as an investigator-initiated study. Dr. Robinson's effort was also supported by the Robert Wood Johnson Clinical Scholars Program at the University of California, Los Angeles. NR 24 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 31 PY 2016 VL 86 IS 22 BP 2056 EP 2062 DI 10.1212/WNL.0000000000002625 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DN9WM UT WOS:000377431400011 PM 27060165 ER PT J AU Quinn, J AF Quinn, Joseph TI Comment: Gene-environment interactions in dementia: Not just another fish story SO NEUROLOGY LA English DT Article AB Many observational studies have shown relationships between dietary omega-3 fatty acids and cognitive outcomes, but relatively few have examined gene-environment interactions due to APOE genotype. In this study, van de Rest et al.(1) highlight the modifying effect of APOE genotype on cognitive effects of dietary omega-3 fatty acids, finding protective effects of dietary seafood/omega-3s only in the epsilon 4 carrier group, which is at higher risk of Alzheimer disease. Prior observational studies that have incorporated APOE genotype have reported mixed results, sometimes concluding that the omega-3 benefit is stronger in the epsilon 4 carriers and sometimes in the epsilon 4 noncarriers. The finding in the present study is strengthened by a recent report from the same group showing an inverse relationship between dietary omega-3 and autopsy-confirmed Alzheimer disease brain pathology, also only in epsilon 4 carriers.(2) However, observational studies and clinicopathologic studies cannot determine with certainty whether dietary or supplemental omega-3s will attenuate cognitive decline in individuals at risk. Randomized, placebo-controlled trials are necessary to definitively answer this question. While most of these have been negative,(3) few have included APOE stratification in the analyses, so may have failed to appreciate genotype-specific effects of omega-3 supplementation. C1 [Quinn, Joseph] Oregon Hlth & Sci Univ, Dept Neurol, Portland VA Med Ctr, Portland, OR 97201 USA. RP Quinn, J (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Portland VA Med Ctr, Portland, OR 97201 USA. FU National Institute on Aging [R01AG031553, R01AG17917]; Judith Zwartz Foundation FX Supported by grants (R01AG031553 and R01AG17917) from the National Institute on Aging. A Scientific Travel Grant provided by the Judith Zwartz Foundation financed travel expenses of Dr. O. van de Rest to Rush University Medical Center in Chicago. NR 3 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 31 PY 2016 VL 86 IS 22 BP 2069 EP 2070 DI 10.1212/WNL.0000000000002728 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DN9WM UT WOS:000377431400013 PM 27164701 ER PT J AU Sano, M Aisen, PS Andrews, HF Tsai, WY Lai, F Dalton, AJ AF Sano, Mary Aisen, Paul S. Andrews, Howard F. Tsai, Wei-Yann Lai, Florence Dalton, Arthur J. CA Int Down Syndrome Alzheimer's Dis TI Vitamin E in aging persons with Down syndrome: A randomized, placebo-controlled clinical trial SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; INTELLECTUAL DISABILITY; LIPID-PEROXIDATION; RADICAL SCAVENGER; COGNITIVE DECLINE; OXIDATIVE DAMAGE; DEMENTIA; ADULTS; PREVALENCE; SUPPLEMENTATION AB Objective:To determine whether vitamin E would slow the progression of cognitive deterioration and dementia in aging persons with Down syndrome (DS).Methods:A randomized, double-blind controlled clinical trial was conducted at 21 clinical sites, and researchers trained in research procedures recruited adults with DS older than 50 years to participate. Participants were randomly assigned to receive 1,000 IU of vitamin E orally twice daily for 3 years or identical placebo. The primary outcome was change on the Brief Praxis Test (BPT). Secondary outcomes included incident dementia and measures of clinical global change, cognition, function, and behavior.Results:A total of 337 individuals were randomized, 168 to vitamin E and 169 to placebo. Both groups demonstrated deterioration on the BPT with no difference between drug and placebo. At baseline, 26% were diagnosed with dementia and there was an overall rate of incident dementia of 11%/year with no difference between groups. There was no effect on the secondary outcome measures. Though numerically higher in the treatment group, there was no difference in the number of adverse events (p = 0.079) and deaths (p = 0.086) between groups.Conclusions:Vitamin E did not slow the progression of cognitive deterioration in older individuals with DS.Classification of evidence:This study provides Class II evidence that vitamin E does not significantly slow the progression of cognitive deterioration in aging persons with DS. C1 [Sano, Mary] Icahn Sch Med Mt Sinai, Alzheimer Dis Res Ctr, Dept Psychiat, New York, NY 10029 USA. [Sano, Mary] James J Peters VAMC, Bronx, NY USA. [Aisen, Paul S.] Univ So Calif, Alzheimers Therapeut Res Inst, San Diego, CA USA. [Andrews, Howard F.] New York State Psychiat Inst & Hosp, Data Coordinating Ctr, New York, NY 10032 USA. [Andrews, Howard F.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 630 W 168th St, New York, NY 10032 USA. [Tsai, Wei-Yann] Columbia Univ Coll Phys & Surg, Div Biostat, 630 W 168th St, New York, NY 10032 USA. [Lai, Florence] McLean Hosp, Dept Neurol, Belmont, MA 02178 USA. [Lai, Florence] Harvard Univ, Sch Med, Boston, MA USA. [Dalton, Arthur J.] New York State Inst Basic Res Dev Disabil, George Jervis Clin, Ctr Aging Studies, 1050 Forest Hill Rd, Staten Isl, NY 10314 USA. RP Sano, M (reprint author), Icahn Sch Med Mt Sinai, Alzheimer Dis Res Ctr, Dept Psychiat, New York, NY 10029 USA.; Sano, M (reprint author), James J Peters VAMC, Bronx, NY USA. EM mary.sano@mssm.edu FU [R010AG16381] FX Supported by grant R010AG16381, A multicenter trial of vitamin E in aging persons with Down syndrome, PI: Arthur Dalton, PhD. NR 35 TC 2 Z9 2 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 31 PY 2016 VL 86 IS 22 BP 2071 EP 2076 DI 10.1212/WNL.0000000000002714 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DN9WM UT WOS:000377431400014 PM 27164691 ER PT J AU Koelman, DLH Chahin, S Mar, SS Venkatesan, A Hoganson, GM Yeshokumar, AK Barreras, P Majmudar, B Klein, JP Chitnis, T Benkeser, DC Carone, M Mateen, FJ AF Koelman, Diederik L. H. Chahin, Salim Mar, Soe S. Venkatesan, Arun Hoganson, George M. Yeshokumar, Anusha K. Barreras, Paula Majmudar, Bittu Klein, Joshua P. Chitnis, Tanuja Benkeser, David C. Carone, Marco Mateen, Farrah J. TI Acute disseminated encephalomyelitis in 228 patients: A retrospective, multicenter US study SO NEUROLOGY LA English DT Article ID PEDIATRIC MULTIPLE-SCLEROSIS; FOLLOW-UP; PROGNOSTIC-FACTORS; CHILDREN; FEATURES; DEMYELINATION; CRITERIA; RELAPSE; DISORDERS; CHILDHOOD AB Objective:To analyze the range of demographic, clinical, MRI, and CSF features of acute disseminated encephalomyelitis (ADEM), a rare, typically monophasic demyelinating disorder, and analyze long-term outcomes including time and risk factors for subsequent clinical events as well as competing diagnoses.Methods:We performed a retrospective, multicenter study in 4 US academic medical centers of all patients clinically diagnosed with ADEM. Initial presentation of pediatric and adult ADEM and monophasic and multiphasic disease were compared. The Aalen-Johansen estimator was used to produce estimates of the probability of transitioning to a multiphasic diagnosis as a function of time since initial diagnosis, treating death and alternative diagnoses as competing risks.Results:Of 228 patients (122 children, age range 1-72 years, 106 male, median follow-up 24 months [25th-75th percentile 6-67], 7 deaths), approximately one quarter (n = 55, 24%) experienced at least one relapse. Relapsing disease in children was more often diagnosed as multiphasic ADEM than in adults (58% vs 21%, p = 0.007), in whom MS was diagnosed more often. Encephalopathy at initial presentation (hazard ratio [HR] 0.383, p = 0.001), male sex (HR 0.394, p = 0.002), and increasing age at onset (HR 0.984, p = 0.035) were independently associated with a longer time to a demyelinating disease relapse in a multivariable model. In 17 patients, diagnoses other than demyelinating disease were concluded in long-term follow-up.Conclusions:Relapsing disease after ADEM is fairly common and associated with a few potentially predictive features at initial presentation. Age-specific guidelines for ADEM diagnosis and treatment may be valuable, and vigilance for other, mostly rare, diseases is imperative. C1 [Koelman, Diederik L. H.; Chitnis, Tanuja; Mateen, Farrah J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Koelman, Diederik L. H.] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Chahin, Salim] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Mar, Soe S.; Hoganson, George M.; Majmudar, Bittu] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Venkatesan, Arun; Yeshokumar, Anusha K.; Barreras, Paula] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Klein, Joshua P.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Klein, Joshua P.; Mateen, Farrah J.] Harvard Univ, Sch Med, Boston, MA USA. [Benkeser, David C.; Carone, Marco] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Mateen, FJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Mateen, FJ (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM fmateen@partners.org FU American Academy of Neurology FX D.L.H. Koelman Hanks the American Academy of Neurology for the G. Milton Shy Medical Student Essay Award to present this paper at the 2016 annual meeting in Vancouver, Canada. NR 33 TC 5 Z9 6 U1 0 U2 2 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 MAY 31 PY 2016 VL 86 IS 22 BP 2085 EP 2093 DI 10.1212/WNL.0000000000002723 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DN9WM UT WOS:000377431400016 PM 27164698 ER PT J AU Gilman, SE Cherkerzian, S Buka, SL Hahn, J Hornig, M Goldstein, JM AF Gilman, S. E. Cherkerzian, S. Buka, S. L. Hahn, J. Hornig, M. Goldstein, J. M. TI Prenatal immune programming of the sex-dependent risk for major depression SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID PITUITARY-ADRENAL AXIS; MULTIPLE-SCLEROSIS; MATERNAL INFECTION; INFLUENZA EPIDEMIC; BRAIN-DEVELOPMENT; FETAL-BRAIN; STRESS; PREGNANCY; EXPOSURE; ACTIVATION AB Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case-control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age = 39.7 years). We assayed concentrations of three pro-inflammatory cytokines, interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-alpha was associated with reduced odds of depression among both male and female offspring (odds ratio (OR) = 0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-alpha to IL-10 ratio, a measure of the ratio of pro-to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (chi(2) = 13.9, degrees of freedom = 4, P=0.008). Among females, higher maternal TNF-alpha: IL-10 was associated with reduced odds of depression (OR = 0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-alpha: IL-10 was associated with elevated odds of depression (OR = 1.86; CI=1.02, 3.39). Thus, the balance between TNF-alpha and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-alpha in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis. C1 [Gilman, S. E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Executive Blvd,Room 7B13M, Rockville, MD 20852 USA. [Gilman, S. E.; Hahn, J.] Harvard Univ, Dept Social & Behav Sci, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gilman, S. E.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gilman, S. E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cherkerzian, S.; Goldstein, J. M.] Connors Ctr Womens Hlth & Gender Biol, Boston, MA USA. [Cherkerzian, S.; Goldstein, J. M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Cherkerzian, S.; Goldstein, J. M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Buka, S. L.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, Providence, RI 02912 USA. [Hornig, M.] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY USA. [Hornig, M.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Goldstein, J. M.] Massachusetts Gen Hosp, Div Psychiat Neurosci, Boston, MA 02114 USA. RP Gilman, SE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Executive Blvd,Room 7B13M, Rockville, MD 20852 USA.; Gilman, SE (reprint author), Harvard Univ, Dept Social & Behav Sci, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.; Gilman, SE (reprint author), Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.; Gilman, SE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM stephen.gilman@nih.gov OI Gilman, Stephen/0000-0002-8331-6419 FU National Institute of Mental Health [P50MH082679, R01MH07467, R01MH090291, R01MH087544]; Office for Research on Women's Health; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We appreciate the contributions of Stuart Tobet and Robert Handa (Co-Principal Investigators of P50 MH082679) for work on sexual differentiation; Anne Remington, JoAnn Donatelli, Harlyn Aizley and Jennifer Walch for data collection and study coordination; and Kathleen McGaffigan for her expertise in data management and statistical analysis. This work was supported in part by grants P50MH082679, R01MH07467 and R01MH090291 (JMG, Principal Investigator), and R01MH087544 (SEG, Principal Investigator) from the National Institute of Mental Health and Office for Research on Women's Health and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 58 TC 3 Z9 3 U1 6 U2 7 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 MAY 31 PY 2016 VL 6 AR e822 DI 10.1038/tp.2016.91 PG 8 WC Psychiatry SC Psychiatry GA DN8CK UT WOS:000377306600001 PM 27244231 ER PT J AU Schmidt, K Joyce, CE Buquicchio, F Brown, A Ritz, J Distel, RJ Yoon, CH Novina, CD AF Schmidt, Karyn Joyce, Cailin E. Buquicchio, Frank Brown, Adam Ritz, Justin Distel, Robert J. Yoon, Charles H. Novina, Carl D. TI The lncRNA SLNCR1 Mediates Melanoma Invasion through a Conserved SRA1-like Region SO CELL REPORTS LA English DT Article ID LONG NONCODING RNAS; RESISTANT PROSTATE-CANCER; FUNCTIONAL DNA ELEMENTS; ANDROGEN-RECEPTOR; HETERODIMER FORMATION; CELL-MIGRATION; GELATINASE B; EXPRESSION; METASTASIS; PATTERNS AB Long non-coding RNAs (lncRNAs) have been implicated in numerous physiological processes and diseases, most notably cancers. However, little is known about the mechanism of many functional lncRNAs. We identified an abundantly expressed lncRNA associated with decreased melanoma patient survival. Increased expression of this lncRNA, SLNCR1, mediates melanoma invasion through a highly conserved sequence similar to that of the lncRNA SRA1. Using a sensitive technique we term RATA (RNA-associated transcription factor array), we show that the brain-specific homeobox protein 3a (Brn3a) and the androgen receptor (AR) bind within and adjacent to SLNCR1's conserved region, respectively. SLNCR1, AR, and Brn3a are specifically required for transcriptional activation of matrix metalloproteinase 9 (MMP9) and increased melanoma invasion. Our observations directly link AR to melanoma invasion, possibly explaining why males experience more melanoma metastases and have an overall lower survival in comparison to females. C1 [Schmidt, Karyn; Joyce, Cailin E.; Buquicchio, Frank; Novina, Carl D.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Schmidt, Karyn; Joyce, Cailin E.; Buquicchio, Frank; Novina, Carl D.] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Schmidt, Karyn; Joyce, Cailin E.; Buquicchio, Frank; Novina, Carl D.] Broad Inst Harvard & MIT, Cambridge, MA 02141 USA. [Brown, Adam] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Ritz, Justin] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Distel, Robert J.] Dana Farber Canc Inst, Belfer Off Dana Farber Innovat, Boston, MA 02115 USA. [Yoon, Charles H.] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Buquicchio, Frank] Northeastern Univ, Boston, MA 02115 USA. RP Novina, CD (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Novina, CD (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA.; Novina, CD (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02141 USA.; Yoon, CH (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM chyoon@bics.bwh.harvard.edu; carl_novina@dfci.harvard.edu OI Brown, Adam/0000-0002-4393-1003 FU NIH [R01 CA140986, R01 CA185151]; Claudia Adams Barr Award; [T32 AI007386] FX We gratefully acknowledge T. Benjamin, M. Hemler, M. Brown, and the members of our laboratory, especially J. Carroll, for technical advice and critical discussions; D. Fisher for melanocytes; M. Herlyn for melanomas; and R. Rubio, Y. Wang, A. Holman, and the entire team of the Dana-Farber Center for Computational Cancer Biology for RNA-seq. This work was supported by funding from NIH grants R01 CA140986 and R01 CA185151 and a Claudia Adams Barr Award (to C.D.N.), and K.S. was supported by funding from T32 AI007386. NR 56 TC 5 Z9 5 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 MAY 31 PY 2016 VL 15 IS 9 BP 2025 EP 2037 DI 10.1016/j.celrep.2016.04.018 PG 13 WC Cell Biology SC Cell Biology GA DN2IO UT WOS:000376887500016 PM 27210747 ER PT J AU Gewirtz, H Dilsizian, V AF Gewirtz, Henry Dilsizian, Vasken TI Integration of Quantitative Positron Emission Tomography Absolute Myocardial Blood Flow Measurements in the Clinical Management of Coronary Artery Disease SO CIRCULATION LA English DT Review DE coronary circulation; coronary disease; fractional flow reserve, myocardial; microvessels; myocardial perfusion imaging; myocardium; regional blood flow ID INTRAVENOUS N-13 AMMONIA; ISCHEMIC-HEART-DISEASE; CARDIAC SYNDROME-X; PHYSIOLOGICAL ASSESSMENT; PERFUSION ABNORMALITIES; NONINVASIVE ASSESSMENT; COMPUTED-TOMOGRAPHY; VELOCITY RESERVE; PROGNOSTIC VALUE; MICROVASCULAR DYSFUNCTION AB In the >40 years since planar myocardial imaging with K-43-potassium was introduced into clinical research and management of patients with coronary artery disease (CAD), diagnosis and treatment have undergone profound scientific and technological changes. One such innovation is the current state-of-the-art hardware and software for positron emission tomography myocardial perfusion imaging, which has advanced it from a strictly research-oriented modality to a clinically valuable tool. This review traces the evolving role of quantitative positron emission tomography measurements of myocardial blood flow in the evaluation and management of patients with CAD. It presents methodology, currently or soon to be available, that offers a paradigm shift in CAD management. Heretofore, radionuclide myocardial perfusion imaging has been primarily qualitative or at best semiquantitative in nature, assessing regional perfusion in relative terms. Thus, unlike so many facets of modern cardiovascular practice and CAD management, which depend, for example, on absolute values of key parameters such as arterial and left ventricular pressures, serum lipoprotein, and other biomarker levels, the absolute levels of rest and maximal myocardial blood flow have yet to be incorporated into routine clinical practice even in most positron emission tomography centers where the potential to do so exists. Accordingly, this review focuses on potential value added for improving clinical CAD practice by measuring the absolute level of rest and maximal myocardial blood flow. Physiological principles and imaging fundamentals necessary to understand how positron emission tomography makes robust, quantitative measurements of myocardial blood flow possible are highlighted. C1 [Gewirtz, Henry] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. [Dilsizian, Vasken] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. RP Dilsizian, V (reprint author), Univ Maryland, Med Ctr, Dept Diagnost Radiol & Nucl Med, 22 S Greene St,Room N2W78, Baltimore, MD 21201 USA. EM vdilsizian@umm.edu NR 107 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 31 PY 2016 VL 133 IS 22 BP 2180 EP 2196 DI 10.1161/CIRCULATIONAHA.115.018089 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN9ZD UT WOS:000377438300015 PM 27245647 ER PT J AU Chee, TT Ryan, AM Wasfy, JH Borden, WB AF Chee, Tingyin T. Ryan, Andrew M. Wasfy, Jason H. Borden, William B. TI Current State of Value-Based Purchasing Programs SO CIRCULATION LA English DT Article DE costs and cost analysis; outcome assessment (health care); reimbursement mechanisms; value-based purchasing ID PAY-FOR-PERFORMANCE; SAFETY-NET HOSPITALS; ACCOUNTABLE CARE ORGANIZATIONS; QUALITY IMPROVEMENT; HEALTH-CARE; MORTALITY; IMPLEMENTATION; DISPARITIES; ENGLAND AB The US healthcare system is rapidly moving toward rewarding value. Recent legislation, such as the Affordable Care Act and the Medicare Access and CHIP Reauthorization Act, solidified the role of value-based payment in Medicare. Many private insurers are following Medicare's lead. Much of the policy attention has been on programs such as accountable care organizations and bundled payments; yet, value-based purchasing (VBP) or pay-for-performance, defined as providers being paid fee-for-service with payment adjustments up or down based on value metrics, remains a core element of value payment in Medicare Access and CHIP Reauthorization Act and will likely remain so for the foreseeable future. This review article summarizes the current state of VBP programs and provides analysis of the strengths, weaknesses, and opportunities for the future. Multiple inpatient and outpatient VBP programs have been implemented and evaluated; the impact of those programs has been marginal. Opportunities to enhance the performance of VBP programs include improving the quality measurement science, strengthening both the size and design of incentives, reducing health disparities, establishing broad outcome measurement, choosing appropriate comparison targets, and determining the optimal role of VBP relative to alternative payment models. VBP programs will play a significant role in healthcare delivery for years to come, and they serve as an opportunity for providers to build the infrastructure needed for value-oriented care. C1 [Chee, Tingyin T.; Borden, William B.] George Washington Univ, Sch Med & Hlth Sci, Dept Med, Washington, DC 20037 USA. [Ryan, Andrew M.] Univ Michigan, Dept Hlth Policy, Ann Arbor, MI 48109 USA. [Wasfy, Jason H.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Wasfy, Jason H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Borden, WB (reprint author), George Washington Univ, 2150 Pennsylvania Ave NW, Washington, DC 20037 USA. EM wborden@mfa.gwu.edu FU Healthcare Delivery Transformation at the George Washington University Medical Faculty Associates; Massachusetts General Physicians Organization FX Dr Borden receives salary as the Director of Healthcare Delivery Transformation at the George Washington University Medical Faculty Associates. Dr Wasfy receives salary as assistant medical director of the Massachusetts General Physicians Organization. The other authors report no conflicts. NR 54 TC 2 Z9 2 U1 8 U2 19 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 MAY 31 PY 2016 VL 133 IS 22 BP 2197 EP 2205 DI 10.1161/CIRCULATIONAHA.115.010268 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN9ZD UT WOS:000377438300016 PM 27245648 ER PT J AU Singhal, V Maffazioli, GD Ackerman, KE Lee, H Elia, EF Woolley, R Kolodny, G Cypess, AM Misra, M AF Singhal, Vibha Maffazioli, Giovana D. Ackerman, Kate E. Lee, Hang Elia, Elisa F. Woolley, Ryan Kolodny, Gerald Cypess, Aaron M. Misra, Madhusmita TI Effect of Chronic Athletic Activity on Brown Fat in Young Women SO PLOS ONE LA English DT Article ID ADIPOSE-TISSUE ACTIVITY; BODY-MASS INDEX; SECRETORY DYNAMICS; ENERGY-EXPENDITURE; ANOREXIA-NERVOSA; COLD; HUMANS; LEPTIN; WHITE; THERMOGENESIS AB Background The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. Purpose We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. Methods The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross-sectional study of 24 women (16 athletes and8 non-athletes) between 18-25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8). We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. Results Athletes and non-athletes did not differ for age or BMI. Compared with non-athletes, athletes had lower percent body fat (p = 0.002), higher percent leanmass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = -0.46, p = 0.02). BAT volume correlated inversely with leanmass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. Conclusions Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit. C1 [Singhal, Vibha; Misra, Madhusmita] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Singhal, Vibha; Maffazioli, Giovana D.; Ackerman, Kate E.; Lee, Hang; Elia, Elisa F.; Woolley, Ryan; Kolodny, Gerald; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. [Singhal, Vibha; Maffazioli, Giovana D.; Ackerman, Kate E.; Woolley, Ryan; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Ackerman, Kate E.] Boston Childrens Hosp, Div Sports Med, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Elia, Elisa F.; Kolodny, Gerald] Beth Israel Deaconess Med Ctr, Dept Radiol, Div Nucl Med & Mol Imaging, 330 Brookline Ave, Boston, MA 02215 USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Singhal, V (reprint author), Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA.; Singhal, V (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Singhal, V (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM vsinghal1@partners.org FU National Institutes of Health [1 UL1 RR025758-01, 1UL1TR001102-01, 1 R01 HD 060827-01A1, K24 HD071843]; Fundacion Alfonso Martin Escudero FX This work was supported by National Institutes of Health Grants 1 UL1 RR025758-01, 1UL1TR001102-01, 1 R01 HD 060827-01A1, and K24 HD071843. E. Franquet was supported by Fundacion Alfonso Martin Escudero. NR 29 TC 3 Z9 3 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2016 VL 11 IS 5 AR e0156353 DI 10.1371/journal.pone.0156353 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN5XX UT WOS:000377146100031 PM 27243823 ER PT J AU Nakagawa, H Sido, JM Reyes, EE Kiers, V Cantor, H Kim, HJ AF Nakagawa, Hidetoshi Sido, Jessica M. Reyes, Edwin E. Kiers, Valerie Cantor, Harvey Kim, Hye-Jung TI Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inflammation; tumor microenvironment; effector cytokines; Treg stability ID CANCER-IMMUNOTHERAPY; CELLS; RESPONSES; MELANOMA; EFFICACY; TARGETS AB Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy. C1 [Nakagawa, Hidetoshi; Sido, Jessica M.; Reyes, Edwin E.; Kiers, Valerie; Cantor, Harvey; Kim, Hye-Jung] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Nakagawa, Hidetoshi; Sido, Jessica M.; Reyes, Edwin E.; Cantor, Harvey; Kim, Hye-Jung] Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Cantor, H; Kim, HJ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA.; Cantor, H; Kim, HJ (reprint author), Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu; Hye-Jung_Kim@dfci.harvard.edu FU NIH [R01AI37562]; LeRoy Schecter Research Foundation FX We thank A. Thornton and E. Shevach for provision of Heliosfl/fl mice and A. Angel for manuscript and figure preparation. These studies were supported in part by NIH Grant R01AI37562 and the LeRoy Schecter Research Foundation (H.C.). NR 25 TC 5 Z9 5 U1 2 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 MAY 31 PY 2016 VL 113 IS 22 BP 6248 EP 6253 DI 10.1073/pnas.1604765113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0VL UT WOS:000376784600051 PM 27185917 ER PT J AU Komura, K Jeong, SH Hinohara, K Qu, FF Wang, XD Hiraki, M Azuma, H Lee, GSM Kantoff, PW Sweeney, CJ AF Komura, Kazumasa Jeong, Seong Ho Hinohara, Kunihiko Qu, Fangfang Wang, Xiaodong Hiraki, Masayuki Azuma, Haruhito Lee, Gwo-Shu Mary Kantoff, Philip W. Sweeney, Christopher J. TI Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE prostate cancer; docetaxel; KDM5D; JARID1D; androgen receptor ID CHEMOHORMONAL THERAPY; PROGRESSION; TRANSCRIPTION; MITOXANTRONE; PREDNISONE; GENOMICS; GENES AB The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity. C1 [Komura, Kazumasa; Azuma, Haruhito] Osaka Med Coll, Dept Urol, Osaka 5698686, Japan. [Komura, Kazumasa; Jeong, Seong Ho; Hinohara, Kunihiko; Qu, Fangfang; Wang, Xiaodong; Hiraki, Masayuki; Lee, Gwo-Shu Mary; Kantoff, Philip W.; Sweeney, Christopher J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Komura, Kazumasa; Kantoff, Philip W.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Sweeney, Christopher J.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Kantoff, PW; Sweeney, CJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Kantoff, PW (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA.; Sweeney, CJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. EM kantoff@mskcc.org; christopher_sweeney@dfci.harvard.edu OI Komura, Kazumasa/0000-0001-5082-3054 FU Louis B. Mayer Foundation FX This work was supported by the Louis B. Mayer Foundation. NR 31 TC 3 Z9 3 U1 3 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 MAY 31 PY 2016 VL 113 IS 22 BP 6259 EP 6264 DI 10.1073/pnas.1600420113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0VL UT WOS:000376784600053 PM 27185910 ER PT J AU McCarty, WJ Usta, OB Yarmush, ML AF McCarty, William J. Usta, O. Berk Yarmush, Martin L. TI A Microfabricated Platform for Generating Physiologically-Relevant Hepatocyte Zonation SO SCIENTIFIC REPORTS LA English DT Article ID PERIVENOUS RAT HEPATOCYTES; DRUG-METABOLIZING-ENZYMES; LIVER ACINUS; SANDWICH CONFIGURATION; INSITU HYBRIDIZATION; GLUTAMINE-SYNTHETASE; OXIDATIVE STRESS; ALLYL ALCOHOL; IN-VITRO; GLUTATHIONE AB In vitro liver models have been important tools for more than 40 years for academic research and preclinical toxicity screening by the pharmaceutical industry. Hepatocytes, the highly metabolic parenchymal cells of the liver, are efficient at different metabolic chemistries depending on their relative spatial location along the sinusoid from the portal triad to the central vein. Although replicating hepatocyte metabolic zonation is vitally important for physiologically-relevant in vitro liver tissue and organ models, it is most often completely overlooked. Here, we demonstrate the creation of spatially-controlled zonation across multiple hepatocyte metabolism levels through the application of precise concentration gradients of exogenous hormone (insulin and glucagon) and chemical (3-methylcholanthrene) induction agents in a microfluidic device. Observed gradients in glycogen storage via periodic acid-Schiff staining, urea production via carbamoyl phosphatase synthetase I staining, and cell viability after exposure to allyl alcohol and acetaminophen demonstrated the in vitro creation of hepatocyte carbohydrate, nitrogen, alcohol degradation, and drug conjugation metabolic zonation. This type of advanced control system will be crucial for studies evaluating drug metabolism and toxicology using in vitro constructs. C1 [McCarty, William J.; Usta, O. Berk; Yarmush, Martin L.] Harvard Univ, Sch Med, Dept Surg, Ctr Engn Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. Shriners Hosp Children, Boston, MA USA. RP Yarmush, ML (reprint author), Harvard Univ, Sch Med, Dept Surg, Ctr Engn Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM ireis@sbi.org FU Microphysiological Systems Consortium grant from the National Center for Advancing Translational Sciences [UH2TR000503]; Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship from the National Institute of Diabetes and Digestive and Kidney Diseases [F32DK098905]; National Institute of Biomedical Imaging and Bioengineering [1R21EB020192-01]; Massachusetts General Hospital Executive Committee on Research [226569]; NIH [P41EB002503] FX This work was supported by a Microphysiological Systems Consortium grant from the National Center for Advancing Translational Sciences (UH2TR000503), a Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship from the National Institute of Diabetes and Digestive and Kidney Diseases (F32DK098905 for WJM), an exploratory grant from the National Institute of Biomedical Imaging and Bioengineering (1R21EB020192-01), and interim funding (#226569) from the Massachusetts General Hospital Executive Committee on Research. Microfluidic devices were fabricated at the BioMEMS Resource Center at the MGH, supported by NIH grant P41EB002503. NR 42 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 31 PY 2016 VL 6 AR 26868 DI 10.1038/srep26868 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2FB UT WOS:000376878400001 PM 27240736 ER PT J AU Rodius, S Androsova, G Gotz, L Liechti, R Crespo, I Merz, S Nazarov, PV de Klein, N Jeanty, C Gonzalez-Rosa, JM Muller, A Bernardin, F Niclou, SP Vallar, L Mercader, N Ibberson, M Xenarios, I Azuaje, F AF Rodius, Sophie Androsova, Ganna Gotz, Lou Liechti, Robin Crespo, Isaac Merz, Susanne Nazarov, Petr V. de Klein, Niek Jeanty, Celine Gonzalez-Rosa, Juan M. Muller, Arnaud Bernardin, Francois Niclou, Simone P. Vallar, Laurent Mercader, Nadia Ibberson, Mark Xenarios, Ioannis Azuaje, Francisco TI Analysis of the dynamic co-expression network of heart regeneration in the zebrafish SO SCIENTIFIC REPORTS LA English DT Article ID MYOCARDIAL-INFARCTION; GENE-EXPRESSION; CARDIAC REGENERATION; EPICARDIAL CELLS; INJURY; CARDIOMYOCYTES; MODEL; CRYOINJURY; TARGET; DIFFERENTIATION AB The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post-injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration. C1 [Rodius, Sophie; Androsova, Ganna; Merz, Susanne; de Klein, Niek; Jeanty, Celine; Niclou, Simone P.; Azuaje, Francisco] Luxembourg Inst Hlth, Dept Oncol, NorLux Neurooncol Lab, L-1526 Luxembourg, Luxembourg. [Gotz, Lou; Liechti, Robin; Crespo, Isaac; Ibberson, Mark; Xenarios, Ioannis] SIB Swiss Inst Bioinformat, Vital IT Syst Biol Div, CH-1015 Lausanne, Switzerland. [Nazarov, Petr V.; Muller, Arnaud; Bernardin, Francois; Vallar, Laurent] LIH, Dept Oncol, Genom Res Unit, L-1526 Luxembourg, Luxembourg. [de Klein, Niek] Vrije Univ Amsterdam, NL-1081 HV Amsterdam, Netherlands. [Gonzalez-Rosa, Juan M.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Gonzalez-Rosa, Juan M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mercader, Nadia] ISCIII, Ctr Nacl Invest Cardiovasc Carlos 3, CNIC, Epicardium Dev & Regenerat Grp, Madrid 28029, Spain. [Xenarios, Ioannis] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [Xenarios, Ioannis] Univ Geneva, Dept Biochem, CH-1211 Geneva 4, Switzerland. [Androsova, Ganna] Univ Luxembourg, LCSB, L-4367 Belvaux, Luxembourg. [de Klein, Niek] Univ Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Mercader, Nadia] Univ Bern, Dept Dev Regenerat, Fac Med, Inst Anat, Bern, Switzerland. RP Azuaje, F (reprint author), Luxembourg Inst Hlth, Dept Oncol, NorLux Neurooncol Lab, L-1526 Luxembourg, Luxembourg.; Xenarios, I (reprint author), SIB Swiss Inst Bioinformat, Vital IT Syst Biol Div, CH-1015 Lausanne, Switzerland.; Xenarios, I (reprint author), Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland.; Xenarios, I (reprint author), Univ Geneva, Dept Biochem, CH-1211 Geneva 4, Switzerland. EM ioannis.xenarios@isb-sib.ch; francisco.azuaje@lih.lu FU Luxembourg's National Research Fund (FNR); Swiss National Research Foundation (SNF), INFUSED project; Comunidad de Madrid [P2010/BMD-2321]; ERC [2013 337703] FX We thank C. Hoffmann and J. Esposito for technical support, A. Feenstra (VUA) for co-supervision of N.K., and R. Schneider (LCSB) for co-supervision of G.A. during her work at LIH and current support at LCSB. This research was funded by Luxembourg's National Research Fund (FNR) and the Swiss National Research Foundation (SNF), INFUSED project (www.infused-project.eu). N.M. was supported by Comunidad de Madrid (Fibroteam P2010/BMD-2321) and the ERC (Starting Grant 2013 337703 zebraHeart). Zebrafish drawing in Figure 1 was adapted from Wikimedia Commons (http://bit.ly/1PL92vj). NR 63 TC 0 Z9 0 U1 9 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 31 PY 2016 VL 6 AR 26822 DI 10.1038/srep26822 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2EO UT WOS:000376877100001 PM 27241320 ER PT J AU Moore, FE Garcia, EG Lobbardi, R Jain, E Tang, Q Moore, JC Cortes, M Molodtsov, A Kasheta, M Luo, CC Garcia, AJ Mylvaganam, R Yoder, JA Blackburn, JS Sadreyev, RI Ceol, CJ North, TE Langenau, DM AF Moore, Finola E. Garcia, Elaine G. Lobbardi, Riadh Jain, Esha Tang, Qin Moore, John C. Cortes, Mauricio Molodtsov, Aleksey Kasheta, Melissa Luo, Christina C. Garcia, Amaris J. Mylvaganam, Ravi Yoder, Jeffrey A. Blackburn, Jessica S. Sadreyev, Ruslan I. Ceol, Craig J. North, Trista E. Langenau, David M. TI Single-cell transcriptional analysis of normal, aberrant, and malignant hematopoiesis in zebrafish SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION ANALYSIS; REGULATED TRANSGENIC ZEBRAFISH; T-ALL; STEM-CELLS; C-MYB; MUTANT ZEBRAFISH; MASS CYTOMETRY; BLOOD STEM; ACTIVATION AB Hematopoiesis culminates in the production of functionally heterogeneous blood cell types. In zebrafish, the lack of cell surface antibodies has compelled researchers to use fluorescent transgenic reporter lines to label specific blood cell fractions. However, these approaches are limited by the availability of transgenic lines and fluorescent protein combinations that can be distinguished. Here, we have transcriptionally profiled single hematopoietic cells from zebrafish to define erythroid, myeloid, B, and T cell lineages. We also used our approach to identify hematopoietic stem and progenitor cells and a novel NK-lysin 4(+) cell type, representing a putative cytotoxic T/NK cell. Our platform also quantified hematopoietic defects in rag2(E450fs) mutant fish and showed that these fish have reduced T cells with a subsequent expansion of NK-lysin 4(+) cells and myeloid cells. These data suggest compensatory regulation of the innate immune system in rag2(E450fs) mutant zebrafish. Finally, analysis of Myc-induced T cell acute lymphoblastic leukemia showed that cells are arrested at the CD4(+)/CD8(+) cortical thymocyte stage and that a subset of leukemia cells inappropriately reexpress stem cell genes, including bmi1 and cmyb. In total, our experiments provide new tools and biological insights into single-cell heterogeneity found in zebrafish blood and leukemia. C1 [Moore, Finola E.; Garcia, Elaine G.; Lobbardi, Riadh; Tang, Qin; Moore, John C.; Molodtsov, Aleksey; Luo, Christina C.; Garcia, Amaris J.; Mylvaganam, Ravi; Langenau, David M.] Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA. [Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Jain, Esha; Langenau, David M.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Cortes, Mauricio; North, Trista E.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Cortes, Mauricio; North, Trista E.] Harvard Med Sch, Boston, MA 02115 USA. [Kasheta, Melissa; Ceol, Craig J.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Kasheta, Melissa; Ceol, Craig J.] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. [Yoder, Jeffrey A.] North Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27607 USA. [Blackburn, Jessica S.] Univ Kentucky, Coll Med, Dept Pathol, Lexington, KY 40536 USA. [Blackburn, Jessica S.] Univ Kentucky, Coll Med, Dept Biochem, Lexington, KY 40536 USA. [Blackburn, Jessica S.] Univ Kentucky, Coll Med, Dept Mol Biol, Lexington, KY 40536 USA. [Blackburn, Jessica S.] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Boston, MA 02114 USA. [Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02139 USA. RP Moore, FE; Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Langenau, DM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02139 USA. EM femoore@mgh.harvard.edu; dlangenau@mgh.harvard.edu FU Alex's Lemonade Stand Foundation; Live Like Bella Foundation for Childhood Cancer; American Cancer Society; Massachusetts General Hospital (MGH) Howard Goodman Fellowship; National Institutes of Health (NIH) [R24OD016761]; NIH [5F32DK098875-03]; MGH Pathology CNY Flow Cytometry Core shared instrumentation grant [1S10RR023440-01A] FX This work was supported by Alex's Lemonade Stand Foundation (D.M. Langenau), The Live Like Bella Foundation for Childhood Cancer (D.M. Langenau), American Cancer Society (D.M. Langenau), the Massachusetts General Hospital (MGH) Howard Goodman Fellowship (D.M. Langenau), and National Institutes of Health (NIH) grant R24OD016761. F.E. Moore is supported by NIH grant 5F32DK098875-03. Flow cytometry and sorting services were supported by MGH Pathology CNY Flow Cytometry Core shared instrumentation grant 1S10RR023440-01A. NR 79 TC 2 Z9 2 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAY 30 PY 2016 VL 213 IS 6 BP 979 EP 992 DI 10.1084/jem.20152013 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5TZ UT WOS:000380846700009 PM 27139488 ER PT J AU Kasckow, J Zickmund, S Gurklis, J Luther, J Fox, L Taylor, M Richmond, I Haas, GL AF Kasckow, John Zickmund, Susan Gurklis, John Luther, James Fox, Lauren Taylor, Melissa Richmond, Ira Haas, Gretchen L. TI Using telehealth to augment an intensive case monitoring program in veterans with schizophrenia and suicidal ideation: A pilot trial SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Telehealth; Suicide ID NEGATIVE SYMPTOMS; RATING-SCALE; DEPRESSION; RISK; RELIABILITY; VALIDITY AB Veterans with schizophrenia admitted for suicidal ideation were recruited into a post-discharge program consisting of Intensive Case Monitoring (ICM) with daily monitoring with the Health Buddy (HB; experimental group) or ICM alone (control group). This study tested the feasibility of the telehealth monitoring intervention in this population. Secondly, we determined whether augmentation of ICM with our intervention for 3 months would result in a reduction in suicidal ideation. Twenty of 25 telehealth participants could set up the device. Monthly adherence for telehealth participants was > 80%. A qualitative analysis of endpoint surveys revealed that the majority of participants had positive responses. In both groups, there were improvements in Beck Scale for Suicidal Ideation (BSS) scores at endpoint relative to baseline. No group differences were present with survival analysis when using remission (i.e., BSS score = 0) as the outcome; however, in a subgroup with a history of suicide attempt, there was a trend (p = .093) for a higher rate of remission for those in the FIB condition. In conclusion, telehealth monitoring for this population appears to be feasible for those who are able to start using the system. The pilot data obtained should help investigators design better telehealth interventions for this population. Published by Elsevier Ireland Ltd. C1 [Kasckow, John; Gurklis, John; Luther, James; Fox, Lauren; Haas, Gretchen L.] VA Pittsburgh Hlth Care Syst, MIRECC & Behav Hlth, Pittsburgh, PA 15240 USA. [Kasckow, John; Haas, Gretchen L.] Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Kasckow, John; Zickmund, Susan] VA Pittsburgh Ctr Hlth & Equity Promot, Pittsburgh, PA 15240 USA. [Zickmund, Susan] Univ Pittsburgh, Dept Med, Med Ctr, 930 Scaife Hall, Pittsburgh, PA 15213 USA. [Taylor, Melissa; Richmond, Ira] VA Pittsburgh Hlth Care Syst, VA Pittsburgh Patient Care Serv, Pittsburgh, PA 15240 USA. RP Kasckow, J (reprint author), VA Pittsburgh Hlth Care Syst, Univ Dr C,Behav Hlth 116a, Pittsburgh, PA 15240 USA. EM kasckowjw@upmc.edu FU VISN 4 MIRECC; VISN 4 CPPF award FX Funded by the VISN 4 MIRECC and a VISN 4 CPPF award. The contents do not represent the views of the US Government or the Department of Veterans Affairs of the US Government. Dr. Kasckow has received assistance from Bosch Health Care for the software and transmission costs associated with this project. NR 21 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAY 30 PY 2016 VL 239 BP 111 EP 116 DI 10.1016/j.psychres.2016.02.049 PG 6 WC Psychiatry SC Psychiatry GA DM7LS UT WOS:000376542700017 PM 27137970 ER PT J AU Price, M Szafranski, DD van Stolk-Cooke, K Gros, DE AF Price, Matthew Szafranski, Derek D. van Stolk-Cooke, Katherine Gros, Daniel E. TI Investigation of abbreviated 4 and 8 item versions of the PTSD Checklist 5 SO PSYCHIATRY RESEARCH LA English DT Article DE PTSD; Screening instruments; Assessment ID POSTTRAUMATIC-STRESS-DISORDER; ECOLOGICAL MOMENTARY ASSESSMENT; DSM-IV; PRIMARY-CARE; CRITERIA; VETERANS; EXPOSURE; ANXIETY; PREVALENCE; DEPRESSION AB Posttraumatic stress disorder (PTSD) is a significant public health concern associated with marked impairment across the lifespan. Exposure to traumatic events alone, however, is insufficient to determine if an individual has PTSD. PTSD is a heterogeneous diagnosis such that assessment of all 20 symptoms is problematic in time-limited treatment settings. Brief assessment tools that identify those at risk for PTSD and measure symptom severity are needed to improve access to care and assess treatment response. The present study evaluated abbreviated measures of PTSD symptoms derived from the PTSD Checklist for DSM-5 (PCL-5) - a 20-item validated measure of PTSD symptoms - across two studies. In the first, using a community sample of adults exposed to a traumatic event, 4- and 8-item versions of the PCL-5 were identified that were highly correlated with the full PCL-5. In the second, using a sample of combat veterans, the 4-and 8-item measures had comparable diagnostic utility to the total-scale PCL-5. These results provide support for an abbreviated measure of the PCL-5 as an alternative to the 20-item total scale. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Price, Matthew; van Stolk-Cooke, Katherine] Univ Vermont, Dept Psychol Sci, 2 Colchester Ave, Burlington, VT 05405 USA. [Szafranski, Derek D.; Gros, Daniel E.] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv, Charleston, SC USA. [Szafranski, Derek D.; Gros, Daniel E.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. RP Price, M (reprint author), Univ Vermont, Dept Psychol Sci, 2 Colchester Ave, Burlington, VT 05405 USA. EM Matthew.Price@uvm.edu FU [CX000845] FX The project was supported by Career Development Award CX000845 awarded to DF Gros. The authors would like to thank Ryan Payne for his help in the preparation of this manuscript. NR 33 TC 2 Z9 2 U1 4 U2 10 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 MAY 30 PY 2016 VL 239 BP 124 EP 130 DI 10.1016/j.psychres.2016.03.014 PG 7 WC Psychiatry SC Psychiatry GA DM7LS UT WOS:000376542700020 PM 27137973 ER PT J AU Keuthen, NJ Tung, ES Tung, MG Curley, EE Flessner, CA AF Keuthen, Nancy J. Tung, Esther S. Tung, Matthew G. Curley, Erin E. Flessner, Christopher A. TI NEO-FFI personality clusters in trichotillomania SO PSYCHIATRY RESEARCH LA English DT Article DE Hair Pulling; Personality; Quality of life; Big five ID 5-FACTOR MODEL; DEPRESSION; UTILITY; PROTOTYPES; SCALE AB The purpose of this study was to determine whether personality prototypes exist among hair pullers and if these groups differ in hair pulling (HP) characteristics, clinical correlates, and quality of life. 164 adult hair pullers completed the NEO-Five Factor Inventory (NEO-FFI; Costa and McCrae, 1992) and self-report measures of HP severity, HP style, affective state, and quality of life. A latent class cluster analysis using NEO-FFI scores was performed to separate participants into clusters. Bonferroni-corrected t-tests were used to compare clusters on HP, affective, and quality of life variables. Multiple regression was used to determine which variables significantly predicted quality of life. Two distinct personality prototypes were identified. Cluster 1 (n=96) had higher neuroticism and lower extraversion, agreeableness, and conscientiousness when compared to cluster 2 (n=68). No significant differences in demographics were reported for the two personality clusters. The clusters differed on extent of focused HP, severity of depression, anxiety, and stress, as well as quality of life. Those in cluster 1 endorsed greater depression, anxiety, and stress, and worse quality of life. Additionally, only depression and cluster membership (based on NEO scores) significantly predicted quality of life. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Keuthen, Nancy J.; Curley, Erin E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Tung, Esther S.] Boston Univ, Dept Psychol, 64 Cummington St, Boston, MA 02215 USA. [Tung, Matthew G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Flessner, Christopher A.] Kent State Univ, Dept Psychol, Kent, OH 44240 USA. RP Keuthen, NJ (reprint author), Trichotillomania Clin, Massachusetts Gen Res Bldg,F1-2,185 Cambridge St, Boston, MA 02114 USA. EM nkeuthen@partners.org RI Flessner, Christopher/K-1483-2015 FU Trichotillomania Learning Center, Inc. (TLC) and its BFRB Precision Medicine Initiative; Greater Kansas City Foundation FX We gratefully recognize financial support for this project from the Trichotillomania Learning Center, Inc. (TLC) and its BFRB Precision Medicine Initiative, as well as the Greater Kansas City Foundation. We also wish to express gratitude to Saraj Mothi for his statistical consultation and Amanda Falcon, Miriam Frank, and Zachary Madison who performed data input and cleaning. NR 25 TC 0 Z9 0 U1 4 U2 11 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 MAY 30 PY 2016 VL 239 BP 196 EP 203 DI 10.1016/j.psychres.2016.03.011 PG 8 WC Psychiatry SC Psychiatry GA DM7LS UT WOS:000376542700032 PM 27016621 ER PT J AU Axelrad, JE Lichtiger, S Yajnik, V AF Axelrad, Jordan E. Lichtiger, Simon Yajnik, Vijay TI Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Inflammatory bowel disease; Cancer; Antitumor necrosis factor; Immunosuppression; Chemotherapy; Radiation ID TUMOR-NECROSIS-FACTOR; PRIMARY SCLEROSING CHOLANGITIS; NONMELANOMA SKIN-CANCER; POPULATION-BASED COHORT; ULCERATIVE-COLITIS; INCREASED RISK; COLORECTAL-CANCER; RHEUMATOID-ARTHRITIS; BIOLOGICS REGISTER; ADVERSE EVENTS AB In patients with inflammatory bowel disease (IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes. C1 [Axelrad, Jordan E.; Lichtiger, Simon] Columbia Univ, Med Ctr, Dept Med, Div Digest & Liver Dis, New York, NY 10032 USA. [Yajnik, Vijay] Massachusetts Gen Hosp, Div Gastroenterol, Dept Med, Boston, MA 02445 USA. RP Yajnik, V (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Dept Med, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02445 USA. EM vyajnik@mgh.harvard.edu OI Axelrad, Jordan/0000-0003-1951-7790 NR 62 TC 10 Z9 10 U1 0 U2 3 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAY 28 PY 2016 VL 22 IS 20 BP 4794 EP 4801 DI 10.3748/wjg.v22.i20.4794 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DN4ZK UT WOS:000377075500002 PM 27239106 ER PT J AU Chen, XL Chen, YH Fan, BJ Xia, MY Wang, L Sun, XH AF Chen, Xueli Chen, Yuhong Fan, Bao Jian Xia, Mingying Wang, Li Sun, Xinghuai TI Screening of the LTBP2 gene in 214 Chinese sporadic CYP1B1-negative patients with primary congenital glaucoma SO MOLECULAR VISION LA English DT Article ID LATENT TGF-BETA; CYTOCHROME P4501B1 CYP1B1; BINDING-PROTEIN 2; PSEUDOEXFOLIATION SYNDROME; SECONDARY GLAUCOMA; MUTATIONS; LOCUS; BUPHTHALMOS; IDENTIFICATION; MEGALOCORNEA AB Purpose: To identify deleterious mutations in the latent transforming growth factor-beta-binding protein 2 (LTBP2) gene in sporadic patients with primary congenital glaucoma (PCG) from a Han Chinese population, which had been excluded for mutations in the CYP1B1 gene. Methods: In this retrospective case-control study, 36 coding exons and adjacent exon-intron boundaries of LTBP2 were amplified with PCR and screened for mutations with Sanger sequencing in DNA samples of 214 sporadic patients with PCG. Sequence variants identified in the patients with PCG were subsequently screened in 100 unaffected control subjects and the unaffected parents of the patients with PCG who had sequence changes in LTBP2. Results: Eight heterozygous single nucleotide polymorphisms (SNPs) in coding regions of LTBP2 were identified in the patients with PCG. Four of these SNPs were missense changes that resulted in the replacement of amino acids (rs2304707, rs116914994, rs45468895, and rs763035721), two of which (rs2304707 and rs116914994) were also present in the control subjects. No significant differences in the frequencies of the missense SNPs were found between the patients with PCG and the controls. The two missense SNPs, rs45468895 and rs763035721, which were each found in one patient also existed in their unaffected parents, suggesting that these two SNPs were not segregated in these families and are unlikely to be a disease-causative variant. In addition, four synonymous SNPs were detected in the patients with PCG (rs61738025, rs862031, rs199805158, and rs12586758). Conclusions: The results showed that no deleterious mutations were found in coding regions of LTBP2 in patients with PCG, suggesting that it is not a causal gene for PCG in the Han Chinese population. C1 [Chen, Xueli; Chen, Yuhong; Wang, Li; Sun, Xinghuai] Fudan Univ, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Eye & ENT Hosp, Shanghai 200031, Peoples R China. [Sun, Xinghuai] Fudan Univ, State Key Lab Med Neurobiol, Inst Brain Sci, Shanghai 200032, Peoples R China. [Sun, Xinghuai] Fudan Univ, Collaborat Innovat Ctr Brain Sci, Shanghai 200032, Peoples R China. [Sun, Xinghuai] Fudan Univ, Minist Hlth, Key Lab Myopia, Shanghai 200031, Peoples R China. [Sun, Xinghuai] Fudan Univ, Shanghai Key Lab Visual Impairment & Restorat, Shanghai 200031, Peoples R China. [Fan, Bao Jian] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Xia, Mingying] Fudan Univ, Sch Life Sci, Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Xia, Mingying] Fudan Univ, Sch Life Sci, Ctr Evolutionary Biol, Shanghai 200433, Peoples R China. RP Sun, XH (reprint author), Fudan Univ, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Eye & ENT Hosp, Shanghai 200031, Peoples R China.; Sun, XH (reprint author), Fudan Univ, State Key Lab Med Neurobiol, Inst Brain Sci, Shanghai 200032, Peoples R China.; Sun, XH (reprint author), Fudan Univ, Collaborat Innovat Ctr Brain Sci, Shanghai 200032, Peoples R China.; Sun, XH (reprint author), Fudan Univ, Minist Hlth, Key Lab Myopia, Shanghai 200031, Peoples R China.; Sun, XH (reprint author), Fudan Univ, Shanghai Key Lab Visual Impairment & Restorat, Shanghai 200031, Peoples R China. EM xhsun@shmu.edu.cn FU Funds for International Cooperation and Exchange of the National Natural Science Foundation of China [81020108017]; National Natural Science Foundation of China [81000401, 81570887] FX The samples used for the analyses described in this manuscript were obtained from the EENT Biobank. We would like to thank all the participants for their valuable contribution to this research. This work was supported in part by the Funds for International Cooperation and Exchange of the National Natural Science Foundation of China (81020108017; Xinghuai Sun) and National Natural Science Foundation of China (81000401, 81570887; Xueli Chen, Yuhong Chen). NR 32 TC 0 Z9 0 U1 2 U2 3 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 28 PY 2016 VL 22 BP 528 EP 535 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DN0WC UT WOS:000376786600001 PM 27293371 ER PT J AU Dodds, SG Livi, CB Parihar, M Hsu, HK Benavides, AD Morris, J Javors, M Strong, R Christy, B Hasty, P Sharp, ZD AF Dodds, Sherry G. Livi, Carolina B. Parihar, Manish Hsu, Hang-Kai Benavides, Adriana D. Morris, Jay Javors, Martin Strong, Randy Christy, Barbara Hasty, Paul Sharp, Zelton Dave TI Adaptations to chronic rapamycin in mice SO PATHOBIOLOGY OF AGING AND AGE-RELATED DISEASES LA English DT Article DE mTORC1; rapamycin; translation; ribosome biogenesis ID EXTENDS LIFE-SPAN; GENETICALLY HETEROGENEOUS MICE; INITIATION-FACTOR 4E; EIF4E/4E-BP RATIO; MAMMALIAN TARGET; MTOR; INHIBITION; CANCER; EIF4E; PHOSPHORYLATION AB Rapamycin inhibits mechanistic (or mammalian) target of rapamycin (mTOR) that promotes protein production in cells by facilitating ribosome biogenesis (RiBi) and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa) extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6) in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs) suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon), while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon). In fat, there was a decrease in eIF4E relative to actin (opposite to colon) but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon). Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive 'pseudo-anabolic' state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences. C1 [Dodds, Sherry G.; Livi, Carolina B.; Parihar, Manish; Hsu, Hang-Kai; Morris, Jay; Christy, Barbara; Hasty, Paul; Sharp, Zelton Dave] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78229 USA. [Livi, Carolina B.] Agilent Technol, Santa Clara, CA USA. [Hsu, Hang-Kai] City Hope Natl Med Ctr, KCRB 2018, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Benavides, Adriana D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Benavides, Adriana D.] Childrens Hosp Philadelphia, Infect Dis Res Div, Philadelphia, PA 19104 USA. [Javors, Martin] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Javors, Martin; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Strong, Randy; Hasty, Paul; Sharp, Zelton Dave] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Strong, Randy] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Christy, Barbara] US Army Inst Surg Res, Coagulat & Blood Res Grp, JBSA Ft Sam Houston, TX USA. [Hasty, Paul; Sharp, Zelton Dave] Canc Therapy & Res Ctr S Texas, 4450 Med Dr, San Antonio, TX 78229 USA. RP Hasty, P; Sharp, ZD (reprint author), Dept Mol Med, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM hastye@uthscsa.edu; sharp@uthscsa.edu FU NCI NIH HHS [R01 CA193835]; NIA NIH HHS [P30 AG013319, U01 AG022307] NR 59 TC 2 Z9 2 U1 1 U2 1 PU CO-ACTION PUBLISHING PI JARFALLA PA RIPVAGEN 7, JARFALLA, SE-175 64, SWEDEN EI 2001-0001 J9 PATHOBIOL AGING AGE JI Pathobiol. Aging Age-relat. Dis. PD MAY 27 PY 2016 VL 6 AR 31688 DI 10.3402/pba.v6.31688 PG 11 WC Pathology SC Pathology GA DT4ET UT WOS:000381433600001 PM 27237224 ER PT J AU Berrueta, M Hemingway-Foday, J Thorsten, VR Goldenberg, RL Carlo, WA Garces, A Patel, A Saleem, S Pasha, O Chomba, E Hibberd, PL Krebs, NF Goudar, S Derman, RJ Esamai, F Liechty, EA Moore, JL McClure, EM Koso-Thomas, M Buekens, PM Belizan, JM Althabe, F AF Berrueta, Mabel Hemingway-Foday, Jennifer Thorsten, Vanessa R. Goldenberg, Robert L. Carlo, Waldemar A. Garces, Ana Patel, Archana Saleem, Sarah Pasha, Omrana Chomba, Elwyn Hibberd, Patricia L. Krebs, Nancy F. Goudar, Shivaprasad Derman, Richard J. Esamai, Fabian Liechty, Edward A. Moore, Janet L. McClure, Elizabeth M. Koso-Thomas, Marion Buekens, Pierre M. Belizan, Jose M. Althabe, Fernando TI Use of antenatal corticosteroids at health facilities and communities in low-and-middle income countries SO REPRODUCTIVE HEALTH LA English DT Article ID PRETERM BIRTH; NEWBORN HEALTH; GESTATIONAL-AGE; SCALE-UP; DEATHS; MORTALITY; SURVIVAL; TRIAL; RISK AB Background: Antenatal corticosteroids (ACS) for women at high risk of preterm birth is an effective intervention to reduce neonatal mortality among preterm babies delivered in hospital settings, but has not been widely used in low-middle resource settings. We sought to assess the rates of ACS use at all levels of health care in low and middle income countries (LMIC). Methods: We assessed rates of ACS in 7 sites in 6 LMIC participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network for Women and Children's Health Research Antenatal Corticosteroids Trial (ACT), a cluster-randomized trial to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of ACS. We conducted this analysis using data from the control clusters, which did not receive any components of the intervention and intended to follow usual care. We included women who delivered an infant with a birth weight <5th percentile, a proxy for preterm birth, and were enrolled in the Maternal Newborn Health (MNH) Registry between October 2011 and March 2014 in all clusters. A survey of the site investigators regarding existing policies on ACS in health facilities and for health workers in the community was part of pre-trial activities. Results: Overall, of 51,523 women delivered in control clusters across all sites, the percentage of <5th percentile babies ranged from 3.5 % in Kenya to 10.7 % in Pakistan. There was variation among the sites in the use of ACS at all hospitals and among those hospitals having cesarean section and neonatal care capabilities (bag and mask and oxygen or mechanical ventilation). Rates of ACS use for <5th percentile babies in all hospitals ranged from 3. 8 % in the Kenya sites to 44.5 % in the Argentina site, and in hospitals with cesarean section and neonatal care capabilities from 0 % in Zambia to 43.5 % in Argentina. ACS were rarely used in clinic or home deliveries at any site. Guidelines for ACS use at all levels of the health system were available for most of the sites. Conclusion: Our study reports an overall low utilization of ACS among mothers of <5th percentile infants in hospital and clinic deliveries in LMIC. C1 [Berrueta, Mabel; Belizan, Jose M.; Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [Hemingway-Foday, Jennifer; Thorsten, Vanessa R.; Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Garces, Ana] Fdn Alimentac & Nutr Ctr Amer & Panama, Guatemala City, Guatemala. [Patel, Archana] Indira Gandhi Govt Med Coll, Lata Med Res Fdn, Nagpur, Maharashtra, India. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Goudar, Shivaprasad] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Derman, Richard J.] Christiana Hlth Care, Newark, DE USA. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Berrueta, M (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. EM mberrueta@iecs.org.ar FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636]; Bill & Melinda Gates Foundation [OPP1132907] FX This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). Additional support was provided to FA and JB from Bill & Melinda Gates Foundation grant OPP1132907. NR 21 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD MAY 27 PY 2016 VL 13 DI 10.1186/s12978-016-0176-2 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6NS UT WOS:000378614400001 PM 27228986 ER PT J AU Rasheedi, S Shun, MC Serrao, E Sowd, GA Qian, J Hao, CL Dasgupta, T Engelman, AN Skowronski, J AF Rasheedi, Sheeba Shun, Ming-Chieh Serrao, Erik Sowd, Gregory A. Qian, Juan Hao, Caili Dasgupta, Twishasri Engelman, Alan N. Skowronski, Jacek TI The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MESSENGER-RNA; STRUCTURAL BASIS; DNA INTEGRATION; NUCLEAR IMPORT; SPLICING FACTORS; SR PROTEINS; 3 END; LEDGF/P75; INFECTION AB HIV-1 favors integration into active genes and gene-enriched regions of host cell chromosomes, thus maximizing the probability of provirus expression immediately after integration. This requires cleavage and polyadenylation specificity factor 6 (CPSF6), a cellular protein involved in pre-mRNA 3' end processing that binds HIV-1 capsid and connects HIV-1 preintegration complexes to intranuclear trafficking pathways that link integration to transcriptionally active chromatin. CPSF6 together with CPSF5 and CPSF7 are known subunits of the cleavage factor I (CFIm) 3' end processing complex; however, CPSF6 could participate in additional protein complexes. The molecular mechanisms underpinning the role of CPSF6 in HIV-1 infection remain to be defined. Here, we show that a majority of cellular CPSF6 is incorporated into the CFIm complex. HIV-1 capsid recruits CFIm in a CPSF6-dependent manner, which suggests that the CFIm-complex mediates the known effects of CPSF6 in HIV-1 infection. To dissect the roles of CPSF6 and other CFIm complex subunits in HIV-1 infection, we analyzed virologic and integration site targeting properties of a CPSF6 variant with mutations that prevent its incorporation into CFIm. We show, somewhat surprisingly, that CPSF6 incorporation into CFIm is not required for its ability to direct preferential HIV-1 integration into genes. The CPSF5 and CPSF7 subunits appear to have only a minor, if any, role in this process even though they appear to facilitate CPSF6 binding to capsid. Thus, CPSF6 alone controls the key molecular interactions that specify HIV-1 preintegration complex trafficking to active chromatin. C1 [Rasheedi, Sheeba; Shun, Ming-Chieh; Qian, Juan; Hao, Caili; Dasgupta, Twishasri; Skowronski, Jacek] Case Western Reserve Sch Med, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. [Serrao, Erik; Sowd, Gregory A.; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. RP Skowronski, J (reprint author), Case Western Reserve Sch Med, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. EM jacek.skowronski@case.edu FU National Institutes of Health [P50 GM082251]; National Institutes of Health Center for AIDS Research [P30 AI036219] FX This work was supported, in whole or in part, by National Institutes of Health Grant P50 GM082251 (to A. N. E. and J. S.). Shared resources at Case Western Reserve University are supported by National Institutes of Health Center for AIDS Research Grant P30 AI036219. The authors declare that they have no conflicts of interest with the contents of this article. NR 53 TC 3 Z9 3 U1 0 U2 4 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 MAY 27 PY 2016 VL 291 IS 22 BP 11809 EP 11819 DI 10.1074/jbc.M116.721647 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN7NZ UT WOS:000377264800030 PM 26994143 ER PT J AU Calabro, FJ Vaina, LM AF Calabro, Finnegan J. Vaina, Lucia Maria TI Scale Changes Provide an Alternative Cue For the Discrimination of Heading, But Not Object Motion SO MEDICAL SCIENCE MONITOR LA English DT Article DE Motion; Optic Flow; Vision Tests ID OPTIC FLOW; MOVING OBSERVERS; 2ND-ORDER MOTION; SELF-MOTION; PERCEPTION; DIRECTION; MOVEMENT; DEPTH; INFORMATION AB Background: Understanding the dynamics of our surrounding environments is a task usually attributed to the detection of motion based on changes in luminance across space. Yet a number of other cues, both dynamic and static, have been shown to provide useful information about how we are moving and how objects around us move. One such cue, based on changes in spatial frequency, or scale, over time has been shown to be useful in conveying motion in depth even in the absence of a coherent, motion-defined flow field (optic flow). Material/Methods: 16 right handed healthy observers (ages 18-28) participated in the behavioral experiments described in this study. Using analytical behavioral methods we investigate the functional specificity of this cue by measuring the ability of observers to perform tasks of heading (direction of self-motion) and 3D trajectory discrimination on the basis of scale changes and optic flow. Results: Statistical analyses of performance on the test-experiments in comparison to the control experiments suggests that while scale changes may be involved in the detection of heading, they are not correctly integrated with translational motion and, thus, do not provide a correct discrimination of 3D object trajectories. Conclusions: These results have the important implication for the type of visual guided navigation that can be done by an observer blind to optic flow. Scale change is an important alternative cue for self-motion. C1 [Calabro, Finnegan J.; Vaina, Lucia Maria] Boston Univ, Dept Biomed Engn, Brain & Vis Res Lab, Boston, MA 02215 USA. [Vaina, Lucia Maria] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Vaina, LM (reprint author), Boston Univ, Dept Biomed Engn, Brain & Vis Res Lab, Boston, MA 02215 USA.; Vaina, LM (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM vaina@bu.edu NR 33 TC 0 Z9 0 U1 0 U2 0 PU INT SCIENTIFIC LITERATURE, INC PI SMITHTOWN PA 361 FOREST LANE, SMITHTOWN, NY 11787 USA SN 1643-3750 J9 MED SCI MONITOR JI Med. Sci. Monitor PD MAY 27 PY 2016 VL 22 BP 1782 EP 1791 DI 10.12659/MSM.898236 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DN0EW UT WOS:000376738200001 PM 27231114 ER PT J AU Malkin, D Garber, JE Strong, LC Friend, SH AF Malkin, David Garber, Judy E. Strong, Louise C. Friend, Stephen H. TI CANCER The cancer predisposition revolution SO SCIENCE LA English DT Editorial Material ID LI-FRAUMENI-SYNDROME; SV40-TRANSFORMED CELLS; FAMILIAL SYNDROME; BREAST-CANCER; P53 GENE; MUTATIONS; NEOPLASMS; SARCOMAS; ANTIGEN C1 [Malkin, David] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada. [Malkin, David] Univ Toronto, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Garber, Judy E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02215 USA. [Strong, Louise C.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Friend, Stephen H.] Sage Bionetworks, Seattle, WA 98109 USA. RP Malkin, D (reprint author), Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada.; Malkin, D (reprint author), Univ Toronto, Dept Pediat, Toronto, ON M5G 1X8, Canada. EM david.malkin@sickkids.ca FU NCI NIH HHS [P30 CA016672] NR 13 TC 2 Z9 2 U1 1 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 27 PY 2016 VL 352 IS 6289 BP 1052 EP 1053 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6RT UT WOS:000376480800018 PM 27230363 ER PT J AU Orkin, SH Reilly, P AF Orkin, Stuart H. Reilly, Philip TI MEDICINE Paying for future success in gene therapy SO SCIENCE LA English DT Editorial Material ID LEBERS CONGENITAL AMAUROSIS; DISEASE; VECTOR C1 [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston Childrens Hosp, Boston, MA 02115 USA. [Reilly, Philip] Third Rock Ventures, Boston, MA 02116 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA.; Orkin, SH (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston Childrens Hosp, Boston, MA 02115 USA.; Reilly, P (reprint author), Third Rock Ventures, Boston, MA 02116 USA. EM stuart_orkin@dfci.harvard.edu; philip@thirdrockventures.com FU Howard Hughes Medical Institute NR 18 TC 2 Z9 2 U1 5 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 27 PY 2016 VL 352 IS 6289 BP 1059 EP 1061 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6RT UT WOS:000376480800023 PM 27230368 ER PT J AU Chu, HT Khosravi, A Kusumawardhani, IP Kwon, AHK Vasconcelos, AC Cunha, LD Mayer, AE Shen, Y Wu, WL Kambal, A Targan, SR Xavier, RJ Ernst, PB Green, DR McGovern, DPB Virgin, H Mazmanian, SK AF Chu, Hiutung Khosravi, Arya Kusumawardhani, Indah P. Kwon, Alice H. K. Vasconcelos, Anilton C. Cunha, Larissa D. Mayer, Anne E. Shen, Yue Wu, Wei-Li Kambal, Amal Targan, Stephan R. Xavier, Ramnik J. Ernst, Peter B. Green, Douglas R. McGovern, Dermot P. B. Virgin, HerbertW. Mazmanian, Sarkis K. TI Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease SO SCIENCE LA English DT Article ID GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; DENDRITIC CELLS; IMMUNE-SYSTEM; AUTOPHAGY; SUSCEPTIBILITY; ATG16L1; COMMENSAL; VARIANT; HERITABILITY AB Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T-regs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T-reg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD. C1 [Chu, Hiutung; Khosravi, Arya; Kusumawardhani, Indah P.; Kwon, Alice H. K.; Shen, Yue; Wu, Wei-Li; Mazmanian, Sarkis K.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Vasconcelos, Anilton C.; Ernst, Peter B.] Univ Calif San Diego, Ctr Vet Sci & Comparat Med, La Jolla, CA 92093 USA. [Cunha, Larissa D.; Green, Douglas R.] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Mayer, Anne E.; Kambal, Amal; Virgin, HerbertW.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Targan, Stephan R.; McGovern, Dermot P. B.] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 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.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Chu, HT; Mazmanian, SK (reprint author), CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. EM hiuchu@caltech.edu; sarkis@caltech.edu RI Cunha, Larissa/I-4204-2012 FU National Institutes of Health (NIH) under a Ruth L. Kirschtein National Research Service Award [DK100109]; NIH [DK097485, PO1DK046763, AI079145, AI40646, U19 AI109725, DK062413, DE023789-01, AI109725, DK078938, GM099535]; Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds; Feintech Family Chair in IBD; Wayne and Gladys Valley Foundation; Lupus Research Institute; Lisa Z. Greer Endowed Chair in IBD Genetics; European Union [305479]; Crohn's and Colitis Foundation of America; Leona M. and Harry B. Helmsley Charitable Trust; Heritage Medical Research Institute FX We thank L. Hwang, E. Park, and M. Salas for clinical research coordination (Cedars-Sinai); A. Maskell, L. Sandoval, and C. Rumaldo for animal husbandry (Caltech); and members of the Mazmanian laboratory for discussions and critical reading of the manuscript. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. This work was supported by the National Institutes of Health (NIH) under a Ruth L. Kirschtein National Research Service Award (DK100109) to H. C.; NIH DK097485 to R.J.X.; NIH PO1DK046763, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds, and The Feintech Family Chair in IBD to S.R.T.; Wayne and Gladys Valley Foundation and NIH AI079145 to P.B.E.; The Lupus Research Institute and NIH AI40646 to D.R.G; NIH U19 AI109725 to H.W.V.; The Lisa Z. Greer Endowed Chair in IBD Genetics, NIH DK062413, NIH DE023789-01, grant 305479 from the European Union, The Crohn's and Colitis Foundation of America, and The Leona M. and Harry B. Helmsley Charitable Trust to D.P.B.M.; NIH AI109725 to H.W.V.; and NIH DK078938, NIH GM099535, The Crohn's and Colitis Foundation of America, and the Heritage Medical Research Institute to S.K.M. Rubicon and ULK1 knockout mice were obtained from D. R. Green and M. Kundu, respectively, under a materials transfer agreement with St. Jude Children's Research Hospital. A provisional patent application entitled "Beneficial Activation of Autophagy Components by the Microbiome" has been filed by H. C., H.W.V., and S.K.M. NR 41 TC 24 Z9 24 U1 24 U2 40 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 27 PY 2016 VL 352 IS 6289 BP 1116 EP 1120 DI 10.1126/science.aad9948 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6RT UT WOS:000376480800043 PM 27230380 ER PT J AU Taggart, LE McMahon, SJ Butterworth, KT Currell, FJ Schettino, G Prise, KM AF Taggart, L. E. McMahon, S. J. Butterworth, K. T. Currell, F. J. Schettino, G. Prise, K. M. TI Protein disulphide isomerase as a target for nanoparticle-mediated sensitisation of cancer cells to radiation SO NANOTECHNOLOGY LA English DT Article DE nanoparticle; bioactivity; thiol; oxidation ID GOLD NANOPARTICLES; CONTRAST AGENTS; COMPUTED-TOMOGRAPHY; X-RAYS; THERAPY; DAMAGE; CYTOTOXICITY; ENHANCEMENT; GENERATION; RADIOSENSITIZATION AB Radiation resistance and toxicity in normal tissues are limiting factors in the efficacy of radiotherapy. Gold nanoparticles (GNPs) have been shown to be effective at enhancing radiation-induced cell death, and were initially proposed to physically enhance the radiation dose deposited. However, biological responses of GNP radiosensitization based on physical assumptions alone are not predictive of radiosensitisation and therefore there is a fundamental research need to determine biological mechanisms of response to GNPs alone and in combination with ionising radiation. This study aimed to identify novel mechanisms of cancer cell radiosensitisation through the use of GNPs, focusing on their ability to induce cellular oxidative stress and disrupt mitochondrial function. Using N-acetyl-cysteine, we found mitochondrial oxidation to be a key event prior to radiation for the radiosensitisation of cancer cells and suggests the overall cellular effects of GNP radiosensitisation are a result of their interaction with protein disulphide isomerase (PDI). This investigation identifies PDI and mitochondrial oxidation as novel targets for radiosensitisation. C1 [Taggart, L. E.; McMahon, S. J.; Butterworth, K. T.; Schettino, G.; Prise, K. M.] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7AE, Antrim, North Ireland. [Currell, F. J.] Queens Univ Belfast, Sch Math & Phys, Belfast BT7 1NN, Antrim, North Ireland. [McMahon, S. J.] Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [Schettino, G.] Natl Phys Lab, Teddington TW11 0LW, Middx, England. RP Taggart, LE (reprint author), Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7AE, Antrim, North Ireland. EM ltaggart04@qub.ac.uk RI Prise, Kevin/N-7872-2015 OI Prise, Kevin/0000-0001-6134-7946 FU Department of Education and Learning, Northern Ireland; European Commission [EC FP7-MC IOF-623630-Radrespro, EC FP7 MC-ITN-608163-Argent] FX Laura Taggart acknowledges Department of Education and Learning, Northern Ireland support for PhD funding. The authors are grateful to the European Commission Framework 7 Programme (grant numbers EC FP7-MC IOF-623630-Radrespro and EC FP7 MC-ITN-608163-Argent) for funding their work. NR 32 TC 3 Z9 3 U1 4 U2 12 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 EI 1361-6528 J9 NANOTECHNOLOGY JI Nanotechnology PD MAY 27 PY 2016 VL 27 IS 21 AR 215101 DI 10.1088/0957-4484/27/21/215101 PG 11 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA DJ9BB UT WOS:000374507600002 PM 27080849 ER PT J AU Fried, R Chan, J Feinberg, L Pope, A Woodworth, KY Faraone, SV Biederman, J AF Fried, Ronna Chan, James Feinberg, Leah Pope, Amanda Woodworth, K. Yvonne Faraone, Stephen V. Biederman, Joseph TI Clinical correlates of working memory deficits in youth with and without ADHD: A controlled study SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article DE children; working memory; executive function; neuropsychology; Attention deficit hyperactivity disorder ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; HYPERACTIVITY DISORDER; EXECUTIVE FUNCTION; ACADEMIC-ACHIEVEMENT; SOCIAL-PROBLEMS; ADULT ADHD; CHILDREN; OUTCOMES; ADOLESCENTS; COMORBIDITY AB Objective: Both working memory (WM; a brain system that provides temporary storage and manipulation of the information) and attention-deficit/hyperactivity disorder (ADHD) have been associated with educational deficits. Since WM deficits are prevalent in children with ADHD, the main aim of the present study was to examine whether educational deficits are driven by working memory deficits or driven by the effect of ADHD itself. Method: Participants were referred youth with (N = 276) and without (N = 241) ADHD ascertained from pediatric and psychiatric sources. Assessment included measures of psychiatric, psychosocial, educational, and cognitive functioning. Education deficits were defined as grade retention or placement in special classes and were assessed using interviews and written rating scales. Working memory was assessed using the Wechsler Intelligence Scale for Children-Revised (WISC-R) Freedom from Distractibility (FFD) factor based on Digit Span, Arithmetic, and Coding. Results: Significantly more youth with ADHD had WM deficits than controls (31.9% vs. 13.7%, p < .05). In ADHD children, WM deficits were significantly (p < .01) associated with an increased risk for grade retention and placement in special classes as well as lower scores on reading and math achievement tests than for ADHD children without WM deficits. In contrast, no other differences were noted in other areas of functioning. Although WM deficits also had some adverse impact on educational and cognitive correlates in non-ADHD controls, these differences failed to attain statistical significance. Conclusion: WM deficits significantly and selectively increase the risk for academic deficits and cognitive dysfunction in children with ADHD beyond those conferred by ADHD. Screening for WM deficits may help identify children with ADHD at high risk for academic and cognitive dysfunction. C1 [Fried, Ronna; Feinberg, Leah; Pope, Amanda; Woodworth, K. Yvonne; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adu, Boston, MA 02114 USA. [Fried, Ronna; Biederman, Joseph] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Chan, James] Boston Childrens Hosp, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Faraone, Stephen V.] Univ Bergen, Dept Biomed, KG Jebsen Ctr Psychiat Disorders, Bergen, Norway. RP Fried, R (reprint author), Massachusetts Gen Hosp, Warren 719, Boston, MA 02114 USA. EM rfried@partners.org FU National Institutes of Health (NIH) [R01MH050657, R01HD036317]; Pediatric Psychopharmacology Research Council Fund FX This work was supported by the National Institutes of Health (NIH) [grant number R01MH050657], [grant number R01HD036317] to J. Biederman; and by the Pediatric Psychopharmacology Research Council Fund. NR 49 TC 2 Z9 2 U1 18 U2 60 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 MAY 27 PY 2016 VL 38 IS 5 BP 487 EP 496 DI 10.1080/13803395.2015.1127896 PG 10 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA DG4HN UT WOS:000372033100001 PM 26902180 ER PT J AU Rouse, DJ Keimig, TW Riley, LE Letourneau, AR Platt, MY AF Rouse, Dwight J. Keimig, Thomas W. Riley, Laura E. Letourneau, Alyssa R. Platt, Mia Y. TI Case 16-2016: A 31-Year-Old Pregnant Woman with Fever SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LISTERIOSIS; INFECTION; WOMEN C1 [Rouse, Dwight J.] Brown Univ, Women & Infants Hosp Rhode Isl, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Rouse, Dwight J.] Brown Univ, Warren Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Keimig, Thomas W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Riley, Laura E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. [Letourneau, Alyssa R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Platt, Mia Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Keimig, Thomas W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Riley, Laura E.] Harvard Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. [Letourneau, Alyssa R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Platt, Mia Y.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Rouse, DJ (reprint author), Brown Univ, Women & Infants Hosp Rhode Isl, Dept Obstet & Gynecol, Providence, RI 02912 USA.; Rouse, DJ (reprint author), Brown Univ, Warren Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 26 PY 2016 VL 374 IS 21 BP 2076 EP 2083 DI 10.1056/NEJMcpc1516451 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DM6EN UT WOS:000376443500012 PM 27223150 ER PT J AU Lincoln, S Kurian, A Desmond, A Yang, S Kobayashi, Y Ford, J Ellisen, L AF Lincoln, S. Kurian, A. Desmond, A. Yang, S. Kobayashi, Y. Ford, J. Ellisen, L. TI Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study SO HUMAN GENOMICS LA English DT Meeting Abstract C1 [Lincoln, S.; Yang, S.; Kobayashi, Y.] Invitae, San Francisco, CA USA. [Kurian, A.] Stanford Med Ctr, Palo Alto, CA USA. [Desmond, A.; Ellisen, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ford, J.] Stanford Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 EI 1479-7364 J9 HUM GENOMICS JI Hum. Genomics PD MAY 26 PY 2016 VL 10 SU 1 MA O24 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DW5LM UT WOS:000383686700025 ER PT J AU Henske, EP Jozwiak, S Kingswood, JC Sampson, JR Thiele, EA AF Henske, Elizabeth P. Jozwiak, Sergiusz Kingswood, J. Christopher Sampson, Julian R. Thiele, Elizabeth A. TI Tuberous sclerosis complex SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; GIANT-CELL ASTROCYTOMA; SPORADIC PULMONARY LYMPHANGIOLEIOMYOMATOSIS; MICRONODULAR PNEUMOCYTE HYPERPLASIA; TSC CLINICAL RECOMMENDATIONS; AUTISM SPECTRUM DISORDERS; RENAL ANGIOMYOLIPOMA; MAMMALIAN TARGET; NATURAL-HISTORY; MOUSE MODEL AB Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure. C1 [Henske, Elizabeth P.] Harvard Med Sch, Brigham & Womens Hosp, Pulm & Crit Care Med Div, 15 Francis St, Boston, MA 02115 USA. [Jozwiak, Sergiusz] Med Univ Warsaw, Dept Pediat Neurol, Warsaw, Poland. [Jozwiak, Sergiusz] Childrens Mem Hlth Inst, Warsaw, Poland. [Kingswood, J. Christopher] Royal Sussex Cty Hosp, Sussex Kidney Unit, Brighton, E Sussex, England. [Sampson, Julian R.] Cardiff Univ, Sch Med, Inst Med Genet, Div Canc & Genet, Cardiff, S Glam, Wales. [Thiele, Elizabeth A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. RP Henske, EP (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Pulm & Crit Care Med Div, 15 Francis St, Boston, MA 02115 USA. EM Ehenske@BWH.Harvard.edu FU 7th Framework Programme of European Commission [602391-2]; Lucy J. Engles Program in TSC/LAM Research FX The work of S.J. in this study has been partially supported by the 7th Framework Programme of European Commission within the large-scale integrating project EPISTOP (Proposal No. 602391-2). The work of E.P.H. was partially supported by the Lucy J. Engles Program in TSC/LAM Research. E.A.T. acknowledges the Carol and James Herscot Center for Children and Adults with TSC at Massachusetts General Hospital. The authors are grateful to J. Nijmeh for assistance with preparation of the manuscript. NR 200 TC 8 Z9 8 U1 14 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD MAY 26 PY 2016 VL 2 AR 16035 DI 10.1038/nrdp.2016.35 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA DT3GX UT WOS:000381370100001 PM 27226234 ER PT J AU Hoban, MD Bauer, DE AF Hoban, Megan D. Bauer, Daniel E. TI A genome editing primer for the hematologist SO BLOOD LA English DT Review ID ZINC-FINGER NUCLEASES; DEFECTIVE LENTIVIRAL VECTORS; PLURIPOTENT STEM-CELLS; HEMATOPOIETIC STEM/PROGENITOR CELLS; MEDIATED TARGETED INTEGRATION; CHRONIC GRANULOMATOUS-DISEASE; BREAK-INDUCED RECOMBINATION; CHIMERIC-ANTIGEN-RECEPTOR; CRISPR-CAS NUCLEASES; DOUBLE-STRAND BREAKS AB Gene editing enables the site-specific modification of the genome. These technologies have rapidly advanced such that they have entered common use in experimental hematology to investigate genetic function. In addition, genome editing is becoming increasingly plausible as a treatment modality to rectify genetic blood disorders and improve cellular therapies. Genome modification typically ensues from site-specific double-strand breaks and may result in a myriad of outcomes. Even single-strand nicks and targeted biochemical modifications that do not permanently alter the DNA sequence (epigenome editing) may be powerful instruments. In this review, we examine the various technologies, describe their advantages and shortcomings for engendering useful genetic alterations, and consider future prospects for genome editing to impact hematology. C1 Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Bauer, DE (reprint author), Boston Childrens Hosp, 1 Blackfan Circle,Karp RB 07007A, Boston, MA 02115 USA. EM bauer@bloodgroup.tch.harvard.edu FU National Institutes of Health (NIH), National Heart, Lung, and Blood Institute [T32HL007574]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases [K08DK093705]; Doris Duke Charitable Foundation; Charles H. Hood Foundation; American Society of Hematology; Borough's Wellcome Fund; Cooley's Anemia Foundation FX M.D.H. is supported by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute grant T32HL007574 and D.E.B. by the NIH, National Institute of Diabetes and Digestive and Kidney Diseases grant K08DK093705 (Career Development Award), the Doris Duke Charitable Foundation, the Charles H. Hood Foundation, the American Society of Hematology, the Borough's Wellcome Fund, and Cooley's Anemia Foundation. NR 165 TC 3 Z9 3 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 MAY 26 PY 2016 VL 127 IS 21 BP 2525 EP 2535 DI 10.1182/blood-2016-01-678151 PG 11 WC Hematology SC Hematology GA DP2QK UT WOS:000378334400006 PM 27053532 ER PT J AU Canver, MC Orkin, SH AF Canver, Matthew C. Orkin, Stuart H. TI Customizing the genome as therapy for the beta-hemoglobinopathies SO BLOOD LA English DT Review ID SICKLE-CELL-DISEASE; ZINC-FINGER NUCLEASES; HEMATOPOIETIC STEM-CELLS; HUMAN FETAL-HEMOGLOBIN; HUMAN IPS CELLS; GENE-THERAPY; IN-VIVO; THALASSEMIA MUTATIONS; GLOBIN GENE; WIDE ASSOCIATION AB Despite nearly complete understanding of the genetics of the beta-hemoglobinopathies for several decades, definitive treatment options have lagged behind. Recent developments in technologies for facile manipulation of the genome (zinc finger nucleases, transcription activator-like effector nucleases, or clustered regularly interspaced short palindromic repeats-based nucleases) raise prospects for their clinical application. The use of genome-editing technologies in autologous CD34(+) hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the beta-globin disorders. Genetic correction strategies relying on the homology-directed repair pathway may repair genetic defects, whereas genetic disruption strategies relying on the nonhomologous end joining pathway may induce compensatory fetal hemoglobin expression. Harnessing the power of genome editing may usher in a second-generation form of gene therapy for the b-globin disorders. C1 [Canver, Matthew C.; Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [F30DK 103359]; NIH National Heart, Lung, and Blood Institute [HL032259, P01HL032262] FX M.C.C. was supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (F30DK 103359). S.H.O. was supported by the NIH National Heart, Lung, and Blood Institute (HL032259 and P01HL032262). NR 173 TC 5 Z9 5 U1 8 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 MAY 26 PY 2016 VL 127 IS 21 BP 2536 EP 2545 DI 10.1182/blood-2016-01-678128 PG 10 WC Hematology SC Hematology GA DP2QK UT WOS:000378334400007 PM 27053533 ER PT J AU Tagde, A Rajabi, H Bouillez, A Alam, M Gali, R Bailey, S Tai, YT Hideshima, T Anderson, K Avigan, D Kufe, D AF Tagde, Ashujit Rajabi, Hasan Bouillez, Audrey Alam, Maroof Gali, Reddy Bailey, Shannon Tai, Yu-Tzu Hideshima, Teru Anderson, Kenneth Avigan, David Kufe, Donald TI MUC1-C drives MYC in multiple myeloma SO BLOOD LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; CARCINOMA-ASSOCIATED ANTIGEN; DOWN-REGULATING TIGAR; LUNG-CANCER CELLS; BETA-CATENIN; C-MYC; PROMOTES PROLIFERATION; ONCOPROTEIN; EXPRESSION; ACTIVATION AB Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples. The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein. The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a beta-catenin/transcription factor 4 (TCF4)-mediated mechanism. In this way, MUC1-C (1) increases beta-catenin occupancy on the MYC promoter, (2) forms a complex with beta-catenin and TCF4, and, in turn, (3) drives MYC transcription. Analysis of MM cells using quantitative real-time reverse transcription polymerase chain reaction arrays further demonstrated that silencing MUC1-C is associated with downregulation of MYC target genes, including CCND2, hTERT, and GCLC. Analysis of microarray data sets further demonstrated that MUC1 levels positively correlate with MYC expression in MM progression and in primary cells from over 800 MM patients. These findings collectively provide convincing evidence that MUC1-C drives MYC expression in MM. C1 [Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey; Alam, Maroof; Bailey, Shannon; Tai, Yu-Tzu; Hideshima, Teru; Anderson, Kenneth; Kufe, Donald] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 830, Boston, MA 02115 USA. [Gali, Reddy] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA USA. [Avigan, David] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Kufe, D (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 830, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu RI Tagde, Ashujit/M-9497-2014 OI Tagde, Ashujit/0000-0002-0770-097X FU National Cancer Institute of the National Institutes of Health [P50CA100707, PO1CA078378] FX This work was supported by the National Cancer Institute of the National Institutes of Health under award numbers P50CA100707 and PO1CA078378. NR 69 TC 16 Z9 16 U1 2 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 26 PY 2016 VL 127 IS 21 BP 2587 EP 2597 DI 10.1182/blood-2015-07-659151 PG 11 WC Hematology SC Hematology GA DP2QK UT WOS:000378334400013 PM 26907633 ER PT J AU Roccaro, AM Sacco, A Shi, JT Chiarini, M Perilla-Glen, A Manier, S Glavey, S Aljawai, Y Mishima, Y Kawano, Y Moschetta, M Correll, M Improgo, MR Brown, JR Imberti, L Rossi, G Castillo, JJ Treon, SP Freedman, ML Van Allen, EM Hide, W Hiller, E Rainville, I Ghobrial, IM AF Roccaro, Aldo M. Sacco, Antonio Shi, Jiantao Chiarini, Marco Perilla-Glen, Adriana Manier, Salomon Glavey, Siobhan Aljawai, Yosra Mishima, Yuji Kawano, Yawara Moschetta, Michele Correll, Mick Improgo, Ma Reina Brown, Jennifer R. Imberti, Luisa Rossi, Giuseppe Castillo, Jorge J. Treon, Steven P. Freedman, Matthew L. Van Allen, Eliezer M. Hide, Winston Hiller, Elaine Rainville, Irene Ghobrial, Irene M. TI Exome sequencing reveals recurrent germ line variants in patients with familial Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; IGM MONOCLONAL GAMMOPATHY; MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; SIGNALING PATHWAYS; SOMATIC MUTATION; KAPPA-B; RISK; PATTERNS; GENOME AB Familial aggregation of Waldenstrom macroglobulinemia (WM) cases, and the clustering of B-cell lymphoproliferative disorders among first-degree relatives of WM patients, has been reported. Nevertheless, the possible contribution of inherited susceptibility to familial WM remains unrevealed. We performed whole exome sequencing on germ line DNA obtained from 4 family members in which coinheritance for WM was documented in 3 of them, and screened additional independent 246 cases by using gene-specific mutation sequencing. Among the shared germ line variants, LAPTM5(c403t) and HCLS1(g496a) were the most recurrent, being present in 3/3 affected members of the index family, detected in 8% of the unrelated familial cases, and present in 0.5% of the nonfamilial cases and in <0.05 of a control population. LAPTM5 and HCLS1 appeared as relevant WM candidate genes that characterized familial WM individuals and were also functionally relevant to the tumor clone. These findings highlight potentially novel contributors for the genetic predisposition to familial WM and indicate that LAPTM5(c403t) and HCLS1(g496a) may represent predisposition alleles in patients with familial WM. C1 [Roccaro, Aldo M.; Sacco, Antonio; Chiarini, Marco; Perilla-Glen, Adriana; Manier, Salomon; Glavey, Siobhan; Aljawai, Yosra; Mishima, Yuji; Kawano, Yawara; Moschetta, Michele; Correll, Mick; Improgo, Ma Reina; Brown, Jennifer R.; Castillo, Jorge J.; Treon, Steven P.; Freedman, Matthew L.; Van Allen, Eliezer M.; Hiller, Elaine; Rainville, Irene; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Roccaro, Aldo M.; Chiarini, Marco; Imberti, Luisa; Rossi, Giuseppe] Spedali Civil Brescia, Dept Hematol, Ctr Ric Ematooncol AIL, I-25125 Brescia, Italy. [Shi, Jiantao] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Roccaro, AM; Ghobrial, IM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM aldo_roccaro@dfci.harvard.edu; irene_ghobrial@dfci.harvard.edu RI Rossi, Giuseppe/K-3376-2016; Sacco, Antonio/K-4681-2016; Chiarini, Marco/K-4983-2016; OI Rossi, Giuseppe/0000-0001-8377-2898; Sacco, Antonio/0000-0003-2945-9416; Chiarini, Marco/0000-0003-1000-0461; Castillo, Jorge/0000-0001-9490-7532 NR 47 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 26 PY 2016 VL 127 IS 21 BP 2598 EP 2606 DI 10.1182/blood-2015-11-680199 PG 9 WC Hematology SC Hematology GA DP2QK UT WOS:000378334400014 PM 26903547 ER PT J AU Akocak, S Alam, MR Shabana, AM Sanku, RKK Vullo, D Thompson, H Swenson, ER Supuran, CT Hies, MA AF Akocak, Suleyman Alam, M. Raqibul Shabana, Ahmed M. Sanku, Rajesh Kishore Kumar Vullo, Daniela Thompson, Harry Swenson, Erik R. Supuran, Claudiu T. Hies, Marc A. TI PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VIVO SELECTIVITY; BREAST-CANCER; CRYSTAL-STRUCTURE; INTRINSIC MARKER; TUMOR HYPOXIA; ISOZYME-IX; DERIVATIVES; BINDING; XII; PH AB A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores, coupled with either ethylene glycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and XII and cytosolic isozymes, identified nanomolar-potent inhibitors against both classes and several compounds with medium isoform selectivity in a detailed structure-activity relationship study. The ability of CA inhibitors to kill tumor cells overexpressing CA IX and XII was tested under normoxic and hypoxic conditions, using 2D and 3D in vitro cellular models. The study identified a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25) able to significantly reduce the viability of colon HT-29, breast MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the potential of polymer conjugates in CA inhibition and cancer treatment. C1 [Akocak, Suleyman; Alam, M. Raqibul; Shabana, Ahmed M.; Sanku, Rajesh Kishore Kumar; Thompson, Harry; Hies, Marc A.] Temple Univ, Sch Pharm, Dept Pharmaceut Sci, 3307 N Broad St, Philadelphia, PA 19140 USA. [Akocak, Suleyman; Alam, M. Raqibul; Shabana, Ahmed M.; Sanku, Rajesh Kishore Kumar; Thompson, Harry; Hies, Marc A.] Temple Univ, Sch Pharm, Molder Ctr Drug Discovery Res, 3307 N Broad St, Philadelphia, PA 19140 USA. [Akocak, Suleyman] Adiyaman Univ, Fac Pharm, Dept Pharmaceut Chem, TR-02040 Adiyaman, Turkey. [Vullo, Daniela; Supuran, Claudiu T.] Univ Florence, Neurofarba Dept, Pharmaceut Sci Sect, Polo Sci, Via Ugo Schiff 6, I-50019 Florence, Italy. [Swenson, Erik R.] Univ Washington, VA Puget Sound Hlth Care Syst, Med Serv, Seattle, WA 98195 USA. RP Hies, MA (reprint author), Temple Univ, Sch Pharm, Dept Pharmaceut Sci, 3307 N Broad St, Philadelphia, PA 19140 USA.; Hies, MA (reprint author), Temple Univ, Sch Pharm, Molder Ctr Drug Discovery Res, 3307 N Broad St, Philadelphia, PA 19140 USA.; Supuran, CT (reprint author), Univ Florence, Neurofarba Dept, Pharmaceut Sci Sect, Polo Sci, Via Ugo Schiff 6, I-50019 Florence, Italy. EM claudiu.supuran@unifi.it; mailies@temple.edu FU Seattle Foundation [255345]; Temple Drug Discovery Initiative, TUSP Dean's Office, Temple Undergraduate Research Program; Turkish Minister of Education FX The financial support of Seattle Foundation (grant 255345), Temple Drug Discovery Initiative, TUSP Dean's Office, Temple Undergraduate Research Program is gratefully acknowledged. S.A. acknowledges the financial support of the Turkish Minister of Education for a Ph.D. scholarship. We would like to acknowledge Dr. Salim Merali and Mr. George Mateo for their help with MALDI-TOF spectra. NR 89 TC 0 Z9 0 U1 3 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 MAY 26 PY 2016 VL 59 IS 10 BP 5077 EP 5088 DI 10.1021/acs.jmedchem.6b00492 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DN1QN UT WOS:000376840600050 PM 27144971 ER PT J AU McNally, R Toms, AV Eck, MJ AF McNally, Randall Toms, Angela V. Eck, Michael J. TI Crystal Structure of the FERM-SH2 Module of Human Jak2 SO PLOS ONE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CYTOKINE RECEPTOR INTERACTION; TYROSINE KINASE; PROTEIN-KINASE; JANUS KINASES; PSEUDOKINASE-DOMAIN; N-TERMINUS; RECOGNITION; ACTIVATION; AUTOINHIBITION AB Jak-family tyrosine kinases mediate signaling from diverse cytokine receptors. Binding of Jaks to their cognate receptors is mediated by their N-terminal region, which contains FERM and SH2 domains. Here we describe the crystal structure of the FERM-SH2 region of Jak2 at 3.0 angstrom resolutn. The structure reveals that these domains and their flanking linker segments interact intimately to form an integrated structural module. The Jak2 FERM-SH2 structure closely resembles that recently described for Tyk2, another member of the Jak family. While the overall architecture and interdomain orientations are preserved between Jak2 and Tyk2, we identify residues in the putative receptor-binding groove that differ between the two and may contribute to the specificity of receptor recognition. Analysis of Jak mutations that are reported to disrupt receptor binding reveals that they lie in the hydrophobic core of the FERM domain, and are thus expected to compromise the structural integrity of the FERM-SH2 unit. Similarly, analysis of mutations in Jak3 that are associated with severe combined immunodeficiency suggests that they compromise Jak3 function by destabilizing the FERM-SH2 structure. C1 [McNally, Randall; Toms, Angela V.; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [McNally, Randall; Toms, Angela V.; Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Toms, Angela V.] Forma Therapeut, Watertown, MA USA. RP Eck, MJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Eck, MJ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM eck@crystal.harvard.edu FU National Institutes of Health [GM110352, 5-T32-CA009361-33] FX This work was supported by National Institutes of Health grant GM110352 (MJE) and National Institutes of Health training grant 5-T32-CA009361-33 (RM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2016 VL 11 IS 5 AR e0156218 DI 10.1371/journal.pone.0156218 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2GQ UT WOS:000376882500084 PM 27227461 ER PT J AU Okbay, A Beauchamp, JP Fontana, MA Lee, JJ Pers, TH Rietveld, CA Turley, P Chen, GB Emilsson, V Meddens, SFW Oskarsson, S Pickrell, JK Thom, K Timshel, P de Vlaming, R Abdellaoui, A Ahluwalia, TS Bacelis, J Baumbach, C Bjornsdottir, G Brandsma, JH Concas, MP Derringer, J Furlotte, NA Galesloot, TE Girotto, G Gupta, R Hall, LM Harris, SE Hofer, E Horikoshi, M Huffman, JE Kaasik, K Kalafati, IP Karlsson, R Kong, A Lahti, J van der Lee, SJ de Leeuw, C Lind, PA Lindgren, KO Liu, T Mangino, M Marten, J Mihailov, E Miller, MB van der Most, PJ Oldmeadow, C Payton, A Pervjakova, N Peyrot, WJ Qian, Y Raitakari, O Rueedi, R Salvi, E Schmidt, B Schraut, KE Shi, JX Smith, AV Poot, RA St Pourcain, B Teumer, A Thorleifsson, G Verweij, N Vuckovic, D Wellmann, J Westra, HJ Yang, JY Zhao, W Zhu, ZH Alizadeh, BZ Amin, N Bakshi, A Baumeister, SE Biino, G Bonnelykke, K Boyle, PA Campbell, H Cappuccio, FP Davies, G De Neve, JE Deloukas, P Demuth, I Ding, J Eibich, P Eisele, L Eklund, N Evans, DM Faul, JD Feitosa, MF Forstner, AJ Gandin, I Gunnarsson, B Halldorsson, BV Harris, TB Heath, AC Hocking, LJ Holliday, EG Homuth, G Horan, MA Hottenga, JJ de Jager, PL Joshi, PK Jugessur, A Kaakinen, MA Kahonen, M Kanoni, S Keltigangas-Jarvinen, L Kiemeney, LALM Kolcic, I Koskinen, S Kraja, AT Kroh, M Kutalik, Z Latvala, A Launer, LJ Lebreton, MP Levinson, DF Lichtenstein, P Lichtner, P Liewald, DCM Loukola, A Madden, PA Magi, R Maki-Opas, T Marioni, RE Marques-Vidal, P Meddens, GA McMahon, G Meisinger, C Meitinger, T Milaneschi, Y Milani, L Montgomery, GW Myhre, R Nelson, CP Nyholt, DR Ollier, WER Palotie, A Paternoster, L Pedersen, NL Petrovic, KE Porteous, DJ Raikkonen, K Ring, SM Robino, A Rostapshova, O Rudan, I Rustichini, A Salomaa, V Sanders, AR Sarin, AP Schmidt, H Scott, RJ Smith, BH Smith, JA Staessen, JA Steinhagen-Thiessen, E Strauch, K Terracciano, A Tobin, MD Ulivi, S Vaccargiu, S Quaye, L van Rooij, FJA Venturini, C Vinkhuyzen, AAE Volker, U Volzke, H Vonk, JM Vozzi, D Waage, J Ware, EB Willemsen, G Attia, JR Bennett, DA Berger, K Bertram, L Bisgaard, H Boomsma, DI Borecki, IB Bultmann, U Chabris, CF Cucca, F Cusi, D Deary, IJ Dedoussis, GV van Duijn, CM Eriksson, JG Franke, B Franke, L Gasparini, P Gejman, PV Gieger, C Grabe, HJ Gratten, J Groenen, PJF Gudnason, V van der Harst, P Hayward, C Hinds, DA Hoffmann, W Hyppnen, E Iacono, WG Jacobsson, B Jarvelin, MR Jockel, KH Kaprio, J Kardia, SLR Lehtimaki, T Lehrer, SF Magnusson, PKE Martin, NG McGue, M Metspalu, A Pendleton, N Penninx, BWJH Perola, M Pirastu, N Pirastu, M Polasek, O Posthuma, D Power, C Province, MA Samani, NJ Schlessinger, D Schmidt, R Sorensen, TIA Spector, TD Stefansson, K Thorsteinsdottir, U Thurik, AR Timpson, NJ Tiemeier, H Tung, JY Uitterlinden, AG Vitart, V Vollenweider, P Weir, DR Wilson, JF Wright, AF Conley, DC Krueger, RF Smith, GD Hofman, A Laibson, DI Medland, SE Meyer, MN Yang, J Johannesson, M Visscher, PM Esko, T Koellinger, PD Cesarini, D Benjamin, DJ AF Okbay, Aysu Beauchamp, Jonathan P. Fontana, Mark Alan Lee, James J. Pers, Tune H. Rietveld, Cornelius A. Turley, Patrick Chen, Guo-Bo Emilsson, Valur Meddens, S. Fleur W. Oskarsson, Sven Pickrell, Joseph K. Thom, Kevin Timshel, Pascal de Vlaming, Ronald Abdellaoui, Abdel Ahluwalia, Tarunveer S. Bacelis, Jonas Baumbach, Clemens Bjornsdottir, Gyda Brandsma, Johannes H. Concas, Maria Pina Derringer, Jaime Furlotte, Nicholas A. Galesloot, Tessel E. Girotto, Giorgia Gupta, Richa Hall, Leanne M. Harris, Sarah E. Hofer, Edith Horikoshi, Momoko Huffman, Jennifer E. Kaasik, Kadri Kalafati, Ioanna P. Karlsson, Robert Kong, Augustine Lahti, Jari van der Lee, Sven J. de Leeuw, Christiaan Lind, Penelope A. Lindgren, Karl-Oskar Liu, Tian Mangino, Massimo Marten, Jonathan Mihailov, Evelin Miller, Michael B. van der Most, Peter J. Oldmeadow, Christopher Payton, Antony Pervjakova, Natalia Peyrot, Wouter J. Qian, Yong Raitakari, Olli Rueedi, Rico Salvi, Erika Schmidt, Brge Schraut, Katharina E. Shi, Jianxin Smith, Albert V. Poot, Raymond A. St Pourcain, Beate Teumer, Alexander Thorleifsson, Gudmar Verweij, Niek Vuckovic, Dragana Wellmann, Juergen Westra, Harm-Jan Yang, Jingyun Zhao, Wei Zhu, Zhihong Alizadeh, Behrooz Z. Amin, Najaf Bakshi, Andrew Baumeister, Sebastian E. Biino, Ginevra Bonnelykke, Klaus Boyle, Patricia A. Campbell, Harry Cappuccio, Francesco P. Davies, Gail De Neve, Jan-Emmanuel Deloukas, Panos Demuth, Ilja Ding, Jun Eibich, Peter Eisele, Lewin Eklund, Niina Evans, David M. Faul, Jessica D. Feitosa, Mary F. Forstner, Andreas J. Gandin, Ilaria Gunnarsson, Bjarni Halldorsson, Bjarni V. Harris, Tamara B. Heath, Andrew C. Hocking, Lynne J. Holliday, Elizabeth G. Homuth, Georg Horan, Michael A. Hottenga, Jouke-Jan de Jager, Philip L. Joshi, Peter K. Jugessur, Astanand Kaakinen, Marika A. Kahonen, Mika Kanoni, Stavroula Keltigangas-Jarvinen, Liisa Kiemeney, Lambertus A. L. M. Kolcic, Ivana Koskinen, Seppo Kraja, Aldi T. Kroh, Martin Kutalik, Zoltan Latvala, Antti Launer, Lenore J. Lebreton, Mael P. Levinson, Douglas F. Lichtenstein, Paul Lichtner, Peter Liewald, David C. M. Loukola, Anu Madden, Pamela A. Magi, Reedik Maki-Opas, Tomi Marioni, Riccardo E. Marques-Vidal, Pedro Meddens, Gerardus A. McMahon, George Meisinger, Christa Meitinger, Thomas Milaneschi, Yusplitri Milani, Lili Montgomery, Grant W. Myhre, Ronny Nelson, Christopher P. Nyholt, Dale R. Ollier, William E. R. Palotie, Aarno Paternoster, Lavinia Pedersen, Nancy L. Petrovic, Katja E. Porteous, David J. Raikkonen, Katri Ring, Susan M. Robino, Antonietta Rostapshova, Olga Rudan, Igor Rustichini, Aldo Salomaa, Veikko Sanders, Alan R. Sarin, Antti-Pekka Schmidt, Helena Scott, Rodney J. Smith, Blair H. Smith, Jennifer A. Staessen, Jan A. Steinhagen-Thiessen, Elisabeth Strauch, Konstantin Terracciano, Antonio Tobin, Martin D. Ulivi, Sheila Vaccargiu, Simona Quaye, Lydia van Rooij, Frank J. A. Venturini, Cristina Vinkhuyzen, Anna A. E. Volker, Uwe Volzke, Henry Vonk, Judith M. Vozzi, Diego Waage, Johannes Ware, Erin B. Willemsen, Gonneke Attia, John R. Bennett, David A. Berger, Klaus Bertram, Lars Bisgaard, Hans Boomsma, Dorret I. Borecki, Ingrid B. Bultmann, Ute Chabris, Christopher F. Cucca, Francesco Cusi, Daniele Deary, Ian J. Dedoussis, George V. van Duijn, Cornelia M. Eriksson, Johan G. Franke, Barbara Franke, Lude Gasparini, Paolo Gejman, Pablo V. Gieger, Christian Grabe, Hans-Jorgen Gratten, Jacob Groenen, Patrick J. F. Gudnason, Vilmundur van der Harst, Pim Hayward, Caroline Hinds, David A. Hoffmann, Wolfgang Hyppnen, Elina Iacono, William G. Jacobsson, Bo Jarvelin, Marjo-Riitta Jockel, Karl-Heinz Kaprio, Jaakko Kardia, Sharon L. R. Lehtimaki, Terho Lehrer, Steven F. Magnusson, Patrik K. E. Martin, Nicholas G. McGue, Matt Metspalu, Andres Pendleton, Neil Penninx, Brenda W. J. H. Perola, Markus Pirastu, Nicola Pirastu, Mario Polasek, Ozren Posthuma, Danielle Power, Christine Province, Michael A. Samani, Nilesh J. Schlessinger, David Schmidt, Reinhold Sorensen, Thorkild I. A. Spector, Tim D. Stefansson, Kari Thorsteinsdottir, Unnur Thurik, A. Roy Timpson, Nicholas J. Tiemeier, Henning Tung, Joyce Y. Uitterlinden, Andre G. Vitart, Veronique Vollenweider, Peter Weir, David R. Wilson, James F. Wright, Alan F. Conley, Dalton C. Krueger, Robert F. Smith, George Davey Hofman, Albert Laibson, David I. Medland, Sarah E. Meyer, Michelle N. Yang, Jian Johannesson, Magnus Visscher, Peter M. Esko, Tonu Koellinger, Philipp D. Cesarini, David Benjamin, Daniel J. CA LifeLines Cohort Study TI Genome-wide association study identifies 74 loci associated with educational attainment SO NATURE LA English DT Article ID HERITABILITY; TRAITS; ACHIEVEMENT; IQ AB Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample(1,2) of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases. C1 [Okbay, Aysu; Rietveld, Cornelius A.; de Vlaming, Ronald; Thurik, A. Roy] Erasmus Univ, Erasmus Sch Econ, Dept Appl Econ, NL-3062 PA Rotterdam, Netherlands. [Okbay, Aysu; Rietveld, Cornelius A.; de Vlaming, Ronald; van der Lee, Sven J.; Amin, Najaf; van Rooij, Frank J. A.; van Duijn, Cornelia M.; Tiemeier, Henning; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Okbay, Aysu; Rietveld, Cornelius A.; Meddens, S. Fleur W.; de Vlaming, Ronald; Palotie, Aarno; Thurik, A. Roy; Koellinger, Philipp D.] Erasmus Univ, Inst Behav & Biol, NL-3062 PA Rotterdam, Netherlands. [Beauchamp, Jonathan P.; Turley, Patrick; Rostapshova, Olga; Laibson, David I.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Fontana, Mark Alan; Benjamin, Daniel J.] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA 90089 USA. [Lee, James J.; Miller, Michael B.; Iacono, William G.; McGue, Matt; Krueger, Robert F.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA. [Pers, Tune H.; Hofman, Albert; Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Pers, Tune H.; Hofman, Albert; Esko, Tonu] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA. [Pers, Tune H.; Timshel, Pascal; Westra, Harm-Jan; de Jager, Philip L.; Esko, Tonu] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Pers, Tune H.; Ahluwalia, Tarunveer S.; Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen, Denmark. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Chen, Guo-Bo; Zhu, Zhihong; Bakshi, Andrew; Marioni, Riccardo E.; Vinkhuyzen, Anna A. E.; Gratten, Jacob; Yang, Jian; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Emilsson, Valur; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Emilsson, Valur] Univ Iceland, Fac Pharmaceut Sci, IS-107 Reykjavik, Iceland. [Meddens, S. Fleur W.; de Leeuw, Christiaan; Posthuma, Danielle; Koellinger, Philipp D.] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, NL-1081 HV Amsterdam, Netherlands. [Meddens, S. Fleur W.; Lebreton, Mael P.; Koellinger, Philipp D.] Univ Amsterdam, Amsterdam Business Sch, NL-1018 TV Amsterdam, Netherlands. [Oskarsson, Sven; Lindgren, Karl-Oskar] Uppsala Univ, Dept Govt, S-75120 Uppsala, Sweden. [Pickrell, Joseph K.] New York Genome Ctr, New York, NY 10013 USA. [Thom, Kevin; Cesarini, David] NYU, Dept Econ, New York, NY 10003 USA. [Timshel, Pascal] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Abdellaoui, Abdel; Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Ahluwalia, Tarunveer S.; Waage, Johannes; Bisgaard, Hans] Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood, COPSAC, DK-2820 Copenhagen, Denmark. [Ahluwalia, Tarunveer S.; Waage, Johannes] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Bacelis, Jonas; Jacobsson, Bo] Sahlgrens Acad, Inst Clin Sci, Dept Obstet & Gynecol, S-41685 Gothenburg, Sweden. [Baumbach, Clemens; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Baumbach, Clemens; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Brandsma, Johannes H.; Poot, Raymond A.] Erasmus MC, Dept Cell Biol, NL-3015 CN Rotterdam, Netherlands. [Concas, Maria Pina; Pirastu, Mario] Natl Res Council Italy, UOS Sassari, Ist Ric Genet & Biomed, I-07100 Sassari, Italy. [Derringer, Jaime] Univ Illinois, Psychol, Champaign, IL 61820 USA. [Furlotte, Nicholas A.; Hinds, David A.; Tung, Joyce Y.] 23andMe Inc, Mountain View, CA 94041 USA. [Galesloot, Tessel E.; Kiemeney, Lambertus A. L. M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6500 HB Nijmegen, Netherlands. [Girotto, Giorgia; Vuckovic, Dragana; Gandin, Ilaria; Gasparini, Paolo; Pirastu, Nicola] Univ Trieste, Dept Med Surg & Hlth Sci, I-34100 Trieste, Italy. [Gupta, Richa; Latvala, Antti; Loukola, Anu; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Hall, Leanne M.; Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Hall, Leanne M.; Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Harris, Sarah E.; Davies, Gail; Liewald, David C. M.; Marioni, Riccardo E.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Harris, Sarah E.; Porteous, David J.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Hofer, Edith; Petrovic, Katja E.; Schmidt, Helena; Schmidt, Reinhold] Gen Hosp, Dept Neurol, A-8036 Graz, Austria. [Hofer, Edith; Petrovic, Katja E.; Schmidt, Helena; Schmidt, Reinhold] Med Univ Graz, A-8036 Graz, Austria. [Hofer, Edith] Gen Hosp, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria. [Horikoshi, Momoko] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England. [Horikoshi, Momoko] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Huffman, Jennifer E.; Marten, Jonathan; Hayward, Caroline; Vitart, Veronique; Wilson, James F.; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Kaasik, Kadri; Lahti, Jari; Keltigangas-Jarvinen, Liisa; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, FIN-00014 Helsinki, Finland. [Kalafati, Ioanna P.; Dedoussis, George V.] Harokopio Univ, Nutr & Dietet, Hlth Sci & Educ, Athens 17671, Greece. [Karlsson, Robert; Lichtenstein, Paul; Pedersen, Nancy L.; Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Lahti, Jari; Raikkonen, Katri; Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki 00014, Finland. [de Leeuw, Christiaan] Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 EC Nijmegen, Netherlands. [Lind, Penelope A.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Quantitat Genet, Brisbane, Qld 4029, Australia. [Liu, Tian] Max Planck Inst Human Dev, Lifespan Psychol, D-14195 Berlin, Germany. [Mangino, Massimo; Quaye, Lydia; Venturini, Cristina; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Mangino, Massimo; Venturini, Cristina] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London SE1 7EH, England. [Mihailov, Evelin; Pervjakova, Natalia; Magi, Reedik; Milani, Lili; Metspalu, Andres; Perola, Markus; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [van der Most, Peter J.; Alizadeh, Behrooz Z.; Vonk, Judith M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Oldmeadow, Christopher; Holliday, Elizabeth G.; Attia, John R.] Hunter Med Res Inst, Publ Hlth Stream, New Lambton, NSW 2305, Australia. [Oldmeadow, Christopher; Holliday, Elizabeth G.; Scott, Rodney J.] Univ Newcastle, Fac Hlth & Med, Newcastle, NSW 2300, Australia. [Payton, Antony; Ollier, William E. R.; Attia, John R.] Univ Manchester, Inst Populat Hlth, Ctr Integrated Genom Med Res, Manchester M13 9PT, Lancs, England. [Payton, Antony] Univ Manchester, Sch Psychol Sci, Human Commun & Deafness, Manchester M13 9PL, Lancs, England. [Pervjakova, Natalia; Eklund, Niina; Koskinen, Seppo; Maki-Opas, Tomi; Salomaa, Veikko; Kaprio, Jaakko; Perola, Markus] THL Natl Inst Hlth & Welf, Dept Hlth, Helsinki 00271, Finland. [Peyrot, Wouter J.; Milaneschi, Yusplitri; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, Psychiat, NL-1081 HL Amsterdam, Netherlands. [Peyrot, Wouter J.; Milaneschi, Yusplitri; Penninx, Brenda W. J. H.] GGZ inGeest, NL-1081 HL Amsterdam, Netherlands. [Qian, Yong; Ding, Jun; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20521, Finland. [Rueedi, Rico; Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Rueedi, Rico; Kutalik, Zoltan] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Salvi, Erika; Cusi, Daniele] Univ Milan, Dept Hlth Sci, I-20142 Milan, Italy. [Schmidt, Brge; Eisele, Lewin; Jockel, Karl-Heinz] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, D-45147 Essen, Germany. [Schraut, Katharina E.; Campbell, Harry; Joshi, Peter K.; Rudan, Igor; Polasek, Ozren; Wilson, James F.] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Smith, Albert V.] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [St Pourcain, Beate; Evans, David M.; McMahon, George; Paternoster, Lavinia; Ring, Susan M.; Sorensen, Thorkild I. 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[Lehrer, Steven F.] Queens Univ, Policy Studies, Kingston, ON K7L 3N6, Canada. [Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia. [Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Pendleton, Neil] Salford Royal Hosp, Inst Brain Behav & Mental Hlth, Ctr Clin & Cognit Neurosci, Manchester M6 8HD, Lancs, England. [Pendleton, Neil] Univ Manchester, Manchester Inst Collaborat Res Ageing, Manchester M13 9PL, Lancs, England. [Polasek, Ozren] Univ Split, Fac Med, Split 21000, Croatia. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1081 HV Amsterdam, Netherlands. [Sorensen, Thorkild I. A.] Bispebjerg Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [Sorensen, Thorkild I. A.] Frederiksberg Univ Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [Thurik, A. Roy] Montpellier Business Sch, F-34080 Montpellier, France. [Thurik, A. Roy] Panteia, NL-2715 CA Zoetermeer, Netherlands. [Tiemeier, Henning] Erasmus MC, Dept Psychiat, NL-3015 GE Rotterdam, Netherlands. [Tiemeier, Henning] Erasmus MC, Dept Child & Adolescent Psychiat, NL-3015 GE Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Conley, Dalton C.] NYU, Dept Sociol, 550 1St Ave, New York, NY 10012 USA. [Conley, Dalton C.] NYU, Sch Med, 550 1St Ave, New York, NY 10016 USA. [Meyer, Michelle N.] Icahn Sch Med Mt Sinai, Grad Coll, Bioeth Program, Schenectady, NY 12308 USA. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Cesarini, David] Res Inst Ind Econ, S-10215 Stockholm, Sweden. RP Koellinger, PD (reprint author), Erasmus Univ, Inst Behav & Biol, NL-3062 PA Rotterdam, Netherlands.; Benjamin, DJ (reprint author), Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA 90089 USA.; Visscher, PM (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.; Koellinger, PD (reprint author), Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, NL-1081 HV Amsterdam, Netherlands.; Koellinger, PD (reprint author), Univ Amsterdam, Amsterdam Business Sch, NL-1018 TV Amsterdam, Netherlands.; Cesarini, D (reprint author), NYU, Dept Econ, New York, NY 10003 USA.; Visscher, PM (reprint author), Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia.; Cesarini, D (reprint author), Res Inst Ind Econ, S-10215 Stockholm, Sweden. EM peter.visscher@uq.edu.au; p.d.koellinger@vu.nl; dac12@nyu.edu; daniel.benjamin@gmail.com RI Verweij, Niek/A-4499-2017; Thurik, Roy/A-9386-2012; Davey Smith, George/A-7407-2013; Magnusson, Patrik/C-4458-2017; Gratten, Jake (Jacob)/G-1485-2011; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; mangino, massimo/F-5134-2011; Franke, Barbara/D-4836-2009; Franke, Lude/P-7036-2016; Staessen, Jan/A-1065-2011; Yang, Jian/A-5852-2010; Ormel, Johan/C-6094-2013; Wijmenga, Cisca/D-2173-2009; Fox, Laura /C-6249-2016; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; Bisgaard, Hans/N-4761-2016; Bertram, Lars/K-3889-2015; Johannesson, Magnus/E-9680-2011 OI Hypponen, Elina/0000-0003-3670-9399; Chen, Guo-Bo/0000-0001-5475-8237; Payton, Antony/0000-0003-0335-152X; Vinkhuyzen, Anna/0000-0003-3352-0603; Bacelis, Jonas/0000-0002-2450-732X; Smith, Blair/0000-0002-5362-9430; Evans, David/0000-0003-0663-4621; Kaprio, Jaakko/0000-0002-3716-2455; Smith, Jennifer/0000-0002-3575-5468; Medland, Sarah/0000-0003-1382-380X; Timpson, Nicholas/0000-0002-7141-9189; Ware, Erin/0000-0003-4731-8158; Lahti, Jari/0000-0002-4310-5297; Halldorsson, Bjarni/0000-0003-0756-0767; Gupta, Richa/0000-0001-7700-5828; Maki-Opas, Tomi/0000-0002-0472-719X; Loukola, Anu-Maria/0000-0003-0542-5967; Meisinger, Christa/0000-0002-9026-6544; Bakshi, Andrew/0000-0001-5650-7036; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Salvi, Erika/0000-0002-2724-2291; vozzi, diego/0000-0002-2902-8184; Girotto, Giorgia/0000-0003-4507-6589; Thurik, Roy/0000-0002-0242-6908; Davey Smith, George/0000-0002-1407-8314; Gratten, Jake (Jacob)/0000-0003-1293-409X; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Cesarini, David/0000-0002-0043-009X; Verweij, Niek/0000-0002-4303-7685; Pendleton, Neil/0000-0003-0794-2386; Gieger, Christian/0000-0001-6986-9554; mangino, massimo/0000-0002-2167-7470; Franke, Barbara/0000-0003-4375-6572; Franke, Lude/0000-0002-5159-8802; Staessen, Jan/0000-0002-3026-1637; Yang, Jian/0000-0003-2001-2474; Deloukas, Panos/0000-0001-9251-070X; Bisgaard, Hans/0000-0003-4131-7592; Bertram, Lars/0000-0002-0108-124X; Johannesson, Magnus/0000-0001-8759-6393 FU Social Science Genetic Association Consortium (SSGAC); Ragnar Soderberg Foundation [E9/11]; Swedish Research Council [421-2013-1061]; Jan Wallander and Tom Hedelius Foundation; ERC [647648 EdGe]; Pershing Square Fund of the Foundations of Human Behavior; NIA/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23, R01-AG042568] FX This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC). This research has also been conducted using the UK Biobank Resource. This study was supported by funding from the Ragnar Soderberg Foundation (E9/11), the Swedish Research Council (421-2013-1061), The Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to NBER, and R01-AG042568 to USC. We thank S. Cunningham, N. Galla and J. Rashtian for research assistance. A full list of acknowledgments is provided in the Supplementary Information. NR 16 TC 36 Z9 36 U1 33 U2 69 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 MAY 26 PY 2016 VL 533 IS 7604 BP 539 EP + DI 10.1038/nature17671 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6EJ UT WOS:000376443100042 PM 27225129 ER PT J AU Li, ZF Alyamani, M Li, JN Rogacki, K Abazeed, M Upadhyay, SK Balk, SP Taplin, ME Auchus, RJ Sharifi, N AF Li, Zhenfei Alyamani, Mohammad Li, Jianneng Rogacki, Kevin Abazeed, Mohamed Upadhyay, Sunil K. Balk, Steven P. Taplin, Mary-Ellen Auchus, Richard J. Sharifi, Nima TI Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy SO NATURE LA English DT Article ID ANDROGEN-RECEPTOR; STEROID 5-ALPHA-REDUCTASE; CYP17A1 INHIBITION; DIHYDROTESTOSTERONE; DEHYDROGENASE; CELLS; ACTIVATION; RESISTANCE; BIOLOGY; RAT AB Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis(1,2). Abiraterone is metabolized in patients to Delta(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5 alpha-reductase substrates, such as testosterone(3). Here, we show that D4A is converted to at least three 5 alpha-reduced and three 5 beta-reduced metabolites in human serum. The initial 5 alpha-reduced metabolite, 3-keto-5 alpha-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5 alpha-reductase inhibitor), 3-keto-5 alpha-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5 beta-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5 alpha-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy. C1 [Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Sharifi, Nima] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. [Rogacki, Kevin; Abazeed, Mohamed] Cleveland Clin, Taussig Canc Inst, Dept Radiat Oncol, Cleveland, OH 44195 USA. [Upadhyay, Sunil K.; Auchus, Richard J.] Univ Michigan, Sch Med, Dept Pharmacol, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA. [Upadhyay, Sunil K.; Auchus, Richard J.] Univ Michigan, Sch Med, Dept Internal Med, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA. [Balk, Steven P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Taplin, Mary-Ellen] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Sharifi, Nima] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44195 USA. [Sharifi, Nima] Cleveland Clin, Taussig Canc Inst, Dept Hematol & Oncol, Cleveland, OH 44195 USA. RP Sharifi, N (reprint author), Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA.; Sharifi, N (reprint author), Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44195 USA.; Sharifi, N (reprint author), Cleveland Clin, Taussig Canc Inst, Dept Hematol & Oncol, Cleveland, OH 44195 USA. EM sharifn@ccf.org FU Howard Hughes Medical Institute; Prostate Cancer Foundation; American Cancer Society [12-038-01-CCE]; National Cancer Institute [R01CA168899, R01CA172382, R01CA190289, P01 CA163227, P50 CA090381]; US Army Medical Research and Materiel Command [PC121382] FX We thank T. Penning for use of the AKR1C2 construct and D. Russell for LY191704. This work was supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award (12-038-01-CCE; to N.S.), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289; to N.S.), a grant from the US Army Medical Research and Materiel Command (PC121382 to Z.L.), a Prostate Cancer Foundation Young Investigator Award (to Z.L.), grants from the National Cancer Institute (P01 CA163227 and P50 CA090381), and a Prostate Cancer Foundation Challenge Award (to S.P.B.). Janssen provided clinical trial support (to M.-E.T.). NR 31 TC 4 Z9 4 U1 6 U2 11 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 MAY 26 PY 2016 VL 533 IS 7604 BP 547 EP + DI 10.1038/nature17954 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6EJ UT WOS:000376443100044 PM 27225130 ER PT J AU Moye, J AF Moye, Jennifer TI Supporting Older Adults and Families with Transitions to Long-Term Care and with Insomnia SO CLINICAL GERONTOLOGIST LA English DT Editorial Material C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA USA. [Moye, Jennifer] Harvard Univ, Sch Med, Boston, MA USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Boston, MA USA.; Moye, J (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM Jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 4 TC 0 Z9 0 U1 0 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PD MAY 26 PY 2016 VL 39 IS 3 BP 165 EP 166 DI 10.1080/07317115.2016.1152943 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DH6VT UT WOS:000372930900001 ER PT J AU O'Connell, DJ Kolde, R Sooknah, M Graham, DB Sundberg, TB Latorre, IJ Mikkelsen, TS Xavier, RJ AF O'Connell, Daniel J. Kolde, Raivo Sooknah, Matthew Graham, Daniel B. Sundberg, Thomas B. Latorre, Isabel J. Mikkelsen, Tarjei S. Xavier, Ramnik J. TI Simultaneous Pathway Activity Inference and Gene Expression Analysis Using RNA Sequencing SO CELL SYSTEMS LA English DT Article ID CELL-DIFFERENTIATION; ENRICHMENT ANALYSIS; CHIP DATA; PARALLEL; TRANSCRIPTION; REGULATORS; CHROMATIN; HALOFUGINONE; MACROPHAGES; ACTIVATION AB Reporter gene assays are a venerable tool for studying signaling pathways, but they lack the throughput and complexity necessary to contribute to a systems-level understanding of endogenous signaling networks. We present a parallel reporter assay, transcription factor activity sequencing (TF-seq), built on synthetic DNA enhancer elements, which enables parallel measurements in primary cells of the transcriptome and transcription factor activity from more than 40 signaling pathways. Using TF-seq in Myd88 (-/-) macrophages, we captured dynamic pathway activity changes underpinning the global transcriptional changes of the innate immune response. We also applied TF-seq to investigate small molecule mechanisms of action and find a role for NF-B-k activation and coordination of the STAT1 response in the macrophage reaction to the anti-inflammatory natural product halofuginone. Simultaneous TF-seq and global gene expression profiling represent an integrative approach for gaining mechanistic insight into pathway activity and transcriptional changes that result from genetic and small molecule perturbations. C1 [O'Connell, Daniel J.; Sooknah, Matthew; Graham, Daniel B.; Latorre, Isabel J.; Xavier, Ramnik J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Kolde, Raivo; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Sundberg, Thomas B.; Xavier, Ramnik J.] Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Mikkelsen, Tarjei S.] Broad Inst, Broad Technol Labs, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Mikkelsen, Tarjei S.] 10X Genom Inc, Pleasanton, CA 94566 USA. RP Xavier, RJ (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu OI Latorre, Isabel/0000-0003-0638-1783 FU LeonaM. and Harry B. Helmsley Charitable Trust; NIH [DK43351, DK097485, AI109725] FX We thank Natalia Nedelsky, Kara Lassen, Hera Vlamakis, and members of the R.J.X. laboratory for critical comments. We thank Jean Wilson of the Albert C. Shaw laboratory for genotyping, harvesting, and shipping Myd88 knockout bones. We thank Luke O'Neill and Annie Curtis for their helpful comments. R.J.X. was supported by The LeonaM. and Harry B. Helmsley Charitable Trust and NIH DK43351, DK097485, and AI109725. NR 49 TC 1 Z9 1 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD MAY 25 PY 2016 VL 2 IS 5 BP 323 EP 334 DI 10.1016/j.cels.2016.04.011 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL1DG UT WOS:000394360100007 PM 27211859 ER PT J AU Bruccoleri, RE Matthew, MK Schulz, JT AF Bruccoleri, Rebecca E. Matthew, Michael K. Schulz, John T. TI Methods in obtaining split-thickness skin grafts from skin reduction surgery specimens SO SPRINGERPLUS LA English DT Article DE Living donor; Skin graft; Abdominoplasty; Dermatome AB Background: To devise a method for obtaining bacterial culture-negative split-thickness skin grafts from specimens removed from living donors undergoing skin reduction surgery. Methods: Specimens were obtained from patients undergoing abdominal skin reduction surgery in inpatient and outpatient surgical settings. Skin specimens were cleaned in a method adapted from the former Yale Skin Bank's methods. The specimens were attached to the autoclave container for the dermatome using towel clips or sutures to provide tension. Normal saline clysis was injected subdermally and a Padgett Electric Dermatome was used to obtain skin grafts. These were then photographed and discarded. Results: Eight specimens were obtained from seven women and one man. The mean age was 46.6 years and mean weight at time of surgery was 87.7 kg. Bacterial cultures obtained from all specimens were negative. All procured grafts were transparent, with visible dermis, suggesting that they could be used in a clinical setting. Conclusion: Bacterial culture-negative split-thickness skin grafts can be obtained from skin reduction surgery specimens, offering a potential source of split-thickness allograft during regional or national shortages. C1 [Bruccoleri, Rebecca E.] Yale New Haven Med Ctr, Dept Emergency Med, 464 Congress Ave,Ste 260, New Haven, CT 06519 USA. [Matthew, Michael K.] Dartmouth Hitchcock Med Ctr, Dept Plast Surg, One Med Ctr Dr, Lebanon, NH 03750 USA. [Schulz, John T.] Massachusetts Gen Hosp, Sumner Redstone Burn Ctr, 55 Fruit St, Boston, MA 02115 USA. RP Bruccoleri, RE (reprint author), Yale New Haven Med Ctr, Dept Emergency Med, 464 Congress Ave,Ste 260, New Haven, CT 06519 USA. EM Rebecca.Bruccoleri@childrens.harvard.edu FU Office of Student Research at Yale School of Medicine FX This study was funded in part by the Office of Student Research at Yale School of Medicine through the Short Term Research Stipend in January 2009. NR 10 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD MAY 25 PY 2016 VL 5 AR 690 DI 10.1186/s40064-016-2330-2 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO2LH UT WOS:000377610900001 PM 27350924 ER PT J AU Garza, JL Mittleman, MA Zhang, JM Christiani, DC Cavallari, JM AF Garza, Jennifer L. Mittleman, Murray A. Zhang, Jinming Christiani, David C. Cavallari, Jennifer M. TI Time Course of Heart Rate Variability Response to PM2.5 Exposure from Secondhand Smoke SO PLOS ONE LA English DT Article ID ENVIRONMENTAL TOBACCO-SMOKE; PARTICULATE AIR-POLLUTION; CARDIOVASCULAR-DISEASE; ASSOCIATION; WORKERS; HEALTH AB Purpose: Exposure to secondhand smoke (SHS) has been associated with decreased heart rate variability (HRV). However, the time course of this association is unclear. Therefore, the objective of this study was to investigate the association between 15-240 minute SHS-related fine particulate matter (PM2.5) moving averages and indices of HRV. Methods: With a panel study design, we used personal monitors to continuously measure PM2.5 and HRV of 35 participants who were exposed to SHS for approximately 6 hours. Results: We observed negative, significant associations between 5-minute HRV indices and 15 minute PM2.5 moving averages and 240 minute PM2.5 moving averages: there was a significant (p<0.01) 7.5% decrease in the 5-minute square root of the mean squared differences of successive normal heart beats associated with (RMSSD), and a significant (p<0.01) 14.7% decrease in the 5-minute high frequency (HF) power associated with the 15 minute PM2.5 moving averages; there was also a significant (p<0.01) 46.9% decrease in the 5-minute RMSSD, and a significant (p<0.01) 77.7% decrease in the 5-minute high frequency (HF) power associated with the 240 minute PM2.5 moving averages. Conclusions: Our findings that exposure to SHS related PM2.5 was associated with HRV support the hypothesis that SHS can affect the cardiovascular system. The negative associations reported between short and longer term PM2.5 and HRV indicate adverse effects of SHS on the cardiovascular system. C1 [Garza, Jennifer L.; Cavallari, Jennifer M.] UConn Hlth, Div Occupat & Environm Med, Farmington, CT USA. [Mittleman, Murray A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mittleman, Murray A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Zhang, Jinming; Christiani, David C.; Cavallari, Jennifer M.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Cavallari, JM (reprint author), UConn Hlth, Div Occupat & Environm Med, Farmington, CT USA.; Cavallari, JM (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. EM Cavallari@uchc.edu FU Flight Attendants Medical Research Institute [YCSA2009-82114]; Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources) [UL1 TR001102]; Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers FX This study was funded by the Flight Attendants Medical Research Institute (FAMRI.org) through a Young Clinical Scientist Award (Cavallari - YCSA2009-82114). This work was conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 25 PY 2016 VL 11 IS 5 AR e0154783 DI 10.1371/journal.pone.0154783 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2GI UT WOS:000376881700009 PM 27223894 ER PT J AU Sarathy, H Henriquez, G Abramowitz, MK Kramer, H Rosas, SE Johns, T Kumar, J Skversky, A Kaskel, F Melamed, ML AF Sarathy, Harini Henriquez, Gabriela Abramowitz, Matthew K. Kramer, Holly Rosas, Sylvia E. Johns, Tanya Kumar, Juhi Skversky, Amy Kaskel, Frederick Melamed, Michal L. TI Abdominal Obesity, Race and Chronic Kidney Disease in Young Adults: Results from NHANES 1999-2010 SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; GLOMERULAR-FILTRATION-RATE; ALL-CAUSE MORTALITY; TO-HIP RATIO; CARDIOVASCULAR-DISEASE; WAIST CIRCUMFERENCE; METABOLIC SYNDROME; US ADULTS; RENAL HEMODYNAMICS; DIABETES-MELLITUS AB Objective Kidney dysfunction in obesity may be independent of and may precede the development of hypertension and/or diabetes mellitus. We aimed to examine if abdominal obesity is associated with early markers of CKD in a young healthy population and whether these associations differ by race and/or ethnicity. Methods We analyzed data from the NHANES 1999-2010 for 6918 young adults ages 20-40 years. Abdominal obesity was defined by gender criteria of waist circumference. CKD markers included estimated glomerular filtration rate and albuminuria >= 30 mg/g. Race stratified analyses were done overall and in subgroups with normal blood pressures, normoglycemia and normal insulin sensitivity. Awareness of CKD was assessed in participants with albuminuria. Results Abdominal obesity was present in over one-third of all young adults and was more prevalent among non-Hispanic blacks (45.4%) versus Mexican-Americans (40.6%) or non-Hispanic whites (37.4%) (P-value = 0.004). Mexican-American young adults with abdominal obesity had a higher odds of albuminuria even among those with normal blood pressure, normal glucose, and normal insulin sensitivity [adjusted odds ratio 4.5; 95% confidence interval (1.6-12.2), p = 0.004]. Less than 5% of young adults with albuminuria of all races and ethnicities had been told they had kidney disease. Conclusion Abdominal obesity in young adults, especially in Mexican-Americans, is independently associated with albuminuria even with normal blood pressures, normoglycemia and normal insulin levels. Greater awareness of CKD is needed to protect this young population from long-standing exposure to abdominal obesity and early progressive renal disease. C1 [Sarathy, Harini; Henriquez, Gabriela; Abramowitz, Matthew K.; Johns, Tanya; Melamed, Michal L.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Henriquez, Gabriela; Skversky, Amy; Kaskel, Frederick] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Abramowitz, Matthew K.; Melamed, Michal L.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Kramer, Holly] Loyola Univ, Hlth Sci Ctr, Div Nephrol & Hypertens, Dept Publ Hlth Sci, Maywood, IL 60153 USA. [Kramer, Holly] Loyola Univ, Hlth Sci Ctr, Div Nephrol & Hypertens, Dept Med, Maywood, IL 60153 USA. [Rosas, Sylvia E.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Rosas, Sylvia E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kumar, Juhi] Weill Cornell Med Ctr, Dept Pediat, New York, NY USA. RP Melamed, ML (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA.; Melamed, ML (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. EM michal.melamed@einstein.yu.edu FU NIH [T32 DK 007110, K23 DK084339, K23 DK099438, R01 DK102952, R34 DK102174]; American Society of Nephrology (ASN Foundation for Kidney Research) FX This project was supported in part by NIH grants T32 DK 007110 (GH and AS), K23 DK084339 (JK), K23 DK099438 (MKA), R01 DK102952 (MLM) and R34 DK102174 (MLM). The project was also supported in part by Gottschalk Awards from the American Society of Nephrology (ASN Foundation for Kidney Research). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 51 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 MAY 25 PY 2016 VL 11 IS 5 AR e0153588 DI 10.1371/journal.pone.0153588 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN2GI UT WOS:000376881700004 PM 27224643 ER PT J AU Kumar, DKV Choi, SH Washicosky, KJ Eimer, WA Tucker, S Ghofrani, J Lefkowitz, A McColl, G Goldstein, LE Tanzi, RE Moir, RD AF Kumar, Deepak Kumar Vijaya Choi, Se Hoon Washicosky, Kevin J. Eimer, William A. Tucker, Stephanie Ghofrani, Jessica Lefkowitz, Aaron McColl, Gawain Goldstein, Lee E. Tanzi, Rudolph E. Moir, Robert D. TI Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ANTIMICROBIAL PEPTIDE; PRECURSOR PROTEIN; CAENORHABDITIS-ELEGANS; BALB/C MICE; BRAIN; EXPRESSION; CELLS; A-BETA(1-42); MUTATIONS; BINDING AB The amyloid-beta peptide (A beta) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting that A beta is an antimicrobial peptide. We present in vivo data showing that A beta expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that A beta oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble A beta oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating beta-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated beta-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that beta-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for A beta, as has been described for other antimicrobial peptides. C1 [Kumar, Deepak Kumar Vijaya; Choi, Se Hoon; Washicosky, Kevin J.; Eimer, William A.; Tucker, Stephanie; Ghofrani, Jessica; Lefkowitz, Aaron; Tanzi, Rudolph E.; Moir, Robert D.] Massachusetts Gen Hosp, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA 02129 USA. [Kumar, Deepak Kumar Vijaya; Choi, Se Hoon; Washicosky, Kevin J.; Eimer, William A.; Tucker, Stephanie; Ghofrani, Jessica; Lefkowitz, Aaron; Tanzi, Rudolph E.; Moir, Robert D.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [McColl, Gawain] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. [Goldstein, Lee E.] Boston Univ, Dept Psychiat, Boston, MA 02215 USA. RP Tanzi, RE; Moir, RD (reprint author), Massachusetts Gen Hosp, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA 02129 USA.; Tanzi, RE; Moir, RD (reprint author), Harvard Univ, Sch Med, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu; moir@helix.mgh.harvard.edu FU NIH [5R01AI081990-02]; Cure Alzheimer's Fund; Helmsley Charitable Trust FX This work was supported by grants from NIH (5R01AI081990-02), the Cure Alzheimer's Fund, and The Helmsley Charitable Trust. NR 73 TC 25 Z9 25 U1 24 U2 52 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 MAY 25 PY 2016 VL 8 IS 340 AR 340ra72 DI 10.1126/scitranslmed.aaf1059 PG 15 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DM6NC UT WOS:000376468600002 PM 27225182 ER PT J AU Klein, K McClure, EM Colaci, D Thorsten, V Hibberd, PL Esamai, F Garces, A Patel, A Saleem, S Pasha, O Chomba, E Carlo, WA Krebs, NF Goudar, S Derman, RJ Liechty, EA Koso-Thomas, M Buekens, PM Belizan, JM Goldenberg, RL Althabe, F AF Klein, Karen McClure, Elizabeth M. Colaci, Daniela Thorsten, Vanessa Hibberd, Patricia L. Esamai, Fabian Garces, Ana Patel, Archana Saleem, Sarah Pasha, Omrana Chomba, Elwyn Carlo, Waldemar A. Krebs, Nancy F. Goudar, Shivaprasad Derman, Richard J. Liechty, Edward A. Koso-Thomas, Marion Buekens, Pierre M. Belizan, Jose M. Goldenberg, Robert L. Althabe, Fernando TI The Antenatal Corticosteroids Trial (ACT): a secondary analysis to explore site differences in a multi-country trial SO REPRODUCTIVE HEALTH LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; MIDDLE-INCOME COUNTRIES; NEWBORN HEALTH REGISTRY; PRETERM BIRTH; PREMATURE-INFANTS; GLOBAL-NETWORK; INTERVENTIONS; PREVENTION; MORTALITY; SURVIVAL AB Background: The Antenatal Corticosteroid Trial (ACT) assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but had no overall impact on neonatal mortality in the targeted < 5th percentile birth weight infants. Being in the intervention clusters was also associated with an overall increase in neonatal deaths. We sought to explore plausible pathways through which this intervention increased neonatal mortality. Methods: We conducted secondary analyses to assess site differences in outcome and potential explanations for the differences in outcomes if found. By site, and in the intervention and control clusters, we evaluated characteristics of the mothers and care systems, the proportion of the < 5th percentile infants and the overall population that received ACS, the rates of possible severe bacterial infection (pSBI), determined from clinical signs, and neonatal mortality rates. Results: There were substantial differences between the sites in both participant and health system characteristics, with Guatemala and Argentina generally having the highest levels of care. In some sites there were substantial differences in the health system characteristics between the intervention and control clusters. The increase in ACS in the intervention clusters was similar among the sites. While overall, there was no difference in neonatal mortality among < 5th percentile births between the intervention and control clusters, Guatemala and Pakistan both had significant reductions in neonatal mortality in the < 5th percentile infants in the intervention clusters. The improvement in neonatal mortality in the Guatemalan site in the < 5th percentile infants was associated with a higher level of care at the site and an improvement in care in the intervention clusters. There was a significant increase overall in neonatal mortality in the intervention clusters compared to the control. Across sites, this increase in neonatal mortality was statistically significant and most apparent in the African sites. This increase in neonatal mortality was accompanied by a significant increase in pSBI in the African sites. Conclusions: The improvement in neonatal mortality in the Guatemalan site in the < 5th percentile infants was associated with a higher level of care and an improvement in care in the intervention clusters. The increase in neonatal mortality in the intervention clusters across all sites was largely driven by the poorer outcomes in the African sites, which also had an increase in pSBI in the intervention clusters. We emphasize that these results come from secondary analyses. Additional prospective studies are needed to assess the effectiveness and safety of ACS on neonatal health in low resource settings. C1 [Klein, Karen; Colaci, Daniela; Belizan, Jose M.; Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [McClure, Elizabeth M.; Thorsten, Vanessa] RTI Int, Durham, NC USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Garces, Ana] Fdn Alimentac & Nut Ctr Amer & Panama, Guatemala City, Guatemala. [Patel, Archana] Indira Gandhi Govt Med Coll, Lata Med Res Fdn, Nagpur, Maharashtra, India. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Goudar, Shivaprasad] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Derman, Richard J.] Christiana Hlth Care, Newark, DE USA. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP Klein, K (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. EM kklein@iecs.org.ar FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636]; Bill & Melinda Gates Foundation; World Health Organization FX This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). FA, JB and KK also received funding from the Bill & Melinda Gates Foundation. Study support was also provided by the World Health Organization. Supplies were donated by Becton Dickson. NR 18 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD MAY 24 PY 2016 VL 13 AR 64 DI 10.1186/s12978-016-0179-z PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP6NP UT WOS:000378614100001 PM 27221319 ER PT J AU Wang, JM Papanicolau-Sengos, A Chintala, S Wei, L Liu, BA Hu, Q Miles, KM Conroy, JM Glenn, ST Costantini, M Magi-Galluzzi, C Signoretti, S Choueiri, T Gallucci, M Sentinelli, S Fazio, VM Poeta, ML Liu, S Morrison, C Pili, R AF Wang, Jianmin Papanicolau-Sengos, Antonios Chintala, Sreenivasulu Wei, Lei Liu, Biao Hu, Qiang Miles, Kiersten Marie Conroy, Jeffrey M. Glenn, Sean T. Costantini, Manuela Magi-Galluzzi, Cristina Signoretti, Sabina Choueiri, Toni Gallucci, Michele Sentinelli, Steno Fazio, Vito M. Poeta, Maria Luana Liu, Song Morrison, Carl Pili, Roberto TI Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation SO ONCOTARGET LA English DT Article DE collecting duct carcinoma; CDKN2A; solute carrier family genes ID RENAL-CELL CARCINOMA; AMINO-ACID TRANSPORTER; TRIPLE-HELIX REPEAT; OF-THE-LITERATURE; CYSTINE/GLUTAMATE ANTIPORTER; CISPLATIN RESISTANCE; MOLECULAR-MECHANISMS; THERAPEUTIC TARGETS; COLORECTAL-CANCER; PANCREATIC-CANCER AB The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 -7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL, which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53, and ZNF521. SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies. C1 [Wang, Jianmin; Wei, Lei; Liu, Biao; Hu, Qiang; Liu, Song] Roswell Pk Canc Inst, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA. [Papanicolau-Sengos, Antonios; Miles, Kiersten Marie; Conroy, Jeffrey M.; Morrison, Carl] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Papanicolau-Sengos, Antonios; Miles, Kiersten Marie; Conroy, Jeffrey M.; Morrison, Carl] Roswell Pk Canc Inst, Ctr Personalized Med, Buffalo, NY 14263 USA. [Chintala, Sreenivasulu; Pili, Roberto] Roswell Pk Canc Inst, Genitourinary Program, Buffalo, NY 14263 USA. [Glenn, Sean T.] Roswell Pk Canc Inst, Canc Genet, Buffalo, NY 14263 USA. [Costantini, Manuela; Gallucci, Michele; Sentinelli, Steno] Regina Elena Natl Canc Inst Rome, Dept Urol, Rome, Italy. [Magi-Galluzzi, Cristina] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Signoretti, Sabina; Choueiri, Toni] Dana Farber, Dept Pathol, Boston, MA USA. [Signoretti, Sabina; Choueiri, Toni] Dana Farber, Kidney Canc Program, Boston, MA USA. [Costantini, Manuela; Fazio, Vito M.] Univ Campus BioMed Rome, Lab Genet & Clin Pathol, Rome, Italy. [Costantini, Manuela; Poeta, Maria Luana] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, Italy. [Chintala, Sreenivasulu; Pili, Roberto] Indiana Univ, Simon Canc Ctr, Genitourinary Program, Indianapolis, IN 46204 USA. RP Pili, R (reprint author), Roswell Pk Canc Inst, Genitourinary Program, Buffalo, NY 14263 USA.; Pili, R (reprint author), Indiana Univ, Simon Canc Ctr, Genitourinary Program, Indianapolis, IN 46204 USA. EM rpili@iu.edu RI Fazio, Vito Michele/H-3007-2016; Gallucci, Michele/K-9600-2016 OI Fazio, Vito Michele/0000-0002-7751-1867; Gallucci, Michele/0000-0002-3637-6531 FU National Cancer Institute at the National Institutes of Health [P30CA016056]; Roswell Park Cancer Institute Alliance Foundation FX This research was supported in part by the National Cancer Institute at the National Institutes of Health (P30CA016056) (R.P.), a grant from the Roswell Park Cancer Institute Alliance Foundation (R.P.), and a donation from the Townson family (R.P.). NR 65 TC 5 Z9 5 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 MAY 24 PY 2016 VL 7 IS 21 BP 29901 EP 29915 DI 10.18632/oncotarget.9093 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4IZ UT WOS:000377746600005 PM 27144525 ER PT J AU Zhang, L Pan, L Xiang, B Zhu, HL Wu, Y Chen, M Guan, PJ Zou, XL Valencia, CA Dong, B Li, JJ Xie, LP Ma, HB Wang, FF Dong, T Shuai, X Niu, T Liu, T AF Zhang, Li Pan, Ling Xiang, Bing Zhu, Huanling Wu, Yu Chen, Meng Guan, Pujun Zou, Xingli Valencia, C. Alexander Dong, Biao Li, Jianjun Xie, Liping Ma, Hongbing Wang, Fangfang Dong, Tian Shuai, Xiao Niu, Ting Liu, Ting TI Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma SO ONCOTARGET LA English DT Article DE myeloma; resistance; exosome; microvesicle; microRNA ID STEM-CELL TRANSPLANTATION; C-REACTIVE-PROTEIN; PLUS DEXAMETHASONE; BORTEZOMIB; MANAGEMENT; INDUCTION; THERAPY; CANCER; PHASE; RETREATMENT AB Multiple myeloma (MM) is the second most common hematologic neoplasms and an appropriate in vivo environment for myeloma cells has potential implications for initiation, progression, and metastasis of MM. Exosomes, entities carrying microRNAs (miRNAs) to target locations, participate in the cross-talk between myeloma cells and nonmalignant components of the in vivo environment. This study disclosed the emerging roles of circulating exosome-associated miRNAs in drug resistance (DR) of MM. To this end, the medical records of consecutively hospitalized MM patients, who received novel agents-based therapies, were analyzed. Then, an optimized procedure was established for exosome isolation and exosomal RNA analysis. The exosome-associated miRNA expression patterns for predicting bortezomib (Bz) resistance of MM were further examined using a microarray. In total, 204 patients were enrolled with DR rates of 36.5%, 73.1% and 81.8% in the bortezomib (Bz), thalidomide and lenalidomide containing groups. The serum total light chain ratio >= 100, CRP >= 20 mg/L, and the second-line usage increased risks of acquired Bz-resistance. Among 68 cases having genetic tests, a high risk factor for predicting de novo DR was 1q21 amplification, which also correlated with lower levels of cholesterol and LDL-C. Moreover, nano-sized exosomes were isolated with significantly increasing internal RNAs and down-regulation of exosomal miR-16-5p, miR-15a-5p and miR-20a-5p, miR-17-5p was revealed in the patients resistant to Bz. The routine workup of MM hardly suggested a value for DR prediction. The circulating exosomes carrying miRNAs provided a window that permits a better understanding of the in vivo intercellular crosstalk in MM patients. C1 [Zhang, Li; Pan, Ling; Xiang, Bing; Zhu, Huanling; Wu, Yu; Chen, Meng; Li, Jianjun; Xie, Liping; Ma, Hongbing; Wang, Fangfang; Dong, Tian; Shuai, Xiao; Niu, Ting; Liu, Ting] Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610064, Peoples R China. [Zhang, Li] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Guan, Pujun] Sichuan Univ, West China Hosp, Dept Radiol, Chengdu 610064, Peoples R China. [Zou, Xingli] North Sichuan Med Coll, Affiliated Hosp, Dept Hematol, Nanchang, Peoples R China. [Valencia, C. Alexander] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Valencia, C. Alexander] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Dong, Biao] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610064, Peoples R China. RP Niu, T; Liu, T (reprint author), Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610064, Peoples R China. EM tingniu1@sina.com; hematologyhuaxi@163.com FU National Natural Science Foundation of China [81302148] FX This work was supported by the National Natural Science Foundation of China for Young Scholars grants 81302148 to Dr. Li Zhang. NR 38 TC 1 Z9 1 U1 7 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 24 PY 2016 VL 7 IS 21 BP 30876 EP 30891 DI 10.18632/oncotarget.9021 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4IZ UT WOS:000377746600079 PM 27129167 ER PT J AU Dykes, SS Gray, AL Coleman, DT Saxena, M Stephens, CA Carroll, JL Pruitt, K Cardelli, JA AF Dykes, Samantha S. Gray, Alana L. Coleman, David T. Saxena, Madhurima Stephens, Charles A. Carroll, Jennifer L. Pruitt, Kevin Cardelli, James A. TI The Arf-like GTPase Arl8b is essential for three-dimensional invasive growth of prostate cancer in vitro and xenograft formation and growth in vivo SO ONCOTARGET LA English DT Article DE Arl8b; lysosome; invasion; xenograft; lipid metabolism ID EXTRACELLULAR-MATRIX DEGRADATION; CATHEPSIN-B ACTIVITY; STEM-CELLS; LYSOSOME TRAFFICKING; TUMOR PROGRESSION; PATHWAYS; COMPLEX; MICROENVIRONMENT; PROTEOLYSIS; METABOLISM AB Cancer is a multistep process that requires cells to respond appropriately to the tumor microenvironment, both in early proliferative stages and in later invasive disease. Arl8b is a lysosome localized Arf-like GTPase that controls the spatial distribution of lysosomes via recruitment of kinesin motors. Common features of the tumor microenvironment such as acidic extracellular pH and various growth factors stimulate lysosome trafficking to the cell periphery (anterograde), which is critical for tumor invasion by facilitating the release of lysosomal proteases to promote matrix remodeling. Herein we report for the first time that Arl8b regulates anterograde lysosome trafficking in response to hepatocyte growth factor, epidermal growth factor, and acidic extracellular pH. Depletion of Arl8b results in juxtanuclear lysosome aggregation, and this effect corresponds with both diminished invasive growth and proteolytic extracellular matrix degradation in a three-dimensional model of prostate cancer. Strikingly, we found that depletion of Arl8b abolishes the ability of prostate cancer cells to establish subcutaneous xenografts in mice. We present evidence that Arl8b facilitates lipid hydrolysis to maintain efficient metabolism for a proliferative capacity in low nutrient environments, suggesting a likely explanation for the complete inability of Arl8b-depleted tumor cells to grow in vivo. In conclusion, we have identified two mechanisms by which Arl8b regulates cancer progression: 1) through lysosome positioning and protease release leading to an invasive phenotype and 2) through control of lipid metabolism to support cellular proliferation. These novel roles highlight that Arl8b is a potential target for the development of novel anti-cancer therapeutics. C1 [Dykes, Samantha S.; Gray, Alana L.; Coleman, David T.; Stephens, Charles A.; Carroll, Jennifer L.; Cardelli, James A.] LSU Hlth Shreveport, Dept Microbiol & Immunol, Shreveport, LA USA. [Dykes, Samantha S.; Gray, Alana L.; Coleman, David T.; Saxena, Madhurima; Carroll, Jennifer L.; Pruitt, Kevin; Cardelli, James A.] LSU Hlth Shreveport, Feist Weiller Canc Ctr, Shreveport, LA USA. [Saxena, Madhurima; Pruitt, Kevin] LSU Hlth Shreveport, Dept Mol & Cellular Physiol, Shreveport, LA USA. [Saxena, Madhurima] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Saxena, Madhurima] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Pruitt, Kevin] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. RP Dykes, SS (reprint author), LSU Hlth Shreveport, Dept Microbiol & Immunol, Shreveport, LA USA.; Dykes, SS (reprint author), LSU Hlth Shreveport, Feist Weiller Canc Ctr, Shreveport, LA USA. EM scohen@lsuhsc.edu FU Carroll Feist predoctoral fellowship FX This work was supported by a Carroll Feist predoctoral fellowship awarded to SSD. NR 52 TC 3 Z9 3 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 24 PY 2016 VL 7 IS 21 BP 31037 EP 31052 DI 10.18632/oncotarget.8832 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4IZ UT WOS:000377746600091 PM 27105540 ER PT J AU Kim, CC Nakamura, MC Hsieh, CL AF Kim, Charles C. Nakamura, Mary C. Hsieh, Christine L. TI Brain trauma elicits non-canonical macrophage activation states SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Innate immunity; Macrophage; Monocyte; Traumatic brain injury; Single-cell RNA sequencing; Neuroinflammation; RNA flow cytometry; Polarization; Neurotrauma; Myeloid cells ID ALTERNATIVE ACTIVATION; INJURY; INFLAMMATION; CCR2; POLARIZATION; HETEROGENEITY; MICROGLIA; DIVERSITY; RESPONSES; PATHWAYS AB Background: Macrophage polarization programs, commonly referred to as "classical" and "alternative" activation, are widely considered as distinct states that are exclusive of one another and are associated with different functions such as inflammation and wound healing, respectively. In a number of disease contexts, such as traumatic brain injury (TBI), macrophage polarization influences the extent of pathogenesis, and efforts are underway to eliminate pathogenic subsets. However, previous studies have not distinguished whether the simultaneous presence of both classical and alternative activation signatures represents the admixture of differentially polarized macrophages or if they have adopted a unique state characterized by components of both classical and alternative activation. Methods: We analyzed the gene expression profiles of individual monocyte-derived brain macrophages responding to TBI using single-cell RNA sequencing. RNA flow cytometry was used as another single-cell analysis technique to validate the single-cell RNA sequencing results. Results: The analysis of signature polarization genes by single-cell RNA sequencing revealed the presence of diverse activation states, including M(IL4), M(IL10), and M(LPS, IFN gamma). However, the expression of a given polarization marker was no more likely than at random to predict simultaneous expression or repression of markers of another polarization program within the same cell, suggesting a lack of exclusivity in macrophage polarization states in vivo in TBI. Also unexpectedly, individual TBI macrophages simultaneously expressed high levels of signature polarization genes across two or three different polarization states and in several distinct and seemingly incompatible combinations. Conclusions: Single-cell gene expression profiling demonstrated that monocytic macrophages in TBI are not comprised of distinctly polarized subsets but are uniquely and broadly activated. TBI macrophage activation in vivo is deeply complex, with individual cells concurrently adopting both inflammatory and reparative features with a lack of exclusivity. These data provide physiologically relevant evidence that the early macrophage response to TBI is comprised of novel activation states that are discordant with the current paradigm of macrophage polarization-a key consideration for therapeutic modulation. C1 [Nakamura, Mary C.; Hsieh, Christine L.] Univ Calif San Francisco, Dept Med, Div Rheumatol, 4150 Clement St 111R, San Francisco, CA 94121 USA. [Nakamura, Mary C.; Hsieh, Christine L.] San Francisco VA Med Ctr, Res Dept, Immunol Sect, 4150 Clement St 111R, San Francisco, CA 94121 USA. [Kim, Charles C.] Univ Calif San Francisco, Dept Med, Div Expt Med, 1001 Potrero Ave,Bldg 3,Room 603,Box 1234, San Francisco, CA 94143 USA. [Kim, Charles C.] Verily, Mountain View, CA 94043 USA. RP Hsieh, CL (reprint author), Univ Calif San Francisco, Dept Med, Div Rheumatol, 4150 Clement St 111R, San Francisco, CA 94121 USA.; Hsieh, CL (reprint author), San Francisco VA Med Ctr, Res Dept, Immunol Sect, 4150 Clement St 111R, San Francisco, CA 94121 USA. EM Christine.hsieh@ucsf.edu OI Kim, Charles/0000-0001-6474-8227 FU NIAID [P30 AI027763]; NIDDK [P30 DK063720]; United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program [I01 BX002690]; NIH R01 grant [AG046282]; Rheumatology Research Foundation; Russell/Engleman Rheumatology Research Center FX CCK was supported by NIAID P30 AI027763 and NIDDK P30 DK063720. CLH and this work was supported by a Career Development Award-2 and a Merit Review Award #I01 BX002690 from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program to CLH. MCN is supported by NIH R01 grant AG046282, the Rheumatology Research Foundation, and the Russell/Engleman Rheumatology Research Center. NR 31 TC 8 Z9 8 U1 2 U2 3 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 MAY 24 PY 2016 VL 13 AR 117 DI 10.1186/s12974-016-0581-z PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DN7UW UT WOS:000377286500002 PM 27220367 ER PT J AU Mark, DB Anstrom, KJ Sheng, SB Baloch, KN Daniels, MR Hoffmann, U Patel, MR Cooper, LS Lee, KL Douglas, PS AF Mark, Daniel B. Anstrom, Kevin J. Sheng, Shubin Baloch, Khaula N. Daniels, Melanie R. Hoffmann, Udo Patel, Manesh R. Cooper, Lawton S. Lee, Kerry L. Douglas, Pamela S. CA PROMISE Investigators TI Quality-of-Life Outcomes With Anatomic Versus Functional Diagnostic Testing Strategies in Symptomatic Patients With Suspected Coronary Artery Disease: Results From the PROMISE Randomized Trial SO CIRCULATION LA English DT Article DE chest pain; coronary artery disease; diagnosis; patient outcome assessment; quality of life ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; CHEST-PAIN; MYOCARDIAL-PERFUSION; COST-EFFECTIVENESS; CLINICAL-OUTCOMES; CT ANGIOGRAPHY; QUESTIONNAIRE; ANGINA AB Background The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial found that initial use of 64 detector-row computed tomography angiography versus standard functional testing strategies (exercise ECG, stress nuclear methods, or stress echocardiography) did not improve clinical outcomes in 10003 stable symptomatic patients with suspected coronary artery disease requiring noninvasive testing. Symptom burden and quality of life (QOL) were major secondary outcomes. Methods and Results We prospectively collected a battery of QOL instruments in 5985 patients at baseline and 6, 12, and 24 months postrandomization. The prespecified primary QOL measures were the Duke Activity Status Index and the Seattle Angina Questionnaire frequency and QOL scales. All comparisons were made as randomized. Baseline variables were well balanced in the 2982 patients randomly assigned to computed tomography angiography testing and the 3003 patients randomly assigned to functional testing. The Duke Activity Status Index improved substantially in both groups over the first 6 months following testing, but we found no evidence for a strategy-related difference (mean difference [anatomic - functional] at 24 months of follow-up, 0.1 [95% confidence interval, -0.9 to 1.1]). Similar results were seen for the Seattle Angina Questionnaire frequency scale (mean difference at 24 months, -0.2; 95% confidence interval, -0.8 to 0.4) and QOL scale (mean difference at 24 months, -0.2; 95% confidence interval, -1.3 to 0.9). None of the secondary QOL measures showed a consistent strategy-related difference. Conclusions In symptomatic patients with suspected coronary artery disease who required noninvasive testing, symptoms and QOL improved significantly. However, a strategy of initial anatomic testing, in comparison with functional testing, did not provide an incremental benefit for QOL over 2 years of follow-up. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01174550. C1 [Mark, Daniel B.; Anstrom, Kevin J.; Sheng, Shubin; Baloch, Khaula N.; Daniels, Melanie R.] Duke Univ, Med Ctr, Outcomes Res Grp, Durham, NC USA. [Mark, Daniel B.; Anstrom, Kevin J.; Sheng, Shubin; Baloch, Khaula N.; Daniels, Melanie R.; Patel, Manesh R.; Lee, Kerry L.; Douglas, Pamela S.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Cooper, Lawton S.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Mark, DB (reprint author), Duke Clin Res Inst, Outcomes Res, 2400 Pratt St,Room 0311,POB 17969, Durham, NC 27715 USA. EM daniel.mark@duke.edu FU National Heart, Lung, and Blood Institute [R01HL098237, R01HL098236, R01HL98305, R01HL098235] FX This work was supported by grants R01HL098237, R01HL098236, R01HL98305, and R01HL098235 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 21 TC 5 Z9 5 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 MAY 24 PY 2016 VL 133 IS 21 BP 1995 EP 2007 DI 10.1161/CIRCULATIONAHA.115.020259 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN3DZ UT WOS:000376943900006 PM 27143676 ER PT J AU Psotka, MA Teerlink, JR AF Psotka, Mitchell A. Teerlink, John R. TI Ivabradine: Role in the Chronic Heart Failure Armamentarium SO CIRCULATION LA English DT Review DE clinical studies as topic; drug therapy; heart failure ID CORONARY-ARTERY-DISEASE; VENTRICULAR SYSTOLIC DYSFUNCTION; PRESERVED EJECTION FRACTION; PLACEBO-CONTROLLED TRIAL; I-F INHIBITOR; RANDOMIZED INTERVENTION TRIAL; CHRONIC STABLE ANGINA; BETA-BLOCKER THERAPY; RATE REDUCTION; ATRIAL-FIBRILLATION AB Ivabradine is approved to reduce hospitalizations for patients with symptomatic heart failure, reduced ejection fraction, and persistently elevated heart rate despite otherwise maximal medical therapy. However, the eligible patient population is a small fraction of those with heart failure overall. This review summarizes the major clinical evidence supporting the use of ivabradine, identifies and discusses areas of uncertainty from the clinical trial data, helps describe the population most likely to benefit, and attempts to place ivabradine within the multifaceted treatment scheme currently used for patients with heart failure and reduced ejection fraction. C1 [Psotka, Mitchell A.; Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol, 111C,Bldg 203,Room 2A-49,4150 Clement St, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu FU Amgen; Bayer; Cytokinetics; Medtronic; Novartis; St. Jude; Trevena; ZS Pharma FX Dr Teerlink has received research funding and honoraria from Amgen, Bayer, Cytokinetics, Medtronic, Novartis, St. Jude, Trevena, and ZS Pharma. Dr Psotka reports no conflicts. NR 65 TC 2 Z9 3 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 24 PY 2016 VL 133 IS 21 BP 2066 EP 2075 DI 10.1161/CIRCULATIONAHA.115.018094 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DN3DZ UT WOS:000376943900012 PM 27217432 ER PT J AU Edlow, BL Lammers, GJ AF Edlow, Brian L. Lammers, Gert Jan TI Bringing posttraumatic sleep-wake disorders out of the dark SO NEUROLOGY LA English DT Editorial Material ID TRAUMATIC BRAIN-INJURY AB The restorative effects of sleep on the brain are widely known. We have all observed how attention, memory, and even executive function can be affected by the quality and duration of the prior night's sleep. The physiologic mechanisms underlying this association between cognitive performance and sleep have yet to be fully elucidated, but sleep may have an important role in promoting the clearance of neuronal waste products such as -amyloid via interstitial spaces in the brain.(1) For patients with traumatic brain injury (TBI), sleep may be necessary for brain healing, as sleep is involved in a broad spectrum of recovery mechanisms including synaptic plasticity.(2) However, despite the role of sleep in facilitating recovery after TBI, a growing body of evidence suggests that many patients with TBI have long-term sleep-wake disturbances. For these patients, the homeostatic sleep-wake circuits that are critical to recovery are themselves disrupted. C1 [Edlow, Brian L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Edlow, Brian L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Lammers, Gert Jan] Leiden Univ, Med Ctr, Dept Neurol & Clin Neurophysiol, Heemstede, Netherlands. [Lammers, Gert Jan] SleepWake Ctr SEIN, Heemstede, Netherlands. RP Edlow, BL (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Edlow, BL (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM bedlow@mgh.harvard.edu NR 9 TC 0 Z9 0 U1 3 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 MAY 24 PY 2016 VL 86 IS 21 BP 1934 EP 1935 DI 10.1212/WNL.0000000000002710 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DN3KD UT WOS:000376959900005 PM 27164689 ER PT J AU Taslimi, S Modabbernia, A Amin-Hanjani, S Barker, FG Macdonald, RL AF Taslimi, Shervin Modabbernia, Amirhossein Amin-Hanjani, Sepideh Barker, Fred G., II Macdonald, R. Loch TI Natural history of cavernous malformation: Systematic review and meta-analysis of 25 studies SO NEUROLOGY LA English DT Article ID BRAIN-STEM CAVERNOMAS; OPTIMAL SEARCH STRATEGIES; HEMORRHAGE RISK; STEREOTACTIC RADIOSURGERY; SURGICAL-MANAGEMENT; CLINICAL ARTICLE; ANALYTIC SURVEY; ANGIOMAS; SERIES; EXPERIENCE AB Objective:We pooled the results of studies on natural history of cavernous malformations (CM) to calculate point estimates and investigate main sources of heterogeneity.Methods:We searched MEDLINE, EMBASE, and ISI Web of Science for relevant studies published before May 2015. We used fixed or random effects models and meta-regression to pool the data.Results:Twenty-five studies were entered into the meta-analysis (90-1,295 patients depending on the analysis). Bleeding was defined as symptomatic hemorrhage plus radiologic evidence of hemorrhage. Sources of heterogeneity were identified as mixture of hemorrhage and rehemorrhage, mixture of rehemorrhage before and after 2 years of first bleeding, brainstem vs other locations, and calculation method. The rehemorrhage rate was higher than the hemorrhage rate (incidence rate ratio 16.5, p < 0.001, 95% confidence interval [CI] 9.7-28.0). Rehemorrhage within 2 years of the first hemorrhage was higher than after that (incidence rate ratio 1.8, p = 0.042, 95% CI 1.5-2.0). In two metaregression models, rough estimate of the annual incidence rate of hemorrhage was 0.3% (95% CI 0.1%-0.5%) and 2.8% (2.5%-3.3%) per person year in nonbrainstem and brainstem lesions and rough estimate of annual rehemorrhage rate per person year was 6.3% (3%-13.2%) and 32.3% (19.8%-52.7%) in nonbrainstem and brainstem lesions. Median time to rehemorrhage was 10.5 months. Posthemorrhage full recovery was 38.8%/person-year (28.7%-48.8%). Posthemorrhage full recovery or minimal disability was 79.5%/person-year (74.3%-84.8%). Mortality after bleeding was 2.2%.Conclusions:The incidence of symptomatic hemorrhage or rehemorrhage is higher in brainstem lesions. First symptomatic hemorrhage increases the chance of symptomatic rehemorrhage, which decreases after 2 years. C1 [Taslimi, Shervin] Univ Toronto, Div Neurosurg, Toronto, ON M5S 1A1, Canada. [Modabbernia, Amirhossein] Mt Sinai Hosp, Icahn Sch Med, Dept Psychiat, New York, NY 10029 USA. [Amin-Hanjani, Sepideh] Univ Illinois, Dept Neurosurg, Chicago, IL USA. [Barker, Fred G., II] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg Serv, Boston, MA 02115 USA. [Macdonald, R. Loch] Univ Toronto, St Michaels Hosp, Labatt Family Ctr Excellence Brain Injury & Traum, Keenan Res Ctr Biomed Sci,Div Neurosurg, Toronto, ON M5S 1A1, Canada. [Macdonald, R. Loch] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Dept Surg, Toronto, ON M5S 1A1, Canada. RP Macdonald, RL (reprint author), Univ Toronto, St Michaels Hosp, Labatt Family Ctr Excellence Brain Injury & Traum, Keenan Res Ctr Biomed Sci,Div Neurosurg, Toronto, ON M5S 1A1, Canada.; Macdonald, RL (reprint author), Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Dept Surg, Toronto, ON M5S 1A1, Canada. EM macdonaldlo@smh.ca NR 45 TC 1 Z9 2 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 24 PY 2016 VL 86 IS 21 BP 1984 EP 1991 DI 10.1212/WNL.0000000000002701 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DN3KD UT WOS:000376959900016 PM 27164680 ER PT J AU Yoshihama, S Roszik, J Downs, I Meissner, TB Vijayan, S Chapuy, B Sidiq, T Shipp, MA Lizee, GA Kobayashi, KS AF Yoshihama, Sayuri Roszik, Jason Downs, Isaac Meissner, Torsten B. Vijayan, Saptha Chapuy, Bjoern Sidiq, Tabasum Shipp, Margaret A. Lizee, Gregory A. Kobayashi, Koichi S. TI NLRC5/MHC class I transactivator is a target for immune evasion in cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MHC class I; CITA; cancer; immune evasion; NLRC5 ID MHC CLASS-I; HLA CLASS-I; NUCLEOTIDE-BINDING DOMAIN; GENE-EXPRESSION; BREAST-CANCER; CELLS; RESPONSES; ANTIGEN; TUMORS; CARCINOGENESIS AB Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and beta 2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers. C1 [Yoshihama, Sayuri; Downs, Isaac; Vijayan, Saptha; Sidiq, Tabasum; Kobayashi, Koichi S.] Texas A&M Hlth Sci Ctr, Dept Microbial Pathogenesis & Immunol, College Stn, TX 77843 USA. [Yoshihama, Sayuri] Chiba Univ, Grad Sch Med, Dept Gastroenterol & Nephrol, Chiba 2608670, Japan. [Roszik, Jason; Lizee, Gregory A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77054 USA. [Meissner, Torsten B.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Chapuy, Bjoern; Shipp, Margaret A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lizee, Gregory A.] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77054 USA. RP Kobayashi, KS (reprint author), Texas A&M Hlth Sci Ctr, Dept Microbial Pathogenesis & Immunol, College Stn, TX 77843 USA. EM kobayashi@medicine.tamhsc.edu OI Vijayan, Saptha/0000-0002-2194-9843 FU NIH [R01DK074738]; Broad Foundation [IBD-0328]; National Multiple Sclerosis Society [PP1779]; Texas A&M Clinical Science and Translational Research Institute, Texas A&M Genomics Grant Program; Center for Translational Environmental and Health Research; Sumitomo Life Welfare and Culture Foundation FX This work was supported by NIH Grant R01DK074738, Broad Foundation Grant IBD-0328, and National Multiple Sclerosis Society Grant PP1779 (to K.S.K.), by the Texas A&M Clinical Science and Translational Research Institute, Texas A&M Genomics Grant Program, and the Center for Translational Environmental and Health Research (K.S.K.). S.Y. is the recipient of a fellowship from the Sumitomo Life Welfare and Culture Foundation. NR 43 TC 8 Z9 8 U1 2 U2 2 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 MAY 24 PY 2016 VL 113 IS 21 BP 5999 EP 6004 DI 10.1073/pnas.1602069113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN0UD UT WOS:000376779900068 PM 27162338 ER PT J AU Blower, MD AF Blower, Michael D. TI Centromeric Transcription Regulates Aurora-B Localization and Activation SO CELL REPORTS LA English DT Article ID CHROMOSOMAL PASSENGER COMPLEX; RNA-BINDING PROTEINS; CELL-DIVISION; CENP-A; CHROMATIN; MITOSIS; MCAK; PHOSPHORYLATION; IDENTIFICATION; KINETOCHORE AB Centromeric transcription is widely conserved; however, it is not clear what role centromere transcription plays during mitosis. Here, I find that centromeres are transcribed in Xenopus egg extracts into a long noncoding RNA (lncRNA; cen-RNA) that localizes to mitotic centromeres, chromatin, and spindles. cen-RNAs bind to the chromosomal passenger complex (CPC) in vitro and in vivo. Blocking transcription or antisense inhibition of cen-RNA leads to a reduction of CPC localization to the inner centromere and misregulation of CPC component Aurora-B activation independently of known centromere recruitment pathways. Additionally, transcription is required for normal bipolar attachment of kinetochores to the mitotic spindle, consistent with a role for cen-RNA in CPC regulation. This work demonstrates that cen-RNAs promote normal kinetochore function through regulation of the localization and activation of the CPC and confirm that lncRNAs are components of the centromere. C1 [Blower, Michael D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Blower, Michael D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Blower, MD (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Blower, MD (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM blower@molbio.mgh.harvard.edu FU Burroughs Wellcome Fund; NIH [RO1 (RO1GM086434)] FX I would like to acknowledge Judith Sharp for comments on the manuscript and members of the M.D.B. lab for useful suggestions. I thank Alexi Arnaoutouv, Hiro Funabiki, Ming Tsai, and Dan Eilat for gifts of antibodies. This work was supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund (to M.D.B) and NIH grant RO1 (RO1GM086434). NR 36 TC 3 Z9 3 U1 0 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 MAY 24 PY 2016 VL 15 IS 8 BP 1624 EP 1633 DI 10.1016/j.celrep.2016.04.054 PG 10 WC Cell Biology SC Cell Biology GA DM9AB UT WOS:000376654500002 PM 27184843 ER PT J AU Degrauwe, N Schlumpf, TB Janiszewska, M Martin, P Cauderay, A Provero, P Riggi, N Suva, ML Paro, R Stamenkovic, I AF Degrauwe, Nils Schlumpf, Tommy B. Janiszewska, Michalina Martin, Patricia Cauderay, Alexandra Provero, Paolo Riggi, Nicolo Suva, Mario-L Paro, Renato Stamenkovic, Ivan TI The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing SO CELL REPORTS LA English DT Article ID MESSENGER-RNA; DIRECT CONVERSION; EXPRESSION DATA; SELF-RENEWAL; CANCER-CELLS; PAR-CLIP; MICRORNA; LIN28; IDENTIFICATION; TRANSLATION AB Cancer stem cells (CSCs) can drive tumor growth, and their maintenance may rely on post-transcriptional regulation of gene expression, including that mediated by microRNAs (miRNAs). The let-7 miRNA family has been shown to induce differentiation by silencing stem cell programs. Let-7-mediated target gene suppression is prevented by LIN28A/B, which reduce let-7 biogenesis in normal embryonic and some cancer stem cells and ensure maintenance of stemness. Here, we find that glioblastoma stem cells (GSCs) lack LIN28 and express both let-7 and their target genes, suggesting LIN28-independent protection from let-7 silencing. Using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we show that insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) binds to let-7 miRNA recognition elements (MREs) and prevents let-7 target gene silencing. Our observations define the RNA-binding repertoire of IMP2 and identify a mechanism whereby it supports GSC and neural stem cell specification. C1 [Degrauwe, Nils; Martin, Patricia; Cauderay, Alexandra; Riggi, Nicolo; Stamenkovic, Ivan] Univ Lausanne, CHUV, Fac Biol & Med, Div Expt Pathol,Inst Pathol, Rue Bugnon 25, CH-1011 Lausanne, Switzerland. [Schlumpf, Tommy B.; Paro, Renato] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Mattenstr 26, CH-4058 Basel, Switzerland. [Janiszewska, Michalina] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Janiszewska, Michalina] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Provero, Paolo] Univ Turin, Dept Mol Biotechnol & Life Sci, I-10126 Turin, Italy. [Suva, Mario-L] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Suva, Mario-L] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Suva, Mario-L] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Suva, Mario-L] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Stamenkovic, I (reprint author), Univ Lausanne, CHUV, Fac Biol & Med, Div Expt Pathol,Inst Pathol, Rue Bugnon 25, CH-1011 Lausanne, Switzerland. EM ivan.stamenkovic@chuv.ch FU Swiss National Scientific Foundation [310030-150024]; Swiss Cancer League [KLS-3365-02-2014]; MEDIC Foundation; Swiss National Scientific Foundation MD-PhD program [323630_145251] FX We thank Jean-Christophe Stehle of the mouse pathology facility for xenograft processing, Prof. Bernard Thorens for sharing IMP2 floxed mouse strain, and the animal facility team of Epalinges. This work was supported by the Swiss National Scientific Foundation (grant 310030-150024), the Swiss Cancer League (grant KLS-3365-02-2014), and a MEDIC Foundation grant to I.S. N.D. was supported by the Swiss National Scientific Foundation MD-PhD program (grant 323630_145251). NR 57 TC 1 Z9 1 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 24 PY 2016 VL 15 IS 8 BP 1634 EP 1647 DI 10.1016/j.celrep.2016.04.086 PG 14 WC Cell Biology SC Cell Biology GA DM9AB UT WOS:000376654500003 PM 27184842 ER PT J AU Wheeler, LA Trifonova, RT Vrbanac, V Barteneva, NS Liu, X Bollman, B Onofrey, L Mulik, S Ranjbar, S Luster, AD Tager, AM Lieberman, J AF Wheeler, Lee Adam Trifonova, Radiana T. Vrbanac, Vladimir Barteneva, Natasha S. Liu, Xing Bollman, Brooke Onofrey, Lauren Mulik, Sachin Ranjbar, Shahin Luster, Andrew D. Tager, Andrew M. Lieberman, Judy TI TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice SO CELL REPORTS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; APTAMER-SIRNA CHIMERAS; PLASMACYTOID DENDRITIC CELLS; INNATE IMMUNE-RESPONSE; GMP-AMP SYNTHASE; I INTERFERON; VAGINAL TRANSMISSION; SEXUAL TRANSMISSION; DISEASE PROGRESSION; RHESUS MACAQUES AB Despite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3-4 weeks. Similarly intravaginal application of type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation, and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission but systemic interferons do not. C1 [Wheeler, Lee Adam; Trifonova, Radiana T.; Barteneva, Natasha S.; Liu, Xing; Bollman, Brooke; Onofrey, Lauren; Mulik, Sachin; Ranjbar, Shahin; Lieberman, Judy] Brigham & Womens Hosp, Program Cellular & Mol Med, 75 Francis St, Boston, MA 02115 USA. [Wheeler, Lee Adam; Trifonova, Radiana T.; Barteneva, Natasha S.; Liu, Xing; Bollman, Brooke; Onofrey, Lauren; Mulik, Sachin; Ranjbar, Shahin; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Wheeler, Lee Adam] Harvard Univ, Sch Med, MD PhD Program, Boston, MA 02115 USA. [Vrbanac, Vladimir; Luster, Andrew D.; Tager, Andrew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02139 USA. RP Lieberman, J (reprint author), Brigham & Womens Hosp, Program Cellular & Mol Med, 75 Francis St, Boston, MA 02115 USA.; Lieberman, J (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. EM judy.lieberman@childrens.harvard.edu FU NIH [AI102816, AI090671, AI078897]; Harvard CFAR [AI060354, P30 AI060354]; Ragon Institute; Cancer Research Institute; Adelstein Fund; Harvard Medical School MD/PhD Program; Point Foundation FX This work was supported by grants from the NIH (AI102816 and AI090671 to J.L.; AI078897 to A.M.T. and A.D.L.), the Harvard CFAR (AI060354 to A.M.T. and A.D.L.), the Ragon Institute (to J.L., A.M.T., and A.D.L.), and fellowships from the Cancer Research Institute, the Adelstein Fund, the Harvard Medical School MD/PhD Program and the Point Foundation (to L.A.W.), and the Harvard CFAR (P30 AI060354 to R.T.). We thank T. Allen and T. Dudek and the Virology Core of the Ragon Institute for providing viral stocks for in vivo studies and E. Oliva, M. Miri, and A. Bodo, MGH Surgical Pathology, and L. Yang, BIDMC, for tissue specimens. NR 50 TC 2 Z9 2 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAY 24 PY 2016 VL 15 IS 8 BP 1715 EP 1727 DI 10.1016/j.celrep.2016.04.048 PG 13 WC Cell Biology SC Cell Biology GA DM9AB UT WOS:000376654500009 PM 27184854 ER PT J AU Najibi, M Labed, SA Visvikis, O Irazoqui, JE AF Najibi, Mehran Labed, Sid Ahmed Visvikis, Orane Irazoqui, Javier Elbio TI An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense SO CELL REPORTS LA English DT Article ID PROTEIN-KINASE-D; CAENORHABDITIS-ELEGANS; PHOSPHOLIPASE-C; LYSOSOMAL BIOGENESIS; INNATE IMMUNITY; D INHIBITORS; IN-VIVO; TRANSCRIPTION FACTORS; RAW264.7 MACROPHAGES; REGULATES AUTOPHAGY AB The mechanisms that tightly control the transcription of host defense genes have not been fully elucidated. We previously identified TFEB as a transcription factor important for host defense, but the mechanisms that regulate TFEB during infection remained unknown. Here, we used C. elegans to discover a pathway that activates TFEB during infection. Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus. Conversely, pharmacological activation of PKD was sufficient to activate TFEB. Furthermore, phospholipase C (PLC) gene plc-1 was also required for TFEB activation, downstream of G alpha q homolog egl-30 and upstream of dkf-1. Using reverse and chemical genetics, we discovered a similar PLC-PKD-TFEB axis in Salmonella-infected mouse macrophages. In addition, PKC alpha was required in macrophages. These observations reveal a previously unknown host defense signaling pathway, which has been conserved across one billion years of evolution. C1 [Najibi, Mehran; Labed, Sid Ahmed; Visvikis, Orane; Irazoqui, Javier Elbio] Harvard Univ, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Lab Comparat Immunol,Res Inst,Med Sch, Boston, MA 02114 USA. [Visvikis, Orane] INSERM, U1065, C3M, Toxines Microbiennes Relat Hote Pathogenes, F-06204 Nice, France. RP Irazoqui, JE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Lab Comparat Immunol,Res Inst,Med Sch, Boston, MA 02114 USA. EM jirazoqui@mgh.harvard.edu RI di Ronza, Alberto/H-7674-2016; VISVIKIS, ORANE/N-1818-2016; OI di Ronza, Alberto/0000-0002-9813-5143; VISVIKIS, ORANE/0000-0001-7719-5836; Irazoqui, Javier/0000-0001-6553-1329 FU NIH Office of Research Infrastructure Programs [P40 OD010440] FX We are grateful for generous intellectual input and technical help provided by Kate Jeffrey (MGH), Christian Reinecker (MGH), Megha Basavappa (MGH), Tatsushi Omatsu (MGH), and three anonymous reviewers. Caenorhabditis elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 69 TC 0 Z9 0 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 MAY 24 PY 2016 VL 15 IS 8 BP 1728 EP 1742 DI 10.1016/j.celrep.2016.04.052 PG 15 WC Cell Biology SC Cell Biology GA DM9AB UT WOS:000376654500010 PM 27184844 ER PT J AU Ravi, A AF Ravi, Anita TI Pimping as a Practice in Medical Education SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Ravi, Anita] US Dept Vet Affairs, 423 Guardian Dr,1310 Blockley Hall, Philadelphia, PA 19104 USA. [Ravi, Anita] Corporal Michael Crensenz Vet Affairs Med Ctr, Clin Scholars Program, Robert Wood Johnson Fdn, 423 Guardian Dr,1310 Blockley Hall, Philadelphia, PA USA. RP Ravi, A (reprint author), US Dept Vet Affairs, 423 Guardian Dr,1310 Blockley Hall, Philadelphia, PA 19104 USA.; Ravi, A (reprint author), Corporal Michael Crensenz Vet Affairs Med Ctr, Clin Scholars Program, Robert Wood Johnson Fdn, 423 Guardian Dr,1310 Blockley Hall, Philadelphia, PA USA. EM ravia@upenn.edu NR 1 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 24 PY 2016 VL 315 IS 20 BP 2236 EP 2236 DI 10.1001/jama.2016.1571 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DM4US UT WOS:000376343000028 PM 27218641 ER PT J AU Hiraki, M Suzuki, Y Alam, M Hinohara, K Hasegawa, M Jin, CN Kharbanda, S Kufe, D AF Hiraki, Masayuki Suzuki, Yozo Alam, Maroof Hinohara, Kunihiko Hasegawa, Masanori Jin, Caining Kharbanda, Surender Kufe, Donald TI MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors SO SCIENTIFIC REPORTS LA English DT Article ID SMALL-MOLECULE INHIBITOR; BH3 MIMETIC ABT-737; TARGETING MCL-1; CARCINOMA CELLS; FAMILY PROTEINS; IN-VITRO; ONCOPROTEIN; RESISTANCE; SURVIVAL; ACTIVATION AB Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK -> ERK and PI3K -> AKT pathways, and in turn destabilizes MCL-1. The small molecules ABT-737 and ABT-263 target BCL-2, BCL-XL and BCL-w, but not MCL-1. We show that treatment with ABT-737 increases reactive oxygen species and thereby MUC1-C expression. In this way, MUC1-C is upregulated in TNBC cells resistant to ABT-737 or ABT-263. We also demonstrate that MUC1-C is necessary for the resistance-associated increases in MCL-1 levels. Significantly, combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and drug resistant TNBC cells. These findings indicate that targeting MUC1-C is a potential strategy for reversing MCL-1-mediated resistance in TNBC. C1 [Hiraki, Masayuki; Suzuki, Yozo; Alam, Maroof; Hinohara, Kunihiko; Hasegawa, Masanori; Jin, Caining; Kharbanda, Surender; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Suzuki, Yozo] Osaka Police Hosp, Dept Surg Gastroenterol, Kitayama Cho 10-31 Tennoji, Osaka, Osaka 5430035, Japan. [Hasegawa, Masanori] Keio Univ, Sch Med, Dept Urol, Shinzyuyku Ku, Shinanomachi 35, Tokyo 1608582, Japan. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health [CA97098, CA166480]; Lung Cancer Research Foundation FX Research reported in this paper was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480, and by the Lung Cancer Research Foundation. NR 59 TC 3 Z9 3 U1 1 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 MAY 24 PY 2016 VL 6 AR 26643 DI 10.1038/srep26643 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM5LD UT WOS:000376389600001 PM 27217294 ER PT J AU Bucholz, EM Butala, NM Normand, SLT Wang, Y Krumholz, HM AF Bucholz, Emily M. Butala, Neel M. Normand, Sharon-Lise T. Wang, Yun Krumholz, Harlan M. TI Association of Guideline-Based Admission Treatments and Life Expectancy After Myocardial Infarction in Elderly Medicare Beneficiaries SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute myocardial infarction; elderly; guidelines; life expectancy; survival ID ACUTE CORONARY SYNDROMES; TO-BALLOON TIME; COOPERATIVE CARDIOVASCULAR PROJECT; QUALITY-OF-CARE; ST-ELEVATION; PERFORMANCE-MEASURES; RANDOMIZED-TRIALS; GRUPPO-ITALIANO; MORTALITY; ASPIRIN AB BACKGROUND Guideline-based admission therapies for acute myocardial infarction (AMI) significantly improve 30-day survival, but little is known about their association with long-term outcomes. OBJECTIVES This study evaluated the association of 5 AMI admission therapies (aspirin, beta-blockers, acute reperfusion therapy, door-to-balloon [D2B] time <= 90 min, and time to fibrinolysis <= 30 min) with life expectancy and years of life saved after AMI. METHODS We analyzed data from the Cooperative Cardiovascular Project, a study of Medicare beneficiaries hospitalized for AMI, with 17 years of follow-up. Life expectancy and years of life saved after AMI were calculated using Cox proportional hazards regression with extrapolation using exponential models. RESULTS Survival for recipients and non-recipients of the 5 guideline-based therapies diverged early after admission and continued to diverge during 17-year follow-up. Receipt of aspirin, beta-blockers, and acute reperfusion therapy on admission was associated with longer life expectancy of 0.78 (standard error [SE]: 0.05), 0.55 (SE: 0.06), and 1.03 (SE: 0.12) years, respectively. Patients receiving primary percutaneous coronary intervention (PCI) within 90 min lived 1.08 (SE: 0.49) years longer than patients with D2B times >90 min, and door-to-needle (D2N) times <= 30 min were associated with 0.55 (SE: 0.12) more years of life. A dose-response relationship was observed between longer D2B and D2N times and shorter life expectancy after AMI. CONCLUSIONS Guideline-based therapy for AMI admission is associated with both early and late survival benefits, and results in meaningful gains in life expectancy and large numbers of years of life saved in elderly patients. (C) 2016 by the American College of Cardiology Foundation. C1 [Bucholz, Emily M.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Bucholz, Emily M.] Yale Univ, Sch Med, New Haven, CT USA. [Bucholz, Emily M.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Butala, Neel M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.; Wang, Yun] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Internal Med, Sect Cardiovasc Med, New Haven, CT 06510 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Robert Wood Johnson Fdn Clin Scholars Program, New Haven, CT USA. [Krumholz, Harlan M.] Yale Univ, Sch Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT USA. RP Krumholz, HM (reprint author), Yale Univ, Sch Med, Dept Internal Med, 1 Church St,Suite 200, New Haven, CT 06510 USA. EM harlan.krumholz@yale.edu FU NHLBI NIH HHS [F30 HL120498, U01 HL105270]; NIGMS NIH HHS [T32 GM007205] NR 48 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 24 PY 2016 VL 67 IS 20 BP 2378 EP 2391 DI 10.1016/j.jacc.2016.03.507 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL9JZ UT WOS:000375960200009 PM 27199062 ER PT J AU Teng, MX Love, MI Davis, CA Djebali, S Dobin, A Graveley, BR Li, S Mason, CE Olson, S Pervouchine, D Sloan, CA Wei, XT Zhan, LJ Irizarry, RA AF Teng, Mingxiang Love, Michael I. Davis, Carrie A. Djebali, Sarah Dobin, Alexander Graveley, Brenton R. Li, Sheng Mason, Christopher E. Olson, Sara Pervouchine, Dmitri Sloan, Cricket A. Wei, Xintao Zhan, Lijun Irizarry, Rafael A. TI A benchmark for RNA-seq quantification pipelines (vol 17, 74, 2016) SO GENOME BIOLOGY LA English DT Correction C1 [Teng, Mingxiang; Love, Michael I.; Irizarry, Rafael A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Teng, Mingxiang; Love, Michael I.; Irizarry, Rafael A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. [Davis, Carrie A.; Dobin, Alexander] Cold Spring Harbor Lab, Funct Genom Grp, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. [Djebali, Sarah; Pervouchine, Dmitri] Bioinformat & Genom Programme Ctr Genom Regulat C, Doctor Aiguader 88, Barcelona 08003, Spain. [Djebali, Sarah; Pervouchine, Dmitri] UPF, Doctor Aiguader 88, Barcelona 08003, Spain. [Graveley, Brenton R.; Olson, Sara; Wei, Xintao; Zhan, Lijun] UConn Hlth Ctr, Inst Syst Genom, Dept Genet & Genome Sci, Farmington, CT 06030 USA. [Li, Sheng; Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Sloan, Cricket A.] Stanford Univ, Dept Genet, 300 Pasteur Dr,MC 5477, Stanford, CA 94305 USA. [Teng, Mingxiang] Harbin Inst Technol, Sch Comp Sci & Technol, Harbin 150006, Peoples R China. RP Irizarry, RA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA.; Irizarry, RA (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. EM rafa@jimmy.harvard.edu NR 1 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 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAY 23 PY 2016 VL 17 AR 107 DI 10.1186/s13059-016-0986-0 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DN7TA UT WOS:000377280400002 ER PT J AU Zeller, T Jaff, MR AF Zeller, Thomas Jaff, Michael R. TI Favorable Angiographic Outcome After Treatment of Infrapopliteal Lesions With Drug-Coated Balloons Without Clinical Benefit What We Learn From a Meta-Analysis SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE angioplasty; drug-coated balloon; infra-popliteal artery; peripheral artery disease ID RANDOMIZED-TRIAL; ELUTING STENTS; ARTERY-DISEASE; FOLLOW-UP; ANGIOPLASTY; REVASCULARIZATION; SFA C1 [Zeller, Thomas] Univ Herzzentrum Freiburg Bad Krozingen, Dept Angiol, Bad Krozingen, Germany. [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Med, Boston, MA 02114 USA. RP Zeller, T (reprint author), Univ Herzzentrum Freiburg Bad Krozingen, Klin Kardiol & Angiol 2, Sudring 15, D-79189 Bad Krozingen, Germany. EM thomas.zeller@universitaets-herzzentrum.de NR 16 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD MAY 23 PY 2016 VL 9 IS 10 BP 1081 EP 1082 DI 10.1016/j.jcin.2016.03.005 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM6KZ UT WOS:000376462400017 PM 27131440 ER PT J AU Hunt, CM Beste, LA Lowy, E Suzuki, A Moylan, CA Tillmann, HL Ioannou, GN Lim, JK Kelley, MJ Provenzale, D AF Hunt, Christine M. Beste, Lauren A. Lowy, Elliott Suzuki, Ayako Moylan, Cynthia A. Tillmann, Hans L. Ioannou, George N. Lim, Joseph K. Kelley, Michael J. Provenzale, Dawn TI Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Hepatitis B; Hepatitis B reactivation; Anti-CD20 antibody; Rituximab; Lymphoma; Chemotherapy; Hepatitis B antivirals; Vaccination; Veteran ID TASK-FORCE RECOMMENDATION; VIRUS-INFECTION; IMMUNOSUPPRESSIVE THERAPY; COST-EFFECTIVENESS; LYMPHOMA PATIENTS; HBV REACTIVATION; CHEMOTHERAPY; RITUXIMAB; PROPHYLAXIS; ADOLESCENTS AB AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement. METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the. 2 test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group. RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, <= 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (p = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up. CONCLUSION: While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes. C1 [Hunt, Christine M.; Moylan, Cynthia A.; Kelley, Michael J.; Provenzale, Dawn] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Hunt, Christine M.; Moylan, Cynthia A.; Kelley, Michael J.; Provenzale, Dawn] Durham VA Med Ctr, Dept Med, Durham, NC 27705 USA. [Beste, Lauren A.; Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Seattle, WA 98108 USA. [Beste, Lauren A.; Lowy, Elliott; Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Beste, Lauren A.; Ioannou, George N.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Lowy, Elliott] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Suzuki, Ayako] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Suzuki, Ayako] Cent Arkansas Vet Heathcare Syst, Div Hepatol, Little Rock, AR 72205 USA. [Tillmann, Hans L.] Eastern Carolina Univ, Dept Med, Greenville, NC 27858 USA. [Lim, Joseph K.] Yale Univ, Sch Med, Yale Liver Ctr, Sect Digest Dis, 333 Cedar St, New Haven, CT 06520 USA. [Kelley, Michael J.] Dept Vet Affairs, Off Patient Care Serv, Washington, DC 20420 USA. [Kelley, Michael J.] Durham Vet Affairs Med Ctr, Hematol Oncol Serv, Durham, NC 27705 USA. [Provenzale, Dawn] Durham Vet Affairs Med Ctr, Cooperat Studies Program Epidemiol Ctr Durham, Durham, NC 27705 USA. [Provenzale, Dawn] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC 27710 USA. RP Hunt, CM (reprint author), Duke Univ, Dept Med, Sch Med, Med, 00550 Hosp South, Durham, NC 27710 USA. EM christine.hunt@va.gov FU Veterans Affairs (VA) Cooperative Studies Program Epidemiology Center-Durham; Puget Sound VA Health Care System; VA Office of Public Health and Human Health Pathogens FX Supported by (in part) by resources from the Veterans Affairs (VA) Cooperative Studies Program Epidemiology Center-Durham, the Puget Sound VA Health Care System, and the VA Office of Public Health and Human Health Pathogens. NR 29 TC 0 Z9 0 U1 0 U2 0 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAY 21 PY 2016 VL 22 IS 19 BP 4732 EP 4740 DI 10.3748/wjg.v22.i19.4732 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DN4ZH UT WOS:000377075200012 PM 27217704 ER PT J AU Singh, SM d'Avila, A Kim, YH Aryana, A Mangrum, JM Michaud, GF Dukkipati, SR Barrett, CD Heist, EK Parides, MK Thorpe, KE Reddy, VY AF Singh, Sheldon M. d'Avila, Andre Kim, Young-Hoon Aryana, Arash Mangrum, J. Michael Michaud, Gregory F. Dukkipati, Srinivas R. Barrett, Conor D. Heist, E. Kevin Parides, Michael K. Thorpe, Kevin E. Reddy, Vivek Y. TI The modified stepwise ablation guided by low-dose ibutilide in chronic atrial fibrillation trial (The MAGIC-AF Study) SO EUROPEAN HEART JOURNAL LA English DT Article DE Arrhythmia; Catheter ablation; Electrophysiology; Atrial fibrillation; Mapping ID PULMONARY VEIN ISOLATION; SUFFICIENT CURRENT CONTROVERSIES; CATHETER-ABLATION; SUBSTRATE MODIFICATION; RANDOMIZED-TRIAL; FOLLOW-UP; MULTICENTER; ELECTROGRAMS; ELIMINATION; DURABILITY AB Aims Complex fractionated atrial electrograms (CFAE) are targeted during persistent atrial fibrillation (AF) ablation. However, many CFAE sites are non-specific resulting in extensive ablation. Ibutilide has been shown to reduce left atrial surface area exhibiting CFAE. We hypothesized that ibutilide administration prior to CFAE ablation would identify sites critical for persistent AF maintenance allowing for improved procedural efficacy and long-term freedom from atrial arrhythmias. Methods and results Two hundred patients undergoing a first-ever persistent AF catheter ablation procedure were randomly assigned to receive either 0.25 mg of intravenous ibutilide or saline placebo upon completion of pulmonary vein isolation. Complex fractionated atrial electrogram sites were then targeted with ablation. The primary efficacy endpoint was the 1-year single procedure freedom from atrial arrhythmia off anti-arrhythmic drugs. Similar procedural characteristics (procedure, fluoroscopy, and ablation times) were observed with both strategies despite a greater reduction in left atrial surface area with CFAE sites (8 vs. 1%, P < 0.0001) and AF termination during CFAE ablation with ibutilide compared with placebo (75 vs. 57%, P = 0.007). The primary efficacy endpoint was achieved in 56% of patients receiving ibutilide and 49% receiving placebo (P = 0.35). No significant differences in peri-procedural complications were observed in both groups. Conclusion Despite a reduction in CFAE area and greater AF termination during CFAE ablation, procedural characteristics and clinical outcomes were unchanged when CFAE ablation was guided by ibutilide administration. C1 [Singh, Sheldon M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Schulich Heart Program, Toronto, ON, Canada. [d'Avila, Andre; Dukkipati, Srinivas R.; Parides, Michael K.; Reddy, Vivek Y.] Icahn Sch Med Mt Sinai, Helmsley Cardiac Arrhythmia Serv, One Gustave L Levy Pl,POB 1030, New York, NY 10029 USA. [d'Avila, Andre] Inst Pesquisa Arritmia Cardiaca, Florianopolis, SC, Brazil. [Kim, Young-Hoon] Korea Univ, Med Ctr, Div Cardiovasc, Seoul, South Korea. [Aryana, Arash] Mercy Gen Hosp, Dign Hlth Heart & Vasc Inst, Sacramento, CA USA. [Mangrum, J. Michael] Univ Virginia, Cardiovasc Med, Charlottesville, VA USA. [Michaud, Gregory F.] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Barrett, Conor D.] Mt Sinai St Lukes Roosevelt Hosp, Al Sabah Arrhythmia Inst, New York, NY USA. [Heist, E. Kevin] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 USA. [Thorpe, Kevin E.] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Dalla Lana Sch Publ Hlth,Keenan Res Ctr, Toronto, ON, Canada. RP Reddy, VY (reprint author), Icahn Sch Med Mt Sinai, Helmsley Cardiac Arrhythmia Serv, One Gustave L Levy Pl,POB 1030, New York, NY 10029 USA. EM vivek.reddy@mountsinai.org FU St Jude Medical, USA FX This research is supported by St Jude Medical, USA. NR 30 TC 4 Z9 4 U1 0 U2 0 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 MAY 21 PY 2016 VL 37 IS 20 BP 1614 EP 1621 DI 10.1093/eurheartj/ehw003 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM2HQ UT WOS:000376168100014 PM 26850076 ER PT J AU Goalstone, ML Pugazhenthi, S AF Goalstone, Marc Lee Pugazhenthi, Subbiah TI Editorial: Molecular Mechanism of Neuronal Dysfunction in the Diabetic Brain SO FRONTIERS IN ENDOCRINOLOGY LA English DT Editorial Material DE Alzheimer's disease; diabetes; neuroinflammation; amyloid precursor protein; editorial ID GLYCATION END-PRODUCTS; DISEASE; SRAGE; RISK C1 [Goalstone, Marc Lee; Pugazhenthi, Subbiah] Denver VA Med Ctr, Denver, CO USA. [Goalstone, Marc Lee; Pugazhenthi, Subbiah] Univ Colorado, Sch Med, Aurora, CO USA. RP Pugazhenthi, S (reprint author), Denver VA Med Ctr, Denver, CO USA.; Pugazhenthi, S (reprint author), Univ Colorado, Sch Med, Aurora, CO USA. EM subbiah.pugazhenthi@ucdenver.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD MAY 20 PY 2016 VL 7 AR 45 DI 10.3389/fendo.2016.00045 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP5BA UT WOS:000378509800001 PM 27242668 ER PT J AU Kantar, RS Lashgari, G Tabet, EI Lewandrowski, GK Carvalho, LA Tannous, BA AF Kantar, Rami S. Lashgari, Ghazal Tabet, Elie I. Lewandrowski, Grant K. Carvalho, Litia A. Tannous, Bakhos A. TI Imaging Tumor Vascularity and Response to Anti-Angiogenic Therapy Using Gaussia Luciferase SO SCIENTIFIC REPORTS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ENDOTHELIAL GROWTH-FACTOR; IN-VIVO; INTEGRIN ALPHA(V)BETA(3); ANTIANGIOGENIC THERAPY; BLOOD-VESSELS; CANCER; EXPRESSION; BIOMARKERS; IDENTIFICATION AB We developed a novel approach to assess tumor vascularity using recombinant Gaussia luciferase (rGluc) protein and bioluminescence imaging. Upon intravenous injection of rGluc followed by its substrate coelenterazine, non-invasive visualization of tumor vascularity by bioluminescence imaging was possible. We applied this method for longitudinal monitoring of tumor vascularity in response to the anti-angiogenic drug tivozanib. This simple and sensitive method could be extended to image blood vessels/vasculature in many different fields. C1 [Kantar, Rami S.; Lashgari, Ghazal; Tabet, Elie I.; Lewandrowski, Grant K.; Carvalho, Litia A.; Tannous, Bakhos A.] Massachusetts Gen Hosp, Dept Neurol, Expt Therapeut & Mol Imaging Lab, Ctr Neurosci, Boston, MA 02114 USA. [Kantar, Rami S.; Lashgari, Ghazal; Tabet, Elie I.; Lewandrowski, Grant K.; Carvalho, Litia A.; Tannous, Bakhos A.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Tannous, BA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Expt Therapeut & Mol Imaging Lab, Ctr Neurosci, Boston, MA 02114 USA.; Tannous, BA (reprint author), Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. EM btannous@hms.harvard.edu FU National Institute of Health (NIH); National institute of Neurological disorders (NINDS) [R01NS064983]; National Cancer Institute (NCI) [R01CA166077]; Shared Instrumentation grant IVIS imaging system [1S10RR025504] FX This study was supported by grants from the National Institute of Health (NIH), the National institute of Neurological disorders (NINDS) R01NS064983 and National Cancer Institute (NCI) R01CA166077 (BAT). The authors acknowledge the support from 1S10RR025504 Shared Instrumentation grant IVIS imaging system that was used to acquire imaging data, and the NIH/NINDS P30NS045776 (BAT) for the production of lentivirus vectors. The authors would also like to thank Dr. Bruce Bryan (Nanolight) for providing the recombinant Gluc protein. NR 37 TC 0 Z9 0 U1 5 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 20 PY 2016 VL 6 AR 26353 DI 10.1038/srep26353 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM7QS UT WOS:000376555700001 PM 27198044 ER PT J AU Kwok, SJJ Kuznetsov, IA Kim, M Choi, M Scarcelli, G Yun, SH AF Kwok, Sheldon J. J. Kuznetsov, Ivan A. Kim, Moonseok Choi, Myunghwan Scarcelli, Giuliano Yun, Seok Hyun TI Selective two-photon collagen crosslinking in situ measured by Brillouin microscopy SO OPTICA LA English DT Article ID KERATOCONUS CORNEAS; 2ND-HARMONIC GENERATION; EX-VIVO; TISSUE; ELASTOGRAPHY; POLYMERIZATION; ORIENTATION; CELLS AB Two-photon polymerization has enabled the precise microfabrication of three-dimensional structures with applications spanning from photonic microdevices, drug delivery systems, and cellular scaffolds. We present two-photon collagen crosslinking (2P-CXL) of intact corneal tissue using riboflavin and femtosecond laser irradiation. The collagen fiber orientations and photobleaching were characterized by second harmonic generation and two-photon fluorescence imaging, respectively. The measurement of local changes in longitudinal mechanical moduli with confocal Brillouin microscopy enabled the visualization of the cross-linked pattern without the perturbation of the surrounding non-irradiated regions. 2P-CXL-induced stiffening was comparable to that achieved with conventional one-photon CXL. Our results demonstrate the ability to selectively stiffen biological tissue in situ at high spatial resolution, with broad implications in ophthalmology, laser surgery, and tissue engineering. (C) 2016 Optical Society of America C1 [Kwok, Sheldon J. J.; Yun, Seok Hyun] MIT, Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kwok, Sheldon J. J.; Kuznetsov, Ivan A.; Kim, Moonseok; Choi, Myunghwan; Scarcelli, Giuliano; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. [Kuznetsov, Ivan A.] Johns Hopkins Univ, Dept Biomed Engn, 3400 North Charles St, Baltimore, MD 21218 USA. [Choi, Myunghwan] Sungkyunkwan Univ, Dept Biomed Engn, Suwon 16419, South Korea. [Choi, Myunghwan] IBS, Ctr Neurosci & Imaging Res, Suwon 16419, South Korea. [Scarcelli, Giuliano] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Yun, SH (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM syun@hms.harvard.edu OI Choi, Myunghwan/0000-0002-4235-7003 FU National Institutes of Health (NIH) [P41-EB015903, R01-EY025454, UL1-RR025758]; National Science Foundation (NSF) [CBET-0853773, EEC-1358296] FX National Institutes of Health (NIH) (P41-EB015903, R01-EY025454, UL1-RR025758); National Science Foundation (NSF) (CBET-0853773, EEC-1358296). NR 34 TC 1 Z9 1 U1 6 U2 13 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2334-2536 J9 OPTICA JI Optica PD MAY 20 PY 2016 VL 3 IS 5 BP 469 EP 472 DI 10.1364/OPTICA.3.000469 PG 4 WC Optics SC Optics GA DM5NE UT WOS:000376395400003 ER PT J AU Maldifassi, MC Baur, R Pierce, D Nourmahnad, A Forman, SA Sigel, E AF Maldifassi, Maria C. Baur, Roland Pierce, David Nourmahnad, Anahita Forman, Stuart A. Sigel, Erwin TI Novel positive allosteric modulators of GABA(A) receptors with anesthetic activity SO SCIENTIFIC REPORTS LA English DT Article ID BENZODIAZEPINE BINDING-SITE; AMINOBUTYRIC ACID(A) RECEPTORS; SINGLE AMINO-ACID; A RECEPTORS; SUBUNIT COMPOSITION; GENERAL-ANESTHETICS; INTERNATIONAL UNION; XENOPUS OOCYTES; ETOMIDATE; STOICHIOMETRY AB GABA(A) receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We previously identified novel ligands of the classical benzodiazepine binding pocket in alpha(1)beta(2)gamma(2) GABA(A) receptors using an experiment-guided virtual screening (EGVS) method. This screen also identified novel ligands for intramembrane low affinity diazepam site(s). In the current study we have further characterized compounds 31 and 132 identified with EGVS as well as 4-O-methylhonokiol. We investigated the site of action of these compounds in alpha(1)beta(2)gamma(2) GABA(A) receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology combined with a benzodiazepine site antagonist and transmembrane domain mutations. All three compounds act mainly through the two beta+/alpha-subunit transmembrane interfaces of the GABA(A) receptors. We then used concatenated receptors to dissect the involvement of individual beta+/alpha-interfaces. We further demonstrated that these compounds have anesthetic activity in a small aquatic animal model, Xenopus laevis tadpoles. The newly identified compounds may serve as scaffolds for the development of novel anesthetics. C1 [Maldifassi, Maria C.; Baur, Roland; Sigel, Erwin] Univ Bern, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland. [Pierce, David; Nourmahnad, Anahita; Forman, Stuart A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Sigel, E (reprint author), Univ Bern, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland. EM sigel@ibmm.unibe.ch FU Swiss National Science Foundation [315230_156929/1]; Beca Chile Postdoctorado from CONICYT, Ministerio de Educacion, Chile FX This work was supported by the Swiss National Science Foundation grant 315230_156929/1. M.C.M. is a recipient of a fellowship (Beca Chile Postdoctorado from CONICYT, Ministerio de Educacion, Chile). Andrea Szabo (Department of Anesthesia Critical Care & Pain Medicine at Massachusetts General Hospital, Boston, MA, USA) helped to perform tadpole loss of righting reflexes studies. 4-O-methylhonokiol was a kind gift by Dr. Wolfgang Schuehly (Karl-Franzens-University, Graz, Austria). NR 54 TC 1 Z9 1 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 20 PY 2016 VL 6 AR 25943 DI 10.1038/srep25943 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM2WW UT WOS:000376209800001 PM 27198062 ER PT J AU Lathan, CS Cronin, A Tucker-Seeley, R Zafar, SY Ayanian, JZ Schrag, D AF Lathan, Christopher S. Cronin, Angel Tucker-Seeley, Reginald Zafar, S. Yousuf Ayanian, John Z. Schrag, Deborah TI Association of Financial Strain With Symptom Burden and Quality of Life for Patients With Lung or Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CARE OUTCOMES RESEARCH; SELF-RATED HEALTH; BREAST-CANCER; SURVEILLANCE CONSORTIUM; SOCIOECONOMIC-STATUS; SOCIAL DISPARITIES; FOLLOW-UP; INEQUALITIES; DIAGNOSIS; SURVIVORS AB Purpose To measure the association between patient financial strain and symptom burden and quality of life (QOL) for patients with new diagnoses of lung or colorectal cancer. Patients and Methods Patients participating in the Cancer Care Outcomes Research and Surveillance study were interviewed about their financial reserves, QOL, and symptom burden at 4 months of diagnosis and, for survivors, at 12 months of diagnosis. We assessed the association of patient-reported financial reserves with patient-reported outcomes including the Brief Pain Inventory, symptom burden on the basis of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, and QOL on the basis of the EuroQoL-5 Dimension scale. Multivariable linear regression models were fit for each outcome and cancer type, adjusting for age, race/ethnicity, sex, income, insurance, stage at diagnosis, and comorbidity. Results Among patients with lung and colorectal cancer, 40% and 33%, respectively, reported limited financial reserves (<2 months). Relative to patients with more than 12 months of financial reserves, those with limited financial reserves reported significantly increased pain (adjusted mean difference, 5.03 [95% CI, 3.29 to 7.22] and 3.45 [95% CI, 1.25 to 5.66], respectively, for lung and colorectal), greater symptom burden (5.25 [95% CI, 3.29 to.22] and 5.31 [95% CI, 3.58 to 7.04]), and poorer QOL (4.70 [95% CI, 2.82 to 6.58] and 5.22 [95% CI, 3.61 to 6.82]). With decreasing financial reserves, a clear dose-response relationship was present across all measures of well-being. These associations were also manifest for survivors reporting outcomes again at 1 year and persisted after adjustment for stage, comorbidity, insurance, and other clinical attributes. Conclusion Patients with cancer and limited financial reserves are more likely to have higher symptom burden and decreased QOL. Assessment of financial reserves may help identify patients who need intensive support. C1 [Lathan, Christopher S.; Cronin, Angel; Tucker-Seeley, Reginald; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zafar, S. Yousuf] Duke Univ, Sch Med, Durham, NC 27706 USA. [Ayanian, John Z.] Univ Michigan, Ann Arbor, MI 48109 USA. [Tucker-Seeley, Reginald] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. RP Lathan, CS (reprint author), Dana Farber Canc Ctr, McGraw Patterson Ctr Populat Sci, 450 Brookline Ave, Boston, MA 02115 USA. EM christopher_lathan@dfci.harvard.edu FU National Cancer Institute [1P50CA148596, K01 CA124581, U01 CA093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA093339, U01 CA093326, CRS 02-164] FX Supported by grants from the National Cancer Institute (1P50CA148596 and K01 CA124581). The Cancer Care Outcomes Research and Surveillance Consortium was supported by grants from the National Cancer Institute to the Statistical Coordinating Center (U01 CA093344) and the National Cancer Institute-supported Primary Data Collection and Research Centers: Dana Farber Cancer Institute/Cancer Research Network (U01 CA093332), Harvard Medical School/Northern California Cancer Center (U01 CA093324), RAND/UCLA (U01 CA093348), University of Alabama at Birmingham (U01 CA093329), University of Iowa (U01 CA093339), University of North Carolina (U01 CA093326) and by a Department of Veteran's Affairs grant to the Durham VA Medical Center (CRS 02-164). NR 51 TC 7 Z9 8 U1 5 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2016 VL 34 IS 15 BP 1732 EP + DI 10.1200/JCO.2015.63.2232 PG 11 WC Oncology SC Oncology GA DL3NS UT WOS:000375541100009 PM 26926678 ER PT J AU Solin, LJ Gray, R Hughes, LL Wood, WC Lowen, MA Badve, SS Baehner, FL Ingle, JN Perez, EA Recht, A Sparano, JA Davidson, NE AF Solin, Lawrence J. Gray, Robert Hughes, Lorie L. Wood, William C. Lowen, Mary Ann Badve, Sunil S. Baehner, Frederick L. Ingle, James N. Perez, Edith A. Recht, Abram Sparano, Joseph A. Davidson, Nancy E. TI Radiation Therapy and the Evolving Definition of Low Risk in Ductal Carcinoma in Situ Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID RECURRENCE RISK; BREAST C1 [Solin, Lawrence J.] Albert Einstein Healthcare Network, Philadelphia, PA USA. [Gray, Robert] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hughes, Lorie L.] Gordon Hosp, Harris Radiat Therapy Ctr, Calhoun, GA USA. [Wood, William C.] Emory Univ, Atlanta, GA 30322 USA. [Lowen, Mary Ann] Baystate Med Ctr, Springfield, MA USA. [Badve, Sunil S.] Indiana Univ, Indianapolis, IN 46204 USA. [Baehner, Frederick L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ingle, James N.] Mayo Clin, Rochester, MN USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Recht, Abram] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Recht, Abram] Harvard Univ, Sch Med, Boston, MA USA. [Sparano, Joseph A.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Davidson, Nancy E.] Univ Pittsburgh, Pittsburgh, PA USA. RP Solin, LJ (reprint author), Albert Einstein Healthcare Network, Philadelphia, PA USA. NR 10 TC 0 Z9 0 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2016 VL 34 IS 15 BP 1824 EP + DI 10.1200/JCO.2016.66.4714 PG 3 WC Oncology SC Oncology GA DL3NS UT WOS:000375541100022 PM 27001578 ER PT J AU Yang, H Wang, HC Levine, YA Gunasekaran, MK Wang, YJ Addorisio, M Zhu, S Li, W Li, JH de Kleijn, DPV Olofsson, PS Warren, HS He, MZ Al-Abed, Y Roth, J Antoine, DJ Chavan, SS Andersson, U Tracey, KJ AF Yang, Huan Wang, Haichao Levine, Yaakov A. Gunasekaran, Manoj K. Wang, Yongjun Addorisio, Meghan Zhu, Shu Li, Wei Li, Jianhua de Kleijn, Dominique P. V. Olofsson, Peder S. Warren, H. Shaw He, Mingzhu Al-Abed, Yousef Roth, Jesse Antoine, Daniel J. Chavan, Sangeeta S. Andersson, Ulf Tracey, Kevin J. TI Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes SO JCI INSIGHT LA English DT Article ID MOBILITY GROUP BOX-1; HEMOGLOBIN SCAVENGER RECEPTOR; STERILE INFLAMMATION; IMMUNE-RESPONSES; CYTOKINE RELEASE; HUMAN MONOCYTES; GUINEA-PIGS; IN-VIVO; HMGB1; PROTEIN AB Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 is a prototypical damage-associated molecular pattern (DAMP) inflammatory mediator. During the course of developing extracorporeal approaches to treating injury and infection, we inadvertently discovered that haptoglobin, the acute phase protein that binds extracellular hemoglobin and targets cellular uptake through CD163, also binds HMGB1. Haptoglobin-HMGB1 complexes elicit the production of antiinflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in WT but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression significantly enhances mortality rates in standardized models of intra-abdominal sepsis in mice. Administration of haptoglobin to WT and to haptoglobin gene-deficient animals confers significant protection. These findings reveal a mechanism for haptoglobin modulation of the inflammatory action of HMGB1, with significant implications for developing experimental strategies targeting HMGB1-dependent inflammatory diseases. C1 [Yang, Huan; Levine, Yaakov A.; Gunasekaran, Manoj K.; Wang, Yongjun; Addorisio, Meghan; Li, Jianhua; Olofsson, Peder S.; Chavan, Sangeeta S.; Tracey, Kevin J.] Northwell Hlth, Lab Biomed Sci, Feinstein Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA. [Wang, Haichao; Zhu, Shu; Li, Wei] Northwell Hlth, Lab Emergency Med, Feinstein Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA. [de Kleijn, Dominique P. V.] Univ Med Ctr, Lab Cardiovasc Immunol, Utrecht, Netherlands. [Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA USA. [He, Mingzhu; Al-Abed, Yousef] Northwell Hlth, Feinstein Inst Med Res, Lab Med Chem, 350 Community Dr, Manhasset, NY 11030 USA. [Roth, Jesse] Northwell Hlth, Feinstein Inst Med Res, Lab Diabet & Diabet Related Disorders, 350 Community Dr, Manhasset, NY 11030 USA. [Antoine, Daniel J.] Univ Liverpool, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool, Merseyside, England. [Andersson, Ulf] Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden. [Levine, Yaakov A.] SetPoint Med Inc, Valencia, CA USA. RP Yang, H (reprint author), Northwell Hlth, Lab Biomed Sci, Feinstein Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA.; Andersson, U (reprint author), Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden. EM hyang@northwell.edu; Ulf.Andersson@ki.se NR 46 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAY 19 PY 2016 VL 1 IS 7 AR e85375 DI 10.1172/jci.insight.85375 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1KZ UT WOS:000387111800002 ER PT J AU Swerdlow, SH Campo, E Pileri, SA Harris, NL Stein, H Siebert, R Advani, R Ghielmini, M Salles, GA Zelenetz, AD Jaffe, ES AF Swerdlow, Steven H. Campo, Elias Pileri, Stefano A. Harris, Nancy Lee Stein, Harald Siebert, Reiner Advani, Ranjana Ghielmini, Michele Salles, Gilles A. Zelenetz, Andrew D. Jaffe, Elaine S. TI The 2016 revision of the World Health Organization classification of lymphoid neoplasms SO BLOOD LA English DT Review ID T-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; GAMMA-DELTA-T; PREDOMINANT HODGKIN LYMPHOMA; IDENTIFIES RECURRENT MUTATIONS; POSITIVE MUCOCUTANEOUS ULCER; PARAFFIN-EMBEDDED TISSUE; FOLLICULAR-LYMPHOMA; BURKITT-LYMPHOMA; LYMPHOPROLIFERATIVE-DISORDER AB A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms. C1 [Swerdlow, Steven H.] Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, 200 Lothrop St, Pittsburgh, PA 15213 USA. [Campo, Elias] Univ Barcelona, Hosp Clin, Dept Pathol, August Pi & Sunyer Biomed Res Inst, Barcelona, Spain. [Pileri, Stefano A.] European Inst Oncol, Haematopathol Unit, Milan, Italy. [Pileri, Stefano A.] Univ Bologna, Sch Med, Dept Expt Diagnost & Specialty Med, Bologna, Italy. [Harris, Nancy Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Harris, Nancy Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stein, Harald] Pathodiagnostik, Berlin, Germany. [Siebert, Reiner] Univ Kiel, Inst Human Genet, Kiel, Germany. [Advani, Ranjana] Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA. [Ghielmini, Michele] Oncol Inst Southern Switzerland, Dept Med Oncol, Bellinzona, Switzerland. [Salles, Gilles A.] Hosp Civils Lyon, Dept Hematol, Lyon, France. [Salles, Gilles A.] Univ Lyon 1, F-69365 Lyon, France. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Zelenetz, Andrew D.] Weill Cornell Med Coll, New York, NY USA. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Swerdlow, SH (reprint author), Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, 200 Lothrop St, Pittsburgh, PA 15213 USA.; Campo, E (reprint author), Univ Barcelona, Hosp Clin, Dept Pathol, E-08036 Barcelona, Spain.; Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, CCR, Bldg 10,Room 3s235, Bethesda, MD 20892 USA. EM swerdlowsh@upmc.edu; ecampo@clinic.cat; elainejaffe@nih.gov RI Campo, elias/O-7192-2016; Siebert, Reiner/A-8049-2010 OI Campo, elias/0000-0001-9850-9793; FU Italian Association for Cancer Research (AIRC, Milan) [10007]; National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center [P30 CA008748]; American Society of Hematology; Josep Carreras Foundation; Fondazione Italiana Linfomi (FIL); Leukemia Clinical Research Foundation; University of Chicago Comprehensive Cancer Center; Beckman Coulter Corporation; Celgene Corporation; Dako; Genentech Corporation; Incyte Corporation; Leica Corporation; Millennium Pharmaceuticals; Pharmacyclics; Seattle Genetics Corporation; Sysmex Corporation; Ventana Medical Systems, Inc of the Roche Group FX S.A.P. was supported in part through the Italian Association for Cancer Research (AIRC, Milan) grant 5x1000 number 10007. A.D.Z. was supported in part through the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant P30 CA008748. The authors acknowledge the unrestricted financial support of the Clinical Advisory Committee meeting held in Chicago, IL, March 31-April 1, 2014 from the following organizations: American Society of Hematology, Josep Carreras Foundation, Fondazione Italiana Linfomi (FIL), Leukemia Clinical Research Foundation, University of Chicago Comprehensive Cancer Center, Beckman Coulter Corporation, Celgene Corporation, Dako, Genentech Corporation, Incyte Corporation, Leica Corporation, Millennium Pharmaceuticals, Pharmacyclics, Seattle Genetics Corporation, Sysmex Corporation, and Ventana Medical Systems, Inc, a member of the Roche Group. NR 159 TC 140 Z9 151 U1 14 U2 25 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 MAY 19 PY 2016 VL 127 IS 20 BP 2375 EP 2390 DI 10.1182/blood-2016-01-643569 PG 16 WC Hematology SC Hematology GA DP2QH UT WOS:000378333900008 PM 26980727 ER PT J AU Arber, DA Orazi, A Hasserjian, R Thiele, J Borowitz, MJ Le Beau, MM Bloomfield, CD Cazzola, M Vardiman, JW AF Arber, Daniel A. Orazi, Attilio Hasserjian, Robert Thiele, Jurgen Borowitz, Michael J. Le Beau, Michelle M. Bloomfield, Clara D. Cazzola, Mario Vardiman, James W. TI The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia SO BLOOD LA English DT Review ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; RISK MYELODYSPLASTIC SYNDROMES; SINGLE CEBPA MUTATIONS; PROGNOSTIC SCORING SYSTEM; STEM-CELL TRANSPLANTATION; ACUTE ERYTHROID LEUKEMIA; PHENOTYPE ACUTE-LEUKEMIA; ESSENTIAL THROMBOCYTHEMIA; MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS AB The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here. C1 [Arber, Daniel A.] Stanford Univ, Dept Pathol, 300 Pasteur Dr H1401 M-C 5627, Stanford, CA 94305 USA. [Orazi, Attilio] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Hasserjian, Robert] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Thiele, Jurgen] Univ Cologne, Inst Pathol, Joseph Stelzmann Str 9, Cologne, Germany. [Borowitz, Michael J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Le Beau, Michelle M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Bloomfield, Clara D.] Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. [Cazzola, Mario] Univ Pavia, Dept Mol Med, Via Palestro 3, I-27100 Pavia, Italy. [Cazzola, Mario] Fdn IRCCS Policlin San Matteo, Dept Hematol Oncol, Pavia, Italy. [Vardiman, James W.] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Arber, DA (reprint author), Stanford Univ, Dept Pathol, 300 Pasteur Dr H1401 M-C 5627, Stanford, CA 94305 USA. EM darber@stanford.edu FU American Society of Hematology; Joseph Carreras Foundation; Fondazione Italiana Linfomi (FIL); Leukemia Clinical Research Foundation; University of Chicago Comprehensive Cancer Center; Beckman Coulter Corporation; Celgene Corporation; Dako; Genentech Corporation; Incyte Corporation; Leica Corporation; Millennium Pharmaceuticals; Pharmacyclics; Seattle Genetics Corporation; Sysmex Corporation; Ventana Medical Systems, Inc of the Roche Group FX This work was supported by the Clinical Advisory Committee meeting (Chicago, IL, March 31-April 1, 2014) from the following organizations: American Society of Hematology, Joseph Carreras Foundation, Fondazione Italiana Linfomi (FIL), Leukemia Clinical Research Foundation, University of Chicago Comprehensive Cancer Center, Beckman Coulter Corporation, Celgene Corporation, Dako, Genentech Corporation, Incyte Corporation, Leica Corporation, Millennium Pharmaceuticals, Pharmacyclics, Seattle Genetics Corporation, Sysmex Corporation, and Ventana Medical Systems, Inc, a member of the Roche Group. NR 134 TC 190 Z9 207 U1 21 U2 30 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 MAY 19 PY 2016 VL 127 IS 20 BP 2391 EP 2405 DI 10.1182/blood-2016-03-643544 PG 15 WC Hematology SC Hematology GA DP2QH UT WOS:000378333900009 PM 27069254 ER PT J AU Teira, P Battiwalla, M Ramanathan, M Barrett, AJ Ahn, KW Chen, M Green, JS Saad, A Antin, JH Savani, BN Lazarus, HM Seftel, M Saber, W Marks, D Aljurf, M Norkin, M Wingard, JR Lindemans, CA Boeckh, M Riches, ML Auletta, JJ AF Teira, Pierre Battiwalla, Minoo Ramanathan, Muthalagu Barrett, A. John Ahn, Kwang Woo Chen, Min Green, Jaime S. Saad, Ayman Antin, Joseph H. Savani, Bipin N. Lazarus, Hillard M. Seftel, Matthew Saber, Wael Marks, David Aljurf, Mahmoud Norkin, Maxim Wingard, John R. Lindemans, Caroline A. Boeckh, Michael Riches, Marcie L. Auletta, Jeffery J. TI Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis SO BLOOD LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; RELAPSE RISK EVIDENCE; CMV REACTIVATION; T-CELLS; HEMATOLOGICAL MALIGNANCIES; REDUCED RISK; ALLO-SCT; DONOR AB Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n=5310); acute lymphoblastic leukemia (ALL, n=1883); chronic myeloid leukemia (CML, n= 1079); and myelodysplastic syndrome (MDS, n= 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR=1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR=1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR=1.49; 95% CI, 1.19-1.88; P =.0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P =.003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse. C1 [Teira, Pierre] Univ Montreal, Hop St Justine, Montreal, PQ H3T 1C5, Canada. [Battiwalla, Minoo; Barrett, A. John] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Med, Div Hematol & Oncol, Worcester, MA USA. [Ahn, Kwang Woo; Chen, Min; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Green, Jaime S.] Univ Minnesota, Dept Med, Div Infect Dis & Int Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Antin, Joseph H.] Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Seftel, Matthew] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Marks, David] Univ Hosp Bristol Natl Hlth Serv Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England. [Aljurf, Mahmoud] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Ridayh, Saudi Arabia. [Norkin, Maxim; Wingard, John R.] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [Lindemans, Caroline A.] Univ Med Ctr Utrecht, Pediat Blood & Marrow Transplantat Program, Utrecht, Netherlands. [Boeckh, Michael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Riches, Marcie L.] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. [Auletta, Jeffery J.] Nationwide Childrens Hosp, Host Def Program, Div Hematol Oncol Bone Marrow Transplant, Columbus, OH USA. [Auletta, Jeffery J.] Nationwide Childrens Hosp, Div Infect Dis, Columbus, OH USA. RP Teira, P (reprint author), Univ Montreal, Hop St Justine, Dept Hematol Oncol, 3175 Chemin Cote St Catherine, Montreal, PQ H3T 1C5, Canada. EM pierre.teira.hsj@ssss.gouv.qc.ca OI Saad, Ayman /0000-0003-0003-0130 FU Public Health Service from National Institutes of Health, National Cancer Institute (NCI), National Heart, Lung and Blood Institute (NHLBI) [5U24-CA076518]; National Institute of Allergy and Infectious Diseases (NIAID) [5U24-CA076518]; NHLBI [5U10HL069294]; NCI [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Alexion; Amgen, Inc; Be the Match Foundation; Bristol Myers Squibb Oncology; Celgene Corporation; Chimerix, Inc; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc; Genzyme Corporation; Gilead Sciences, Inc; Health Research, Inc; Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Jazz Pharmaceuticals, Inc; Jeff Gordon Children's Foundation; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co, Inc; Mesoblast; Millennium: The Takeda Oncology Co.; Miltenyi Biotec, Inc; National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Co, Ltd.-Japan; Oxford Immunotec; Perkin Elmer, Inc; Pharmacyclics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Spectrum Pharmaceuticals, Inc; St. Baldrick's Foundation; Sunesis Pharmaceuticals, Inc; Swedish Orphan Biovitrum, Inc; Telomere Diagnostics, Inc; TerumoBCT; Therakos, Inc; University of Minnesota; Wellpoint, Inc. FX This study was conducted on behalf of the Infection and Immune Reconstitution Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) which includes more than 400 members. The CIBMTR is supported by Public Health Service grant/cooperative agreement 5U24-CA076518 from the National Institutes of Health, National Cancer Institute (NCI), National Heart, Lung and Blood Institute (NHLBI), and National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Alexion; *Amgen, Inc; anonymous donation to the Medical College of Wisconsin; Be the Match Foundation; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc; Genzyme Corporation; *Gilead Sciences, Inc; Health Research, Inc Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; *Jazz Pharmaceuticals, Inc; Jeff Gordon Children's Foundation; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc; Mesoblast; *Millennium: The Takeda Oncology Co.; *Miltenyi Biotec, Inc; National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Co, Ltd.-Japan; Oxford Immunotec; Perkin Elmer, Inc; Pharmacyclics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; *Spectrum Pharmaceuticals, Inc; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc; Swedish Orphan Biovitrum, Inc; Telomere Diagnostics, Inc; TerumoBCT; Therakos, Inc; University of Minnesota; and *Wellpoint, Inc. *Corporate members. NR 41 TC 13 Z9 13 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 19 PY 2016 VL 127 IS 20 BP 2427 EP 2438 DI 10.1182/blood-2015-11-679639 PG 12 WC Hematology SC Hematology GA DP2QH UT WOS:000378333900013 PM 26884374 ER PT J AU Forcade, E Kim, HT Cutler, C Wang, K Alho, AC Nikiforow, S Ho, VT Koreth, J Armand, P Alyea, EP Blazar, BR Soiffer, RJ Antin, JH Ritz, J AF Forcade, Edouard Kim, Haesook T. Cutler, Corey Wang, Kathy Alho, Ana C. Nikiforow, Sarah Ho, Vincent T. Koreth, John Armand, Philippe Alyea, Edwin P. Blazar, Bruce R. Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome TI Circulating T follicular helper cells with increased function during chronic graft-versus-host disease SO BLOOD LA English DT Article ID MINOR HISTOCOMPATIBILITY ANTIGEN; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CXC CHEMOKINE RECEPTOR-5; B-CELL; CHRONIC GVHD; ANTIBODY-RESPONSES; BRONCHIOLITIS OBLITERANS; CLINICAL-TRIALS; TFH CELLS; TRANSPLANTATION AB Chronic graft-versus-host disease (cGVHD) remains a major late complication of allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have established that both donor B and T cells contribute to immune pathology in cGVHD but the mechanisms responsible for coordinated B- and T-cell responses directed against recipient antigens have not been understood. T follicular helper cells (TFH) play an important role in the regulation of B-cell immunity. We performed extensive phenotypic and functional analysis of circulating TFH (cTFH) and B cells in 66 patients after HSCT. Patients with active cGVHD had a significantly lower frequency of cTFH compared with patients without cGVHD. This was associated with higher CXCL13 plasma levels suggesting increased homing of TFH to secondary lymphoid organs. In patients with active cGVHD, cTFH phenotype was skewed toward a highly activated profile with predominance of T helper 2 (Th2)/Th17 subsets. Activated cTFH in patients with cGVHD demonstrated increased functional ability to promote B-cell immunoglobulin secretion and maturation. Moreover, the activation signature of cTFH was highly correlated with increased B-cell activation and plasmablast maturation in patients after transplant. These studies provide new insights into the immune pathogenesis of human cGVHD and identify TFH as a key coordinating element supporting B-cell involvement in this disease. C1 [Forcade, Edouard; Cutler, Corey; Wang, Kathy; Alho, Ana C.; Nikiforow, Sarah; Ho, Vincent T.; Koreth, John; Armand, Philippe; Alyea, Edwin P.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Forcade, Edouard; Cutler, Corey; Wang, Kathy; Alho, Ana C.; Nikiforow, Sarah; Ho, Vincent T.; Koreth, John; Armand, Philippe; Alyea, Edwin P.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Forcade, Edouard; Cutler, Corey; Wang, Kathy; Alho, Ana C.; Nikiforow, Sarah; Ho, Vincent T.; Koreth, John; Armand, Philippe; Alyea, Edwin P.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Harvard Univ, Sch Med, Boston, MA USA. [Forcade, Edouard] Bordeaux Univ, CNRS, UMR 5164, Bordeaux, France. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kim, Haesook T.] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Blazar, Bruce R.] Univ Minnesota, Div Blood & Marrow Transplantat, Minneapolis, MN USA. [Ritz, Jerome] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jerome_ritz@dfci.harvard.edu FU National Institutes of Health, National Cancer Institute [P01CA142106, CA183559, CA183560]; Leukemia and Lymphoma Translational Research Grant [6462-15]; MD-PhD Program (Bordeaux Teaching Hospital, France) FX This work was supported by National Institutes of Health, National Cancer Institute grants P01CA142106, CA183559, CA183560, Leukemia and Lymphoma Translational Research Grant 6462-15, and the MD-PhD Program (Bordeaux Teaching Hospital, France). NR 47 TC 6 Z9 6 U1 2 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 19 PY 2016 VL 127 IS 20 BP 2489 EP 2497 DI 10.1182/blood-2015-12-688895 PG 9 WC Hematology SC Hematology GA DP2QH UT WOS:000378333900019 PM 26944544 ER PT J AU Ng, LC Harerimana, B AF Ng, L. C. Harerimana, B. TI Mental health care in post-genocide Rwanda: evaluation of a program specializing in posttraumatic stress disorder and substance abuse SO GLOBAL MENTAL HEALTH LA English DT Article DE Genocide; mental health services; mental illness; policy and systems; program evaluation; Rwanda ID MIDDLE-INCOME COUNTRIES; SCALE-UP; TRAUMA; SERVICES; ILLNESS; BARRIERS; SYSTEM; DISCRIMINATION; SCHIZOPHRENIA; PERSPECTIVES AB Background. Following the genocide, millions of Rwandans are likely living with posttraumatic stress disorder (PTSD). Le Centre Psychotherapeutique Icyizere provides the only specialized treatment for PTSD in the Rwandan healthcare system. Methods. Demographics, diagnosis, treatment, outcomes, and scores on assessments of functioning and PTSD were recorded from clinical charts of all patients receiving care between October 2013 and 2014. Descriptive statistics and within-group t tests comparing functional impairment and PTSD symptoms at intake to discharge and follow-up were calculated. Results. A total of 719 patients (55.08% male) received care. Patients were more educated, more likely to live in the capital, and less likely to be married than the general population. Patients reported high desire for, and strong satisfaction with, care. Most patients (55.60%) were still in care by the end of the program evaluation. Functioning improved from intake to discharge (p < 0.001), and improvements were sustained at follow-up (p < 0.001). Most adults were diagnosed with psychotic disorders, substance use disorders, or depression. Only 20 patients were diagnosed with PTSD, and symptoms were improved at discharge (p = 0.003). Conclusions. This program evaluation demonstrated the utility of a low-resource information management system to provide clarity about the patient population and outcomes. Results suggest that services are effective and sustainable, although people with PTSD were not the primary recipients of care. Disparities in care by diagnosis, education, marital status, and geography are discussed. Results have contributed to changes in service delivery and care and efforts to increase access to care. C1 [Ng, L. C.] Massachusetts Gen Hosp, Dept Psychiat, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Ng, L. C.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Harerimana, B.] Neuropsychiat Hosp CARAES Ndera, Kigali, Rwanda. RP Ng, LC (reprint author), Chester M Pierce MD Div Global Psychiat, 25 Staniford St,2nd Floor, Boston, MA USA. EM lng4@mgh.harvard.edu NR 52 TC 0 Z9 0 U1 7 U2 7 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2054-4251 J9 GLOB MENT HEALTH JI Glob. Ment. Health PD MAY 19 PY 2016 VL 3 AR e18 DI 10.1017/gmh.2016.12 PG 11 WC Psychiatry SC Psychiatry GA DN3WO UT WOS:000376995000001 ER PT J AU Scott, WR Zhang, WH Loh, M Tan, ST Lehne, B Afzal, U Peralta, J Saxena, R Ralhan, S Wander, GS Bozaoglu, K Sanghera, DK Elliott, P Scott, J Chambers, JC Kooner, JS AF Scott, William R. Zhang, Weihua Loh, Marie Tan, Sian-Tsung Lehne, Benjamin Afzal, Uzma Peralta, Juan Saxena, Richa Ralhan, Sarju Wander, Gurpreet S. Bozaoglu, Kiymet Sanghera, Dharambir K. Elliott, Paul Scott, James Chambers, John C. Kooner, Jaspal S. TI Investigation of Genetic Variation Underlying Central Obesity amongst South Asians SO PLOS ONE LA English DT Article ID FOR-GESTATIONAL-AGE; METABOLIC-SYNDROME; FAT DISTRIBUTION; WAIST CIRCUMFERENCE; DNA METHYLATION; BLACK-AFRICAN; BIRTH-WEIGHT; CARDIOVASCULAR-DISEASE; LONGITUDINAL CHANGES; INSULIN SENSITIVITY AB South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of similar to 250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10(-8); variants showing equivocal association with WHR (P<1x10(-5)) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population- specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10(-6) or grouped by gene locus at P<2.5x10(-6). At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10(-8)). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans. C1 [Scott, William R.; Zhang, Weihua; Loh, Marie; Lehne, Benjamin; Afzal, Uzma; Elliott, Paul; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Epidemiol & Biostat, Norfolk Pl, London, England. [Scott, William R.; Tan, Sian-Tsung; Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, Du Cane Rd, London, England. [Zhang, Weihua; Tan, Sian-Tsung; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Southall, Middx, England. [Peralta, Juan] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Genom Comp Ctr, Brownsville, TX USA. [Saxena, Richa] Massachusetts Gen Hosp, Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Ralhan, Sarju; Wander, Gurpreet S.] Hero DMC Heart Inst, Ludhiana, Punjab, India. [Bozaoglu, Kiymet] Baker IDI Heart & Diabet Inst, Genom & Syst Biol, Melbourne, Vic, Australia. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Ctr Neurosci, Oklahoma City, OK USA. [Elliott, Paul; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Norfolk Pl, London, England. [Scott, James; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, Du Cane Rd, London, England. RP Scott, WR (reprint author), Univ London Imperial Coll Sci Technol & Med, Epidemiol & Biostat, Norfolk Pl, London, England.; Scott, WR (reprint author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, Du Cane Rd, London, England. EM wrscott@doctors.org.uk OI Bozaoglu, Kiymet/0000-0002-0807-2813 FU National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; British Heart Foundation [SP/04/002]; Medical Research Council [G0601966, G0700931]; Wellcome Trust [084723/Z/08/Z]; National Institute for Health Research [RP-PG-0407-10371]; National Institute of Health [KO1TW006087]; Fogarty International Center [R01DK082766]; National Institute of Diabetes and Digestive and Kidney Diseases; University of Oklahoma Health Sciences Center, Oklahoma City, USA; Mauritius Ministry of Health and Quality of Life; Australian Government National Health and Medical Research Council NHMRC [1020285, 1037916]; Victorian Government's OIS Program; US National Institutes of Health [DK-25446] FX The LOLIPOP study is supported by the National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002, https://www.bhf.org.uk/), the Medical Research Council (G0601966, G0700931, http://www.mrc.ac.uk/), the Wellcome Trust (084723/Z/08/Z, http://www.wellcome.ac.uk/), and the National Institute for Health Research (RP-PG-0407-10371, http://www.nihr.ac.uk/research/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), and the NIHR (RP-PG-0407-10371). The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The Sikh Diabetes Study is supported by National Institute of Health grants KO1TW006087, funded by the Fogarty International Center, R01DK082766, funded by National Institute of Diabetes and Digestive and Kidney Diseases, and a seed grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. The Mauritius Family Study is supported by the Mauritius Ministry of Health and Quality of Life, Australian Government National Health and Medical Research Council NHMRC project grant numbers 1020285 and 1037916, the Victorian Government's OIS Program, and partly funded by US National Institutes of Health Grant DK-25446. We thank the participants and research staff who made the study possible. NR 71 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2016 VL 11 IS 5 AR e0155478 DI 10.1371/journal.pone.0155478 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM4BR UT WOS:000376291100048 PM 27195708 ER PT J AU Wu, H Fuxreiter, M AF Wu, Hao Fuxreiter, Monika TI The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules SO CELL LA English DT Review ID INTRINSICALLY DISORDERED PROTEINS; LOW-COMPLEXITY DOMAINS; RNA-POLYMERASE-II; SIGNALING COMPLEXES; PHASE-TRANSITIONS; LIQUID DROPLETS; CRYSTAL-STRUCTURE; FUZZY COMPLEXES; PRION FORMATION; FG HYDROGELS AB We here attempt to achieve an integrated understanding of the structure and dynamics of a number of higher-order assemblies, including amyloids, various kinds of signalosomes, and cellular granules. We propose that the synergy between folded domains, linear motifs, and intrinsically disordered regions regulates the formation and intrinsic fuzziness of all higher-order assemblies, creating a structural and dynamic continuum. We describe how such regulatory mechanisms could be influenced under pathological conditions. C1 [Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Fuxreiter, Monika] Univ Debrecen, Dept Biochem & Mol Biol, Lab Prot Dynam, MTA DE Momentum, H-4010 Debrecen, Hungary. RP Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Wu, H (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Fuxreiter, M (reprint author), Univ Debrecen, Dept Biochem & Mol Biol, Lab Prot Dynam, MTA DE Momentum, H-4010 Debrecen, Hungary. EM wu@crystal.harvard.edu; fmoni@med.unideb.hu FU NIAID NIH HHS [R01 AI045937, R01 AI050872]; NICHD NIH HHS [DP1 HD087988] NR 97 TC 12 Z9 12 U1 11 U2 30 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 MAY 19 PY 2016 VL 165 IS 5 BP 1055 EP 1066 DI 10.1016/j.cell.2016.05.004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM6QT UT WOS:000376478200008 PM 27203110 ER PT J AU Kuriakose, SM Singh, R Uzonna, JE AF Kuriakose, Shiby M. Singh, Rani Uzonna, Jude E. TI Host Intracellular Signaling Events and Pro-inflammatory Cytokine Production in African Trypanosomiasis SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE African trypanosomiasis; intracellular signaling peptides and proteins; pro-inflammatory cytokines; innate immune response; host-parasite interactions ID REGULATORY T-CELLS; NECROSIS-FACTOR-ALPHA; VARIANT SURFACE GLYCOPROTEIN; TOLL-LIKE RECEPTORS; ALTERNATIVELY ACTIVATED MACROPHAGES; MEDIATES EARLY MORTALITY; APOLIPOPROTEIN L-I; NITRIC-OXIDE; INNATE IMMUNITY; CONGOLENSE INFECTIONS AB Pathogens, such as bacteria, viruses, and parasites, possess specific molecules or proteins that are recognized by several host innate immune receptors, leading to the activation of several intracellular signaling molecules and pathways. The magnitude and quality of these events significantly affect the outcome of infection. African trypanosomes, including Trypanosoma congolense, are capable of manipulating the host immune response, including the activity of macrophages, which are the key immune cells that contribute to the immunopathogenesis of African trypanosomiasis. Although it is known that immune hyperactivation and excessive pro-inflammatory cytokine production are the hallmarks of African trypanosomiasis, the mechanisms through which these events are triggered are poorly defined. However, it is known that macrophages may play a significant role in these processes, because phagocytosis of trypanosomes by macrophages initiates intracellular signal transduction cascades that lead to the release of pro-inflammatory cytokines and alteration in cell function. This review highlights recent progress in our understanding of the innate immune receptors, signaling pathways, and transcription factors involved in T. congolense-induced pro-inflammatory cytokine production in macrophages. It will reveal the existence of complex signaling events through which the parasite modulates the host immune response, thus identifying novel targets that could aid in designing strategies to effectively control the disease. C1 [Kuriakose, Shiby M.; Singh, Rani; Uzonna, Jude E.] Univ Manitoba, Fac Hlth Sci, Dept Immunol, Winnipeg, MB, Canada. [Singh, Rani] Harvard Univ, Sch Dent Med, Dept Immunol & Infect Dis, Forsyth Inst, Cambridge, MA 02138 USA. RP Uzonna, JE (reprint author), Univ Manitoba, Fac Hlth Sci, Dept Immunol, Winnipeg, MB, Canada. EM jude.uzonna@umanitoba.ca FU Natural Sciences and Engineering Research Council of Canada; Research Manitoba; Research Manitoba Doctoral Fellowship FX Funding for this work was provided, in part, by the Natural Sciences and Engineering Research Council of Canada and Research Manitoba (JU). SK is supported by Research Manitoba Doctoral Fellowship. NR 97 TC 0 Z9 0 U1 5 U2 8 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 MAY 19 PY 2016 VL 7 AR 181 DI 10.3389/fimmu.2016.00181 PG 10 WC Immunology SC Immunology GA DM0UL UT WOS:000376061200001 PM 27242788 ER PT J AU Middelbeek, RJ Brown, FM Patti, ME AF Middelbeek, Roeland J. Brown, Florence M. Patti, Mary-Elizabeth TI Weight Loss and Health Status after Bariatric Surgery in Adolescents SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Middelbeek, Roeland J.; Brown, Florence M.; Patti, Mary-Elizabeth] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Patti, ME (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM maryelizabeth.patti@joslin.harvard.edu NR 4 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1988 EP 1989 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600016 PM 27192680 ER PT J AU Michler, RE Smith, PK Parides, MK Ailawadi, G Thourani, V Moskowitz, AJ Acker, MA Hung, JW Chang, HL Perrault, LP Gillinov, AM Argenziano, M Bagiella, E Overbey, JR Moquete, EG Gupta, LN Miller, MA Taddei-Peters, WC Jeffries, N Weisel, RD Rose, EA Gammie, JS DeRose, JJ Puskas, JD Dagenais, F Burks, SG El-Hamamsy, I Milano, CA Atluri, P Voisine, P O'Gara, PT Gelijns, AC AF Michler, R. E. Smith, P. K. Parides, M. K. Ailawadi, G. Thourani, V. Moskowitz, A. J. Acker, M. A. Hung, J. W. Chang, H. L. Perrault, L. P. Gillinov, A. M. Argenziano, M. Bagiella, E. Overbey, J. R. Moquete, E. G. Gupta, L. N. Miller, M. A. Taddei-Peters, W. C. Jeffries, N. Weisel, R. D. Rose, E. A. Gammie, J. S. DeRose, J. J., Jr. Puskas, J. D. Dagenais, F. Burks, S. G. El-Hamamsy, I. Milano, C. A. Atluri, P. Voisine, P. O'Gara, P. T. Gelijns, A. C. CA CTSN TI Two-Year Outcomes of Surgical Treatment of Moderate Ischemic Mitral Regurgitation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; CHRONIC HEART-FAILURE; MYOCARDIAL-INFARCTION; PROGNOSTIC VALUE; BYPASS SURGERY; SURVIVAL; REVASCULARIZATION; TRIAL; ECHOCARDIOGRAPHY; VIABILITY AB BACKGROUND In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS At 2 years, the mean (+/- SD) LVESVI was 41.2 +/- 20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2 +/- 20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P = 0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P = 0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P< 0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.) C1 [Michler, R. E.; DeRose, J. J., Jr.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Cardiothorac & Vasc Surg, New York, NY USA. [Parides, M. K.; Moskowitz, A. J.; Chang, H. L.; Bagiella, E.; Overbey, J. R.; Moquete, E. G.; Gupta, L. N.; Gelijns, A. C.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Int Ctr Hlth Outcomes & Innovat Res InCHOIR, New York, NY 10029 USA. [Argenziano, M.] Columbia Univ, Coll Phys & Surg, Dept Surg, Div Cardiothorac Surg, New York, NY USA. [Rose, E. A.; Puskas, J. D.] Mt Sinai Hlth Syst, Dept Cardiac Surg, New York, NY USA. [Smith, P. K.; Milano, C. A.] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. [Ailawadi, G.; Burks, S. G.] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Thourani, V.] Emory Univ, Sch Med, Div Cardiothorac Surg, Clin Res Unit, Atlanta, GA 30322 USA. [Acker, M. A.; Atluri, P.] Univ Penn, Sch Med, Dept Surg, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Hung, J. W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Gara, P. T.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Perrault, L. P.; El-Hamamsy, I.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Weisel, R. D.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Weisel, R. D.] Univ Toronto, Toronto Gen Hosp, Div Cardiovasc Surg, Univ Hlth Network, Toronto, ON M5G 1L7, Canada. [Weisel, R. D.] Univ Toronto, Div Cardiac Surg, Toronto, ON, Canada. [Dagenais, F.; Voisine, P.] Hop Laval, Inst Univ Cardiol Quebec, Quebec City, PQ, Canada. [Gillinov, A. M.] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44195 USA. [Miller, M. A.; Taddei-Peters, W. C.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Jeffries, N.] NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. [Gammie, J. S.] Univ Maryland, Med Ctr, Dept Surg, Baltimore, MD 21201 USA. RP Gelijns, AC (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, 1Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM annetine.gelijns@mountsinai.org OI Moskowitz, Alan/0000-0002-4412-9450; Browndyke, Jeffrey/0000-0002-8573-7073 FU National Institutes of Health; Canadian Institutes of Health Research FX Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988. NR 25 TC 16 Z9 16 U1 2 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1932 EP 1941 DI 10.1056/NEJMoa1602003 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600006 PM 27040451 ER PT J AU Ronthal, M Venna, N Hunter, GJ Frosch, MP AF Ronthal, Michael Venna, Nagagopal Hunter, George J. Frosch, Matthew P. TI Case 15-2016: A 32-Year-Old Man with Olfactory Hallucinations and Paresthesias SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PRIMARY SJOGREN-SYNDROME; BRAIN-TUMORS; SARCOIDOSIS; NEUROSARCOIDOSIS; MANIFESTATIONS; INFLIXIMAB; PROGRESS; LESIONS; MASS C1 [Ronthal, Michael] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Venna, Nagagopal] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hunter, George J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ronthal, Michael; Venna, Nagagopal] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Hunter, George J.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Ronthal, M (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA.; Ronthal, M (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. NR 25 TC 0 Z9 0 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 19 PY 2016 VL 374 IS 20 BP 1966 EP 1975 DI 10.1056/NEJMcpc1516449 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DM1OX UT WOS:000376116600011 PM 27192675 ER PT J AU Nielsen, CS Jans, O Orsnes, T Foss, NB Troelsen, A Husted, H AF Nielsen, Christian Skovgaard Jans, Oivind Orsnes, Thue Foss, Nicolai Bang Troelsen, Anders Husted, Henrik TI Combined Intra-Articular and Intravenous Tranexamic Acid Reduces Blood Loss in Total Knee Arthroplasty A Randomized, Double-Blind, Placebo-Controlled Trial SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID TOTAL HIP; CLINICAL-TRIAL; TOURNIQUET USE; REPLACEMENT; METAANALYSIS; TRANSFUSION; EFFICACY; FIXATION; OUTCOMES; RSA AB Background: In total knee arthroplasty, both intravenous (IV) and intra-articular (IA) administration of tranexamic acid (TXA) have been shown to reduce blood loss in several randomized controlled trials, although routine use of systemic TXA is considerably more common. However, to our knowledge, the additional benefit of IA administration of TXA when combined with IV administration, without the use of a tourniquet, has not been previously investigated. Thus, the aim of this study was to evaluate whether combined IV and IA administration of TXA reduced total blood loss compared with IV-only administration of TXA. Methods: In this randomized, double-blind, placebo-controlled trial, 60 patients scheduled for total knee arthroplasty were randomized to one of two interventions. The TXA IV and IA group received combined administration of TXA consisting of 1 g administered intravenously preoperatively and 3 g diluted in 100 mL of saline solution administered intra-articularly after closure of the capsule. The TXA IV and placebo group received 1 g of TXA administered intravenously only and 100 mL of saline solution administered intra-articularly. IA TXA was administrated through a needle. The primary outcome was the 24-hour calculated blood loss. Secondary outcomes were blood loss on postoperative day 2, thromboembolic complications, and transfusion rate. Blood loss was calculated by hemoglobin differences using the Gross formula. Results: Data on the primary outcome were available for all 60 included patients. Baseline characteristics were comparable between the allocation groups. The mean 24-hour blood loss (and standard deviation) was 466 +/- 313 mL in the TXA IV and IA group compared with 743 +/- 358 mL in the TXA IV and placebo group; treatment effect (difference), 277 mL (95% confidence interval [CI], 103 to 451 mL) (p = 0.002). Second-day blood loss was 644 +/- 382 mL in the TXA IV and IA group compared with 1017 +/- 519 mL in the TXA IV and placebo group; treatment effect, 373 mL (95% CI, 132 to 614 mL) (p = 0.003). No thromboembolic complications were observed within 90 days postoperatively. Conclusions: The combined administration of IV and IA TXA resulted in a clinically relevant reduction in blood loss of 37% compared with IV TXA alone both at 24 hours postoperatively and on postoperative day 2. No thromboembolic complications were observed. C1 [Nielsen, Christian Skovgaard; Jans, Oivind; Orsnes, Thue; Foss, Nicolai Bang; Troelsen, Anders; Husted, Henrik] Copenhagen Univ Hosp Hvidovre, Dept Orthopaed Surg, Copenhagen, Denmark. [Foss, Nicolai Bang] Copenhagen Univ Hosp Hvidovre, Dept Anesthesia, Copenhagen, Denmark. [Nielsen, Christian Skovgaard] Massachusetts Gen Hosp, Dept Orthopaed Surg, Harris Orthopaed Lab, Boston, MA 02114 USA. [Jans, Oivind] Rigshosp, Sect Surg Pathophysiol, DK-2100 Copenhagen, Denmark. [Jans, Oivind; Troelsen, Anders; Husted, Henrik] Lundbeck Fdn Ctr Fast Track Hip & Knee Arthroplas, Copenhagen, Denmark. RP Nielsen, CS (reprint author), Copenhagen Univ Hosp Hvidovre, Dept Orthopaed Surg, Copenhagen, Denmark.; Nielsen, CS (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Harris Orthopaed Lab, Boston, MA 02114 USA. EM christianskovgaard@dadlnet.dk; oeivind.jans@rh.regionh.dk; Thue.Oersnes@regionh.dk; nicolai.bang.foss@regionh.dk; henrikhusted@dadlnet.dk NR 36 TC 11 Z9 12 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAY 18 PY 2016 VL 98 IS 10 BP 835 EP 841 DI 10.2106/JBJS.15.00810 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DP6XZ UT WOS:000378644500010 PM 27194493 ER PT J AU Schaffert, DH Okholm, AH Sorensen, RS Nielsen, JS Torring, T Rosen, CB Kodal, ALB Mortensen, MR Gothelf, KV Kjems, J AF Schaffert, David H. Okholm, Anders H. Sorensen, Rasmus S. Nielsen, Jesper S. Torring, Thomas Rosen, Christian B. Kodal, Anne Louise B. Mortensen, Michael R. Gothelf, Kurt V. Kjems, Jorgen TI Intracellular Delivery of a Planar DNA Origami Structure by the Transferrin-Receptor Internalization Pathway SO SMALL LA English DT Article ID DRUG-DELIVERY; MEDIATED ENDOCYTOSIS; GENE-DELIVERY; TARGETED TRANSPORT; CANCER-THERAPY; PH CHANGES; CELLS; NANOSTRUCTURES; BINDING; SYSTEM AB DNA origami provides rapid access to easily functionalized, nanometer-sized structures making it an intriguing platform for the development of defined drug delivery and sensor systems. Low cellular uptake of DNA nanostructures is a major obstacle in the development of DNA-based delivery platforms. Herein, significant strong increase in cellular uptake in an established cancer cell line by modifying a planar DNA origami structure with the iron transport protein transferrin (Tf) is demonstrated. A variable number of Tf molecules are coupled to the origami structure using a DNA-directed, site-selective labeling technique to retain ligand functionality. A combination of confocal fluorescence microscopy and quantitative (qPCR) techniques shows up to 22-fold increased cytoplasmic uptake compared to unmodified structures and with an efficiency that correlates to the number of transferrin molecules on the origami surface. C1 [Schaffert, David H.; Okholm, Anders H.; Sorensen, Rasmus S.; Nielsen, Jesper S.; Kjems, Jorgen] Univ Aarhus, Dept Mol Biol & Genet, CF Mollers Alle 3, DK-8000 Aarhus C, Denmark. [Schaffert, David H.; Okholm, Anders H.; Sorensen, Rasmus S.; Nielsen, Jesper S.; Torring, Thomas; Rosen, Christian B.; Kodal, Anne Louise B.; Mortensen, Michael R.; Gothelf, Kurt V.; Kjems, Jorgen] Univ Aarhus, Ctr DNA Nanotechnol, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. [Schaffert, David H.; Okholm, Anders H.; Sorensen, Rasmus S.; Nielsen, Jesper S.; Torring, Thomas; Rosen, Christian B.; Kodal, Anne Louise B.; Mortensen, Michael R.; Gothelf, Kurt V.; Kjems, Jorgen] Univ Aarhus, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. [Torring, Thomas; Rosen, Christian B.; Kodal, Anne Louise B.; Mortensen, Michael R.; Gothelf, Kurt V.] Univ Aarhus, Dept Chem, Langelandsgade 140, DK-8000 Aarhus C, Denmark. [Schaffert, David H.] BASF, D-67056 Ludwigshafen, Germany. [Sorensen, Rasmus S.] Harvard Univ, Sch Med, Wyss Inst, Boston, MA 02115 USA. [Sorensen, Rasmus S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kjems, J (reprint author), Univ Aarhus, Dept Mol Biol & Genet, CF Mollers Alle 3, DK-8000 Aarhus C, Denmark.; Kjems, J (reprint author), Univ Aarhus, Ctr DNA Nanotechnol, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.; Kjems, J (reprint author), Univ Aarhus, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark. EM jk@mbg.au.dk FU Center for DNA Nanotechnology (CDNA); Danish National Research Foundation [DNRF81]; Aarhus University, Graduate School of Science and Technology FX D.H.S. and A.H.O. contributed equally to this work. The authors thank Claus Bus and Rita Rosendahl for valuable assistance. This work was supported by the Center for DNA Nanotechnology (CDNA), the Danish National Research Foundation (DNRF81) and Aarhus University, Graduate School of Science and Technology. NR 35 TC 5 Z9 5 U1 17 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD MAY 18 PY 2016 VL 12 IS 19 BP 2634 EP 2640 DI 10.1002/smll.201503934 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DP3VN UT WOS:000378424100013 PM 27032044 ER PT J AU Chung, Y Hancock, KE Delgutte, B AF Chung, Yoojin Hancock, Kenneth E. Delgutte, Bertrand TI Neural Coding of Interaural Time Differences with Bilateral Cochlear Implants in Unanesthetized Rabbits SO JOURNAL OF NEUROSCIENCE LA English DT Article DE binaural hearing; cochlear implant; inferior colliculus; interaural time difference; temporal coding ID INFERIOR COLLICULUS NEURONS; ELECTRICAL-STIMULATION; AUDITORY-NERVE; FINE-STRUCTURE; PULSE TRAINS; SPEECH-PERCEPTION; PITCH PERCEPTION; POINT-NEURON; LOCALIZATION; SENSITIVITY AB Although bilateral cochlear implants (CIs) provide improvements in sound localization and speech perception in noise over unilateral CIs, bilateral CI users' sensitivity to interaural time differences (ITDs) is still poorer than normal. In particular, ITD sensitivity of most CI users degrades with increasing stimulation rate and is lacking at the high carrier pulse rates used in CI processors to deliver speech information. To gain a better understanding of the neural basis for this degradation, we characterized ITD tuning of single neurons in the inferior colliculus (IC) for pulse train stimuli in an unanesthetized rabbit model of bilateral CIs. Approximately 73% of IC neurons showed significant ITD sensitivity in their overall firing rates. On average, ITD sensitivity was best for pulse rates near 80-160 pulses per second (pps) and degraded for both lower and higher pulse rates. The degradation in ITD sensitivity at low pulse rates was caused by strong, unsynchronized background activity that masked stimulus-driven responses in many neurons. Selecting synchronized responses by temporal windowing revealed ITD sensitivity in these neurons. With temporal windowing, both the fraction of ITD-sensitive neurons and the degree of ITD sensitivity decreased monotonically with increasing pulse rate. To compare neural ITD sensitivity to human performance in ITD discrimination, neural just-noticeable differences (JNDs) in ITD were computed using signal detection theory. Using temporal windowing at lower pulse rates, and overall firing rate at higher pulse rates, neural ITD JNDs were within the range of perceptual JNDs in human CI users over a wide range of pulse rates. C1 [Chung, Yoojin; Hancock, Kenneth E.; Delgutte, Bertrand] Massachusetts Eye & Ear, Eaton Peabody Labs, Boston, MA 02114 USA. [Chung, Yoojin; Hancock, Kenneth E.; Delgutte, Bertrand] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA. RP Chung, Y (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. EM yoojin.chung@gmail.com FU National Institutes of Health Grants [R01 DC005775, P30 DC005209]; Massachusetts Eye and Ear through Curing Kids Fund; Hearing Health Foundation Emerging Research Grant FX This work was supported by National Institutes of Health Grants R01 DC005775 and P30 DC005209, Massachusetts Eye and Ear through the Curing Kids Fund, and the Hearing Health Foundation Emerging Research Grant (Y.C.). We thank Bernhard Laback, Katharina Egger, and Piotr Majdak for sharing ITD threshold data from human subjects. We thank Connie Miller, Melissa McKinnon, and Michelle Vhudzijena for technical assistance, and Michael Kaplan for advice regarding surgery. NR 50 TC 1 Z9 1 U1 2 U2 5 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 MAY 18 PY 2016 VL 36 IS 20 BP 5520 EP 5531 DI 10.1523/JNEUROSCI.3795-15.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DP2OX UT WOS:000378329700010 PM 27194332 ER PT J AU Gymrek, M Farjoun, Y AF Gymrek, Melissa Farjoun, Yossi TI Recommendations for open data science SO GIGASCIENCE LA English DT Editorial Material DE Reproducible research; Open science; Best practices AB Life science research increasingly relies on large-scale computational analyses. However, the code and data used for these analyses are often lacking in publications. To maximize scientific impact, reproducibility, and reuse, it is crucial that these resources are made publicly available and are fully transparent. We provide recommendations for improving the openness of data-driven studies in life sciences. C1 [Gymrek, Melissa] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Gymrek, Melissa] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Farjoun, Yossi] Broad Inst MIT & Harvard, Data Sci & Data Engn, Cambridge, MA USA. RP Gymrek, M (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.; Gymrek, M (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM gymrek@broadinstitute.org NR 7 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 2047-217X J9 GIGASCIENCE JI GigaScience PD MAY 18 PY 2016 VL 5 AR 22 DI 10.1186/s13742-016-0127-4 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM6VK UT WOS:000376490600002 PM 27195107 ER PT J AU Allen, JD Torres, MI Tom, LS Leyva, B Galeas, AV Ospino, H AF Allen, Jennifer D. Torres, Maria Idali Tom, Laura S. Leyva, Bryan Galeas, Ana V. Ospino, Hosffman TI Dissemination of evidence-based cancer control interventions among Catholic faith-based organizations: results from the CRUZA randomized trial SO IMPLEMENTATION SCIENCE LA English DT Article DE Latinos; Hispanics; Faith-based organizations; Catholic; Cancer screening; Evidence-based interventions; Implementation science; Organizational capacity; Capacity building; Community-based participatory research ID HEALTH DISPARITIES; IMPLEMENTATION SCIENCE; SCREENING BEHAVIORS; CONCEPTUAL-FRAMEWORK; PREVENTION PROGRAMS; COMMUNITY CAPACITY; AFRICAN-AMERICANS; CHURCH; LATINAS; DESIGN AB Background: The CRUZA randomized trial tested the efficacy of an organizational-level intervention to increase the capacity of Catholic faith-based organizations (FBOs) serving Latinos to implement evidence-based strategies (EBS) for cancer control. Methods: Thirty-one Catholic parishes were enrolled. Twenty were randomized to a "capacity enhancement" (CE) intervention and 11 to a "standard dissemination" (SD) condition. Each received a Program Implementation Manual and Toolkit of materials culturally adapted for FBOs with Latino audiences for five types of EBS recommended by the US Preventive Services Community Guide. CE parishes were offered a menu of capacity-building activities over a 3-month period, while SD parishes were provided a one-time consultation by an Intervention Specialist. Baseline and follow-up surveys compared the number and types of EBS offered. Results: At baseline, only one parish had offered any cancer-related program in the prior year, yet a third (36 %) had offered some other type of health program or service. At post-intervention follow-up, all parishes offered a greater number of EBS. The only statistically significant difference between CE and SD groups was the number of parishes offering small media interventions (90 % in CE, 64 % in SD; p < 0.05). Conclusions: All parishes increased the number of cancer control activities offered to their members. These findings suggest that Catholic parishes may already have capacity to implement EBS if they are appropriately adapted and packaged and may only require low levels of support to carry out programming. Further research is needed to examine the extent to which program offerings continued after the period of grant funding. C1 [Allen, Jennifer D.] Tufts Univ, Community Hlth Program, Medford, MA 02155 USA. [Allen, Jennifer D.] Tufts Univ, Dept Publ Hlth & Community Med, Medford, MA 02155 USA. [Allen, Jennifer D.; Tom, Laura S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Torres, Maria Idali; Galeas, Ana V.] Univ Massachusetts, Mauricio Gaston Inst Latino Community Dev & Publ, Boston, MA 02125 USA. [Leyva, Bryan] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Ospino, Hosffman] Boston Coll, Chestnut Hill, MA 02167 USA. RP Allen, JD (reprint author), Tufts Univ, Community Hlth Program, Medford, MA 02155 USA.; Allen, JD (reprint author), Tufts Univ, Dept Publ Hlth & Community Med, Medford, MA 02155 USA.; Allen, JD (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM jennifer.allen@tufts.edu FU National Cancer Institute [U54CA156732, U48DP001946]; National Institute on Minority Health and Health Disparities [R21MD005976]; Centers for Disease Control and Prevention FX This work was supported in part by the National Cancer Institute (U54CA156732, UMASS Boston/Dana-Farber Harvard Cancer Center Comprehensive Cancer Partnership Program), the National Institute on Minority Health and Health Disparities (R21MD005976), and through a cooperative agreement by the Centers for Disease Control and Prevention with the National Cancer Institute (U48DP001946, Massachusetts Cancer Prevention and Control Research Network). The authors gratefully acknowledge the time and insights provided by study participants and our community advisory committee. We also acknowledge the many contributions made by Milagros Abreu, Amanda Bartholomew, Lois Biener, Deb Bowen, Melissa Colon, Daisy Diaz, Karen Emmons, Ericka Gonzalez, Elizabeth Gonzalez Suarez, Elizabeth Harden, Christina Hernandez, Lina Jandorf, Alan Juarez, Ruth Lederman, Laura Linnan, Carol Lowenstein, Hannah Mills, Rosalyn Negron, Aida Palencia, Beninson Pena, John Perez, Luciano Ramos, Lori-Anne Ramsey, Bianka Recinos, Maria Sesma, Sarfaraz Shaikh, Rachel Tsavalakoglou, Emeli Valverde, Bryan Weiner and from the UMASS Boston Center for Survey Research-Scott McInerny, Lee Hargraves, Philip Brenner, George Markos. NR 72 TC 0 Z9 0 U1 4 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 MAY 18 PY 2016 VL 11 AR 74 DI 10.1186/s13012-016-0430-6 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DM1GF UT WOS:000376092700002 PM 27193768 ER PT J AU Pinto, F Pertega-Gomes, N Vizcaino, JR Andrade, RP Carcano, FM Reis, RM AF Pinto, Filipe Pertega-Gomes, Nelma Vizcaino, Jose R. Andrade, Raquel P. Carcano, Flavio M. Reis, Rui Manuel TI Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer SO ONCOTARGET LA English DT Article DE Brachyury; prostate cancer; therapy resistance ID EPITHELIAL-MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR BRACHYURY; MITOXANTRONE PLUS PREDNISONE; DEPRIVATION THERAPY; INCREASED SURVIVAL; CARCINOMA-CELLS; DOCETAXEL; EXPRESSION; ASSOCIATION; CABAZITAXEL AB Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients. C1 [Pinto, Filipe; Reis, Rui Manuel] Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, Braga, Portugal. [Pinto, Filipe; Reis, Rui Manuel] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Pertega-Gomes, Nelma] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Vizcaino, Jose R.] Ctr Hosp Porto, Dept Pathol, Oporto, Portugal. [Andrade, Raquel P.] Univ Algarve, Ctr Biomed Res, CBMR, Faro, Portugal. [Andrade, Raquel P.] Univ Algarve, Dept Med & Biomed Sci, Regenerat Med Program, Faro, Portugal. [Carcano, Flavio M.] Barretos Canc Hosp, Dept Clin Oncol, Barretos, SP, Brazil. [Carcano, Flavio M.; Reis, Rui Manuel] Barretos Canc Hosp, Mol Oncol Res Ctr, Barretos, SP, Brazil. RP Reis, RM (reprint author), Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, Braga, Portugal.; Reis, RM (reprint author), ICVS 3Bs PT Govt Associate Lab, Braga, Portugal.; Reis, RM (reprint author), Barretos Canc Hosp, Mol Oncol Res Ctr, Barretos, SP, Brazil. EM rreis@ecsaude.uminho.pt OI Pinto, Filipe/0000-0003-2330-9863; Andrade, Raquel/0000-0002-0397-5917; Reis, Rui/0000-0002-9639-7940 FU ICVS; Molecular Oncology Research Center; FCT [SFRH/BD/81369/2011]; National Counsel of Technological and Scientific Development (CNPq); [UID/BIM/04773/2013 CBMR 1334] FX This study was partially supported by the ICVS, and Molecular Oncology Research Center internal research founds and by UID/BIM/04773/2013 CBMR 1334. F. Pinto received fellowship from FCT ref SFRH/BD/81369/2011. R.M. Reis has a National Counsel of Technological and Scientific Development (CNPq) scholarship. NR 44 TC 2 Z9 2 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 17 PY 2016 VL 7 IS 20 BP 28891 EP 28902 DI 10.18632/oncotarget.8499 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HO UT WOS:000377742600011 PM 27049720 ER PT J AU Wang, AL Wu, H Chen, C Hu, C Qi, ZP Wang, WC Yu, KL Liu, XC Zou, FM Zhao, Z Wu, JX Liu, J Liu, FY Wang, L Stone, RM Galinksy, IA Griffin, JD Zhang, SC Weisberg, EL Liu, J Liu, QS AF Wang, Aoli Wu, Hong Chen, Cheng Hu, Chen Qi, Ziping Wang, Wenchao Yu, Kailin Liu, Xiaochuan Zou, Fengming Zhao, Zheng Wu, Jiaxin Liu, Juan Liu, Feiyang Wang, Li Stone, Richard M. Galinksy, Ilene A. Griffin, James D. Zhang, Shanchun Weisberg, Ellen L. Liu, Jing Liu, Qingsong TI Dual Inhibition of AKT/FLT3-ITD by A674563 Overcomes FLT3 Ligand-Induced Drug Resistance in FLT3-ITD positive AML SO ONCOTARGET LA English DT Article DE acute myeloid leukemia; FLT3-ITD; AKT; A6745763; FLT3-Ligand ID ACUTE MYELOID-LEUKEMIA; KINASE INHIBITOR; IN-VIVO; PROGRESS; POTENT AB The FLT3-ITD mutation is one of the most prevalent oncogenic mutations in AML. Several FLT3 kinase inhibitors have shown impressive activity in clinical evaluation, however clinical responses are usually transient and clinical effects are rapidly lost due to drug resistance. One of the resistance mechanisms in the AML refractory patients involves FLT3-ligand induced reactivation of AKT and/or ERK signaling via FLT3 wt kinase. Via a screen of numerous AKT kinase inhibitors, we identified the well-established orally available AKT inhibitor, A674563, as a dual suppressor of AKT and FLT3-ITD. A674563 suppressed FLT3-ITD positive AML both in vitro and in vivo. More importantly, compared to other FLT3 inhibitors, A674563 is able to overcome FLT3 ligand-induced drug resistance through simultaneous inhibition of FLT3-ITD- and AKT-mediated signaling. Our findings suggest that A674563 might be a potential drug candidate for overcoming FLT3 ligand-mediated drug resistance in FLT3-ITD positive AML. C1 [Wang, Aoli; Wu, Hong; Chen, Cheng; Hu, Chen; Qi, Ziping; Wang, Wenchao; Yu, Kailin; Liu, Xiaochuan; Zou, Fengming; Zhao, Zheng; Wu, Jiaxin; Liu, Juan; Liu, Feiyang; Wang, Li; Liu, Jing; Liu, Qingsong] Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China. [Wang, Aoli; Wu, Hong; Liu, Xiaochuan; Wu, Jiaxin; Liu, Feiyang; Liu, Qingsong] Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China. [Chen, Cheng; Hu, Chen; Qi, Ziping; Wang, Wenchao; Zou, Fengming; Zhao, Zheng; Wang, Li; Zhang, Shanchun; Liu, Jing; Liu, Qingsong] CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China. [Stone, Richard M.; Galinksy, Ilene A.; Griffin, James D.; Weisberg, Ellen L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Zhang, Shanchun] Hefei Cosource Med Technol Co LTD, Hefei 230031, Anhui, Peoples R China. [Liu, Qingsong] Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. RP Liu, J; Liu, QS (reprint author), Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China.; Liu, QS (reprint author), Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China.; Liu, J; Liu, QS (reprint author), CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China.; Weisberg, EL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA.; Liu, QS (reprint author), Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. EM Ellen_weisberg@dfci.harvard.edu; jingliu@hmfl.ac.cn; qsliu97@hmfl.ac.cn OI liu, jing/0000-0001-9513-3591 FU Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC) [2015SRG-HSC022]; Chinese Academy of Sciences; Anhui Province Natural Science Foundation Annual Key Program [1301023011]; China "Thousand Talents Program" FX This work is supported by Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC # 2015SRG-HSC022). J. Liu, Q. Liu and W. Wang are supported by the grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014-2016)" from Chinese Academy of Sciences. Z. Zhao is supported by Anhui Province Natural Science Foundation Annual Key Program (grant number: 1301023011). Prof. Q. Liu was supported by China "Thousand Talents Program", and Prof. J. Liu and W. Wang by "Hundred Talents Program" of The Chinese Academy of Sciences. NR 19 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 17 PY 2016 VL 7 IS 20 BP 29131 EP 29142 DI 10.18632/oncotarget.8675 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HO UT WOS:000377742600030 PM 27074558 ER PT J AU Singh, H Liu, Y Xiao, XL Lin, L Kim, J Van Hummelen, P Wu, CL Bass, AJ Saylor, PJ AF Singh, Harshabad Liu, Yang Xiao, Xiuli Lin, Ling Kim, Jaegil Van Hummelen, Paul Wu, Chin-Lee Bass, Adam J. Saylor, Philip J. TI Whole exome sequencing of urachal adenocarcinoma reveals recurrent NF1 mutations SO ONCOTARGET LA English DT Article DE urachal adenocarcinoma; NF1; whole exome sequencing ID TESTICULAR-TUMORS; CARCINOMA; CANCER AB Urachal adenocarcinoma is a rare bladder malignancy arising from the urachal remnant. Given its rarity and the lack of knowledge about its genetic characteristics, optimal management of this cancer is not well defined. Practice patterns vary and outcomes remain poor. In order to identify the genomic underpinnings of this malignancy, we performed whole exome sequencing using seven tumor/normal pairs of formalin fixed archival specimens. We identified recurrent evidence of MAP-kinase pathway activation as three patients had neurofibromin 1 (NF1) mutations, with one of these patients also harboring an oncogenic KRAS G13D mutation. We also observed recurrent evidence of Wnt/beta-catenin pathway activation as three patients had oncogenic mutations in APC or RNF43. In addition, somatic copy number analysis revealed focal chromosome 12p amplifications in three samples, resembling findings from testicular germ cell tumors. We describe the genomic landscape of this malignancy in our institutional cohort and propose investigation of the therapeutic potential for MAP-K pathway inhibition in the subset of patients who show evidence of its activation. C1 [Singh, Harshabad; Saylor, Philip J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Singh, Harshabad; Liu, Yang; Xiao, Xiuli; Lin, Ling; Van Hummelen, Paul; Bass, Adam J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Xiao, Xiuli; Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kim, Jaegil] Broad Inst, Cambridge, MA USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA.; Bass, AJ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM adam_bass@dfci.harvard.edu; psaylor@mgh.harvard.edu FU Massachusetts General Hospital Genitourinary Malignancies Program FX This work was sponsored by the Massachusetts General Hospital Genitourinary Malignancies Program. NR 11 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 17 PY 2016 VL 7 IS 20 BP 29211 EP 29215 DI 10.18632/oncotarget.8640 PG 5 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO4HO UT WOS:000377742600037 PM 27078850 ER PT J AU Wasfy, MM Baggish, AL AF Wasfy, Meagan M. Baggish, Aaron L. TI Endurance Exercise and the Right Ventricle: Weak Link, Innocent Bystander, or Key Ingredient? SO CIRCULATION LA English DT Editorial Material DE Editorials; athlete's heart; exercise; fibrosis; heart ventricles ID HEART; DYSFUNCTION; MORPHOLOGY; ATHLETE; HARM C1 [Wasfy, Meagan M.; Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org NR 16 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 17 PY 2016 VL 133 IS 20 BP 1913 EP 1915 DI 10.1161/CIRCULATIONAHA.116.022418 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DM8MT UT WOS:000376618600005 PM 27073130 ER PT J AU Brittain, EL Talati, M Fessel, JP Zhu, H Penner, N Calcutt, MW West, JD Funke, M Lewis, GD Gerszten, RE Hamid, R Pugh, ME Austin, ED Newman, JH Hemnes, AR AF Brittain, Evan L. Talati, Megha Fessel, Joshua P. Zhu, He Penner, Niki Calcutt, M. Wade West, James D. Funke, Mitch Lewis, Gregory D. Gerszten, Robert E. Hamid, Rizwan Pugh, Meredith E. Austin, Eric D. Newman, John H. Hemnes, Anna R. TI Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension SO CIRCULATION LA English DT Article DE fatty acids; heart ventricles; hypertension; pulmonary; lipid metabolism; lipids; magnetic resonance spectroscopy; pulmonary circulation ID INSULIN-RESISTANCE; RESONANCE-SPECTROSCOPY; HEART; DYSFUNCTION; OXIDATION; ACYLCARNITINES; HYPERTROPHY; MUSCLE; STEATOSIS; COMMON AB Background The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH. Methods and Results We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.41.3% triglyceride versus 0.22 +/- 0.11% triglyceride, P=0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH, we demonstrated reduced FA oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV. Conclusions Abnormalities in FA metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggest that lipotoxicity may arise from reduction in FA oxidation. C1 [Brittain, Evan L.] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, 2525 West End Ave,Suite 300, Nashville, TN 37203 USA. [Brittain, Evan L.] Vanderbilt Univ, Med Ctr, Vanderbilt Translat & Clin Cardiovasc Ctr, Nashville, TN 37203 USA. [Talati, Megha; Fessel, Joshua P.; Penner, Niki; West, James D.; Funke, Mitch; Pugh, Meredith E.; Newman, John H.; Hemnes, Anna R.] Vanderbilt Univ, Sch Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37203 USA. [Zhu, He] Vanderbilt Univ, Inst Imaging Sci, Nashville, TN 37203 USA. [Calcutt, M. Wade] Vanderbilt Univ, Dept Biochem, Nashville, TN 37203 USA. [Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Lewis, Gregory D.; Gerszten, Robert E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Gerszten, Robert E.] Broad Inst & Harvard, Cambridge, MA 02139 USA. [Hamid, Rizwan] Vanderbilt Univ, Sch Med, Dept Pediat, Div Med Genet & Genom Med, Nashville, TN 37203 USA. [Austin, Eric D.] Vanderbilt Univ, Sch Med, Dept Pediat, Div Allergy Immunol & Pulm Med, Nashville, TN 37203 USA. RP Brittain, EL (reprint author), Vanderbilt Univ, Sch Med, Div Cardiovasc Med, 2525 West End Ave,Suite 300, Nashville, TN 37203 USA. EM evan.brittain@vanderbilt.edu FU American Heart Association [13FTF16070002]; Pulmonary Hypertension Association Proof-of-Concept Award; Actelion Entelligence Young Investigator Award; National Institutes of Health [K08 HL093363, K23 HL098743, K08 HL121174, R01 122417-01, 1P0 HL108800-01A1]; NCRR/NIH [1 UL1 RR024975]; Core Laboratory for Cardiovascular Translational and Clinical Research; Vanderbilt Heart Bio-repository FX American Heart Association Fellow to Faculty Grant #13FTF16070002, Pulmonary Hypertension Association Proof-of-Concept Award, and Actelion Entelligence Young Investigator Award (to Dr Brittain), National Institutes of Health (K08 HL093363 [to Dr Hemnes], K23 HL098743 [to Dr Austin], K08 HL121174 [to Dr Fessel], R01 122417-01 [to Dr Hemnes], 1P0 HL108800-01A1 [to Drs Brittain, Hemnes, Pugh, Newman, and Austin]), and NCRR/NIH (1 UL1 RR024975 [to Vanderbilt University School of Medicine]). This work was supported in part by the Core Laboratory for Cardiovascular Translational and Clinical Research and the Vanderbilt Heart Bio-repository. NR 38 TC 5 Z9 5 U1 2 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 MAY 17 PY 2016 VL 133 IS 20 BP 1936 EP 1944 DI 10.1161/CIRCULATIONAHA.115.019351 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DM8MT UT WOS:000376618600008 PM 27006481 ER PT J AU Lushaj, EB Schreiner, A Jonuzi, B Badami, A DeOliveira, N Lozonschi, L AF Lushaj, Entela B. Schreiner, Athanasia Jonuzi, Besa Badami, Abbasali DeOliveira, Nilto Lozonschi, Lucian TI Short-term clinical outcomes after off-pump coronary artery bypass grafting at a single Veterans Affairs Medical Center SO JOURNAL OF CARDIOTHORACIC SURGERY LA English DT Article DE CABG; Off-Pump; Outcomes; Veterans Affairs ID ON-PUMP; SURGERY; METAANALYSIS; SURVIVAL; RISK AB Background: We retrospectively assessed the outcomes after coronary revascularization at a single Veterans Affairs Medical Center when a strategy of assigning higher risk patients to off-pump coronary artery bypass grafting (CABG) was employed. Methods: Over a 5 year period all consecutive patients that underwent CABG at our VA Medical Center were assigned to a surgeon who either performs the CABG exclusively off-pump or to one who performed the CABG on-pump. The higher risk patients were assigned preferentially for off-pump revascularization. VASQIP (VA Hospitals Surgical Quality Improvement Program) data between 10/2007 and 12/2012 were retrospectively reviewed at our VA Medical Center and the short term outcomes were assessed. Results: A total of 252 consecutive patients underwent off-pump CABG (n = 170) and on-pump CABG (n = 82). There were significantly more patients with low LVEF (<45 %; p = 0.008) and cerebrovascular disease in the off-pump group (p = 0.024). The number of patients smoking at the time of surgery was significantly higher in the off-pump group (p = 0.002) as well. The 30-day composite morbidity and mortality was 6 % for all CABG patients and significantly lower with off-pump vs. on-pump CABG (3.5 % vs. 11 %; p = 0.019). There were no conversions from off-pump to on-pump surgery. Conclusions: A selective strategy to direct higher risk patients towards an off-pump revascularization yielded favorable outcomes in an unselected veteran population treated at a single VA Medical Center over a 5 year period. C1 [Lushaj, Entela B.; Jonuzi, Besa; Badami, Abbasali; DeOliveira, Nilto; Lozonschi, Lucian] Univ Wisconsin, Div Cardiothorac Surg, Dept Surg, Sch Med & Publ Hlth, 600 Highland Ave, Madison, WI 53792 USA. [Schreiner, Athanasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Lozonschi, L (reprint author), Univ Wisconsin, Div Cardiothorac Surg, Dept Surg, Sch Med & Publ Hlth, 600 Highland Ave, Madison, WI 53792 USA. EM Lozon@surgery.wisc.edu FU University of Wisconsin, Department of Surgery FX This work was funded by the University of Wisconsin, Department of Surgery. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflict of interest to disclose. NR 13 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8090 J9 J CARDIOTHORAC SURG JI J. Cardiothorac. Surg. PD MAY 17 PY 2016 VL 11 AR 83 DI 10.1186/s13019-016-0480-5 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM6ZZ UT WOS:000376502900001 PM 27185173 ER PT J AU Rost, NS Cloonan, L Kanakis, AS Fitzpatrick, KM Azzariti, DR Clarke, V Lourenco, CM Germain, DP Politei, JM Homola, GA Sommer, C Uceyler, N Sims, KB AF Rost, Natalia S. Cloonan, Lisa Kanakis, Allison S. Fitzpatrick, Kaitlin M. Azzariti, Danielle R. Clarke, Virginia Lourenco, Charles M. Germain, Dominique P. Politei, Juan M. Homola, Gyoergy A. Sommer, Claudia Ueceyler, Nurcan Sims, Katherine B. TI Determinants of white matter hyperintensity burden in patients with Fabry disease SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; ENZYME REPLACEMENT THERAPY; SMALL VESSEL DISEASE; ISCHEMIC-STROKE; INTRACRANIAL VOLUME; YOUNG-PATIENTS; LESIONS; MRI; INVOLVEMENT; PROGRESSION AB Objective:Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD).Methods:Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses.Results:Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm(3) (interquartile range 1.8-4.0). Age ( 0.02, p = 0.008) and history of stroke ( 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burdenas well as WMHV predictorsvaried by decade of life in this cohort of patients with FD (p < 0.0001).Conclusions:In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed. C1 [Rost, Natalia S.; Cloonan, Lisa; Kanakis, Allison S.; Fitzpatrick, Kaitlin M.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Rost, Natalia S.; Azzariti, Danielle R.; Clarke, Virginia; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Lourenco, Charles M.] Univ Sao Paulo, Sch Med Riberirao Preto, Neurogenet Unit, BR-05508 Sao Paulo, Brazil. [Germain, Dominique P.] Paris Saclay Univ, Univ Versailles St Quentin Yvelines, Div Med Genet, Paris, France. [Politei, Juan M.] Fdn Estudio Enfermedades Neurometab FESEN, Buenos Aires, DF, Argentina. [Homola, Gyoergy A.] Univ Wurzburg, Dept Neuroradiol, Wurzburg, Germany. [Sommer, Claudia; Ueceyler, Nurcan] Univ Wurzburg, Dept Neurol, Wurzburg, Germany. [Sommer, Claudia; Ueceyler, Nurcan] Univ Wurzburg, Fabry Ctr Interdisciplinary Therapy FAZIT, Wurzburg, Germany. RP Rost, NS (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA.; Rost, NS (reprint author), Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. EM nrost@partners.org RI Sommer, Claudia/A-9820-2010; OI Sommer, Claudia/0000-0002-7064-5002; Uceyler, Nurcan/0000-0001-6973-6428 FU NIH-NINDS [K23NS064052]; Genzyme FX Supported by NIH-NINDS K23NS064052 (N.S.R.) and an investigator sponsored grant from Genzyme (K.B.S, PI). NR 29 TC 0 Z9 1 U1 1 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 MAY 17 PY 2016 VL 86 IS 20 BP 1880 EP 1886 DI 10.1212/WNL.0000000000002673 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DN0US UT WOS:000376782000009 PM 27164662 ER PT J AU Davies, MR Liu, XH Lee, L Laron, D Ning, AY Kim, HT Feeley, BT AF Davies, Michael R. Liu, Xuhui Lee, Lawrence Laron, Dominique Ning, Anne Y. Kim, Hubert T. Feeley, Brian T. TI TGF-beta Small Molecule Inhibitor SB431542 Reduces Rotator Cuff Muscle Fibrosis and Fatty Infiltration By Promoting Fibro/Adipogenic Progenitor Apoptosis SO PLOS ONE LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; SKELETAL-MUSCLE; MESENCHYMAL PROGENITORS; RAT MODEL; SUPRASCAPULAR NERVE; PROGNOSTIC-FACTORS; UP-REGULATION; REPAIR; TEAR; SB-431542 AB Rotator cuff tears represent a large burden of muscle-tendon injuries in our aging population. While small tears can be repaired surgically with good outcomes, critical size tears are marked by muscle atrophy, fibrosis, and fatty infiltration, which can lead to failed repair, frequent re-injury, and chronic disability. Previous animal studies have indicated that Transforming Growth Factor-beta (TGF-beta) signaling may play an important role in the development of these muscle pathologies after injury. Here, we demonstrated that inhibition of TGF-beta 1 signaling with the small molecule inhibitor SB431542 in a mouse model of massive rotator cuff tear results in decreased fibrosis, fatty infiltration, and muscle weight loss. These observed phenotypic changes were accompanied by decreased fibrotic, adipogenic, and atrophy-related gene expression in the injured muscle of mice treated with SB431542. We further demonstrated that treatment with SB431542 reduces the number of fibro/adipogenic progenitor (FAP) cells-an important cellular origin of rotator cuff muscle fibrosis and fatty infiltration, in injured muscle by promoting apoptosis of FAPs. Together, these data indicate that the TGF-beta pathway is a critical regulator of the degenerative muscle changes seen after massive rotator cuff tears. TGF-beta promotes rotator cuff muscle fibrosis and fatty infiltration by preventing FAP apoptosis. TGF-beta regulated FAP apoptosis may serve as an important target pathway in the future development of novel therapeutics to improve muscle outcomes following rotator cuff tear. C1 [Liu, Xuhui; Lee, Lawrence; Kim, Hubert T.; Feeley, Brian T.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. [Davies, Michael R.; Liu, Xuhui; Laron, Dominique; Ning, Anne Y.; Kim, Hubert T.; Feeley, Brian T.] Univ Calif San Francisco, Dept Orthopaed Surg, San Francisco, CA 94143 USA. RP Feeley, BT (reprint author), San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA.; Feeley, BT (reprint author), Univ Calif San Francisco, Dept Orthopaed Surg, San Francisco, CA 94143 USA. EM feeleyb@orthosurg.ucsf.edu FU U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Grant [1I01BX002680]; Orthopedic Research and Education Foundation Career Development and Stem Cell Research Grants FX This material is based upon work supported by U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Grant (1I01BX002680) and Orthopedic Research and Education Foundation Career Development and Stem Cell Research Grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 2 Z9 2 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 MAY 17 PY 2016 VL 11 IS 5 AR e0155486 DI 10.1371/journal.pone.0155486 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3YJ UT WOS:000376282300038 PM 27186977 ER PT J AU Scekic-Zahirovic, J Sendscheid, O El Oussini, H Jambeau, M Sun, Y Mersmann, S Wagner, M Dieterle, S Sinniger, J Dirrig-Grosch, S Drenner, K Birling, MC Qiu, JS Zhou, Y Li, HR Fu, XD Rouaux, C Shelkovnikova, T Witting, A Ludolph, AC Kiefer, F Storkebaum, E Lagier-Tourenne, C Dupuis, L AF Scekic-Zahirovic, Jelena Sendscheid, Oliver El Oussini, Hajer Jambeau, Melanie Sun, Ying Mersmann, Sina Wagner, Marina Dieterle, Stephane Sinniger, Jerome Dirrig-Grosch, Sylvie Drenner, Kevin Birling, Marie-Christine Qiu, Jinsong Zhou, Yu Li, Hairi Fu, Xiang-Dong Rouaux, Caroline Shelkovnikova, Tatyana Witting, Anke Ludolph, Albert C. Kiefer, Friedemann Storkebaum, Erik lagier-Tourenne, Clotilde Dupuis, Luc TI Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss SO EMBO JOURNAL LA English DT Article DE amyotrophic lateral sclerosis; frontotemporal dementia; FUS; motor neuron degeneration; PY-NLS ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; WILD-TYPE FUS; RNA GRANULES; BASOPHILIC INCLUSIONS; TRUNCATING MUTATIONS; NUCLEAR-LOCALIZATION; STRESS GRANULES; DISEASES ALS; FAMILIAL ALS AB FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. C1 [Scekic-Zahirovic, Jelena; El Oussini, Hajer; Dieterle, Stephane; Sinniger, Jerome; Dirrig-Grosch, Sylvie; Rouaux, Caroline; Dupuis, Luc] Fac Med, INSERM U1118, Strasbourg, France. [Scekic-Zahirovic, Jelena; El Oussini, Hajer; Dieterle, Stephane; Sinniger, Jerome; Dirrig-Grosch, Sylvie; Rouaux, Caroline; Dupuis, Luc] Univ Strasbourg, UMR S1118, Strasbourg, France. [Sendscheid, Oliver; Mersmann, Sina; Wagner, Marina; Storkebaum, Erik] Max Planck Inst Mol Biomed, Mol Neurogenet Lab, D-48149 Munster, Germany. [Sendscheid, Oliver; Mersmann, Sina; Wagner, Marina; Storkebaum, Erik] Univ Munster, Fac Med, D-48149 Munster, Germany. [Jambeau, Melanie; Sun, Ying; Drenner, Kevin; lagier-Tourenne, Clotilde] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Jambeau, Melanie; Sun, Ying; Drenner, Kevin; lagier-Tourenne, Clotilde] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Birling, Marie-Christine] Inst Clin Souris, Illkirch Graffenstaden, France. [Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Shelkovnikova, Tatyana] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales. [Witting, Anke; Ludolph, Albert C.] Univ Ulm, Dept Neurol, D-89069 Ulm, Germany. [Kiefer, Friedemann] Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Mammalian Cell Signaling Lab, D-48149 Munster, Germany. [lagier-Tourenne, Clotilde] Harvard Univ, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol,Med Sch, Charlestown, MA USA. RP Dupuis, L (reprint author), Fac Med, INSERM U1118, Strasbourg, France.; Dupuis, L (reprint author), Univ Strasbourg, UMR S1118, Strasbourg, France.; Storkebaum, E (reprint author), Max Planck Inst Mol Biomed, Mol Neurogenet Lab, D-48149 Munster, Germany.; Storkebaum, E (reprint author), Univ Munster, Fac Med, D-48149 Munster, Germany.; Lagier-Tourenne, C (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.; Lagier-Tourenne, C (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.; Lagier-Tourenne, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol,Med Sch, Charlestown, MA USA. EM erik.storkebaum@mpi-muenster.mpg.de; clagier-tourenne@mgh.harvard.edu; ldupuis@unistra.fr RI Dupuis, Luc/A-6981-2012; Storkebaum, Erik/B-5389-2017 OI Birling, Marie-Christine/0000-0002-3372-8108; Storkebaum, Erik/0000-0002-9519-5642 FU ALS Association Investigator Initiated Award [2235, 3209]; Frick Foundation; Association Francaise contre les Myopathies [18280]; Target ALS [13-0840]; Virtual Helmholtz Institute "RNA dysmetabolism in ALS and FTD" (WP2); Association de recherche sur la SLA (ArSLA); State North Rhine Westphalia; Minna-James-Heineman-Stiftung; Max Planck Society; German National Academic Foundation; Ludwig Institute for Cancer Research FX We thank Dr. Pico Caroni for providing the ChAT-CRE knockin mice and helpful discussions. We thank Marlene Bartos for her help in achieving this project. We are grateful to Dr. Don W. Cleveland and the members of his group for tremendous support and fruitful discussions. This work is supported by an ALS Association Investigator Initiated Award (grants 2235 and 3209; to LD and CLT); the Frick Foundation (award 2013 to LD and CLT, award 2010 to ES); Association Francaise contre les Myopathies (grant #18280; to LD, CLT and ES); Target ALS (grant 13-0840; to CLT); Virtual Helmholtz Institute "RNA dysmetabolism in ALS and FTD" (WP2, to LD, AW and ACL); Association de recherche sur la SLA (ArSLA; to LD); State North Rhine Westphalia (to ES); Minna-James-Heineman-Stiftung (to ES); and the Max Planck Society (to ES). JSZ received a Erasmus Mundus Neurotime Fellowship to perform these studies. OS received a fellowship from the German National Academic Foundation. CLT received salary support from the Ludwig Institute for Cancer Research. NR 100 TC 7 Z9 7 U1 5 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD MAY 17 PY 2016 VL 35 IS 10 BP 1077 EP 1097 DI 10.15252/embj.201592559 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DM2NW UT WOS:000376184500007 PM 26951610 ER PT J AU Schildberg, FA Klein, SR Freeman, GJ Sharpe, AH AF Schildberg, Frank A. Klein, Sarah R. Freeman, Gordon J. Sharpe, Arlene H. TI Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family SO IMMUNITY LA English DT Review ID T-CELL-ACTIVATION; REGULATES PD-1 EXPRESSION; EMBRYONIC STEM-CELLS; IFN-GAMMA PRODUCTION; CUTTING EDGE; B7 FAMILY; PROGRAMMED DEATH-1; CTLA-4 GENE; COSTIMULATORY MOLECULE; AUTOIMMUNE-DISEASE AB Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases, and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways. C1 [Schildberg, Frank A.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Schildberg, Frank A.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Klein, Sarah R.; Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Sharpe, AH (reprint author), Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu FU NIH [P01AI056299, P50CA101942]; Novartis; Roche FX The authors would like to thank their colleagues for critical discussions. This work was supported by grants from NIH (P01AI056299 and P50CA101942 to A.H.S. and G.J.F.). G.J.F. has patents/pending royalties on the PD-1 pathway from Bristol-Myers-Squibb, Roche, Merck, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, and Novartis. A.H.S. has received sponsored research support from Novartis and Roche. She has patents/pending royalties from Roche and Novartis. Because of space restrictions, we were able to cite only a fraction of the relevant literature and apologize to colleagues whose contributions might not be appropriately acknowledged in this review. NR 201 TC 18 Z9 18 U1 14 U2 25 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 MAY 17 PY 2016 VL 44 IS 5 BP 955 EP 972 DI 10.1016/j.immuni.2016.05.002 PG 18 WC Immunology SC Immunology GA DM6QW UT WOS:000376478500001 PM 27192563 ER PT J AU Barry, MJ Albertsen, PC AF Barry, Michael J. Albertsen, Peter C. TI Is Prostate-Specific Antigen Screening "Proven Ineffective Care"? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CANCER C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Connecticut, Sch Med, Farmington, CT USA. [Barry, Michael J.] Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,Suite 802, Boston, MA 02114 USA. [Albertsen, Peter C.] Univ Connecticut, Ctr Hlth, Dept Surg, 263 Farmington Ave, Farmington, CT 06030 USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,Suite 802, Boston, MA 02114 USA. EM mbarry@mgh.harvard.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 17 PY 2016 VL 164 IS 10 BP 687 EP + DI 10.7326/M15-3025 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DL8GF UT WOS:000375878500018 PM 26902323 ER PT J AU Jagsi, R Griffith, KA Jones, R Perumalswami, CR Ubel, P Stewart, A AF Jagsi, Reshma Griffith, Kent A. Jones, Rochelle Perumalswami, Chithra R. Ubel, Peter Stewart, Abigail TI Sexual Harassment and Discrimination Experiences of Academic Medical Faculty SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Jagsi, Reshma; Jones, Rochelle] Univ Michigan, Dept Radiat Oncol, 1500 E Med Ctr Dr,UHB2C490-SPC 5010, Ann Arbor, MI 48109 USA. [Griffith, Kent A.] Univ Michigan, Ctr Canc Biostat, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Perumalswami, Chithra R.] Univ Michigan, US Dept Vet Affairs, Ann Arbor, MI 48109 USA. [Ubel, Peter] Duke Univ, Fuqua Sch Business, Durham, NC 27706 USA. [Stewart, Abigail] Univ Michigan, Dept Psychol, 580 Union Dr, Ann Arbor, MI 48109 USA. RP Jagsi, R (reprint author), Univ Michigan, Dept Radiat Oncol, 1500 E Med Ctr Dr,UHB2C490-SPC 5010, Ann Arbor, MI 48109 USA. EM rjagsi@med.umich.edu OI Jagsi, Reshma/0000-0001-6562-1228 FU NCATS NIH HHS [UL1TR000433]; NHLBI NIH HHS [5 R01 HL101997-04, R01 HL101997] NR 5 TC 5 Z9 5 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 17 PY 2016 VL 315 IS 19 BP 2120 EP 2121 DI 10.1001/jama.2016.2188 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DL9PN UT WOS:000375975300025 PM 27187307 ER PT J AU Ashburner, JM Singer, DE AF Ashburner, Jeffrey M. Singer, Daniel E. TI REPLY: Recent Diabetes and Atrial Fibrillation Report Diverges From Pre-Existing Evidence SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID RISK; STROKE; COHORT C1 [Ashburner, Jeffrey M.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. RP Ashburner, JM (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jashburner@mgh.harvard.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 17 PY 2016 VL 67 IS 19 BP 2319 EP 2319 DI 10.1016/j.jacc.2016.02.060 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DL1QK UT WOS:000375406600023 PM 27173048 ER PT J AU Mounir, Z Korn, JM Westerling, T Lin, F Kirby, CA Schirle, M McAllister, G Hoffman, G Ramadan, N Hartung, A Feng, Y Kipp, DR Quinn, C Fodor, M Baird, J Schoumacher, M Meyer, R Deeds, J Buchwalter, G Stems, T Keen, N Sellers, WR Brown, M Pagliarini, RA AF Mounir, Zineb Korn, Joshua M. Westerling, Thomas Lin, Fallon Kirby, Christina A. Schirle, Markus McAllister, Gregg Hoffman, Greg Ramadan, Nadire Hartung, Anke Feng, Yan Kipp, David Randal Quinn, Christopher Fodor, Michelle Baird, Jason Schoumacher, Marie Meyer, Ronald Deeds, James Buchwalter, Gilles Stems, Travis Keen, Nicholas Sellers, William R. Brown, Myles Pagliarini, Raymond A. TI ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor SO ELIFE LA English DT Article ID PROTEIN ARGININE METHYLTRANSFERASES; GENE FUSIONS; THERAPY; COMPLEX; DNA; TMPRSS2-ERG; RESISTANCE; EPITHELIUM; POLYCOMB AB The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR's ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation. C1 [Mounir, Zineb; Korn, Joshua M.; Lin, Fallon; Kipp, David Randal; Quinn, Christopher; Fodor, Michelle; Baird, Jason; Schoumacher, Marie; Meyer, Ronald; Deeds, James; Keen, Nicholas; Sellers, William R.; Pagliarini, Raymond A.] Novartis Inst BioMed Res, Dept Oncol, Cambridge, MA USA. [Westerling, Thomas; Buchwalter, Gilles; Brown, Myles] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA. [Westerling, Thomas; Buchwalter, Gilles; Brown, Myles] Harvard Univ, Sch Med, Ctr Funct Canc Epigenet, Boston, MA USA. [Westerling, Thomas; Buchwalter, Gilles; Brown, Myles] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kirby, Christina A.; Stems, Travis] Novartis Inst BioMed Res, Ctr Prote Chem, Cambridge, MA USA. [Schirle, Markus; McAllister, Gregg; Hoffman, Greg; Ramadan, Nadire; Feng, Yan] Novartis Inst Biomed Res, Dev & Mol Pathways, Cambridge, MA USA. [Hartung, Anke] Novartis Inst Bio Med Resarch, Novartis Res Fdn, Genom Inst, San Diego, CA USA. [Mounir, Zineb] Genentech Inc, San Francisco, CA 94080 USA. [Hartung, Anke] Organovo, San Diego, CA USA. [Kipp, David Randal; Quinn, Christopher; Fodor, Michelle; Baird, Jason; Schoumacher, Marie] Labs Servier, Neuilly Sur Seine, France. [Buchwalter, Gilles] Celgene Avil Res, Bedford, MA USA. RP Pagliarini, RA (reprint author), Novartis Inst BioMed Res, Dept Oncol, Cambridge, MA USA. EM raymond.pagliarini@novartis.com FU Novartis FX Novartis Dana Farber/Novartis drug discovery program Thomas Westerling Gilles Buchwalter Myles Brown; All authors except Thomas Westerling, Gilles Buchwalter, and Myles Brown received no external funding for this work. NR 30 TC 3 Z9 3 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 MAY 16 PY 2016 VL 5 AR e13964 DI 10.7554/eLife.13964 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DP8WH UT WOS:000378778100001 ER PT J AU Fiore, A Zhang, JT Shao, P Yun, SH Scarcelli, G AF Fiore, Antonio Zhang, Jitao Shao, Peng Yun, Seok Hyun Scarcelli, Giuliano TI High-extinction virtually imaged phased array-based Brillouin spectroscopy of turbid biological media SO APPLIED PHYSICS LETTERS LA English DT Article ID LIGHT-SCATTERING; MICROSCOPY; ETALONS AB Brillouin microscopy has recently emerged as a powerful technique to characterize the mechanical properties of biological tissue, cell, and biomaterials. However, the potential of Brillouin microscopy is currently limited to transparent samples, because Brillouin spectrometers do not have sufficient spectral extinction to reject the predominant non-Brillouin scattered light of turbid media. To overcome this issue, we combined a multi-pass Fabry-Perot interferometer with a two-stage virtually imaged phased array spectrometer. The Fabry-Perot etalon acts as an ultra-narrow band-pass filter for Brillouin light with high spectral extinction and low loss. We report background-free Brillouin spectra from Intralipid solutions and up to 100lm deep within chicken muscle tissue. (C) 2016 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). C1 [Fiore, Antonio; Zhang, Jitao; Scarcelli, Giuliano] Univ Maryland, Fishell Dept Bioengn, College Pk, MD 20742 USA. [Shao, Peng; Yun, Seok Hyun] Harvard Univ, Sch Med, 50 Blossom St, Boston, MA 02114 USA. [Shao, Peng; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. RP Scarcelli, G (reprint author), Univ Maryland, Fishell Dept Bioengn, College Pk, MD 20742 USA. EM scarc@umd.edu OI Shao, Peng/0000-0003-2394-0612 FU National Institutes of Health [K25EB015885, R21EY023043, R01EY025454]; National Science Foundation [CMMI-1537027, CBET-0853773]; Human Frontier Science Program; Ministry of Science of Korea, under the "ICT Consilience Creative Program" [IITP-2015-R0346-15-1007] FX This work was supported in part by the National Institutes of Health (K25EB015885, R21EY023043, and R01EY025454); National Science Foundation (CMMI-1537027 and CBET-0853773); Human Frontier Science Program (Young Investigator Grant) and the Ministry of Science of Korea, under the "ICT Consilience Creative Program" (IITP-2015-R0346-15-1007). NR 19 TC 3 Z9 3 U1 5 U2 6 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0003-6951 EI 1077-3118 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD MAY 16 PY 2016 VL 108 IS 20 AR 203701 DI 10.1063/1.4948353 PG 3 WC Physics, Applied SC Physics GA DN4HE UT WOS:000377024000055 PM 27274097 ER PT J AU Perlis, RH Perlis, CS AF Perlis, Roy H. Perlis, Clifford S. TI Physician Payments from Industry Are Associated with Greater Medicare Part D Prescribing Costs SO PLOS ONE LA English DT Article ID CONFLICTS-OF-INTEREST AB Background The U.S. Physician Payments Sunshine Act mandates the reporting of payments or items of value received by physicians from drug, medical device, and biological agent manufacturers. The impact of these payments on physician prescribing has not been examined at large scale. Methods We linked public Medicare Part D prescribing data and Sunshine Act data for 2013. Physician payments were examined descriptively within specialties, and then for association with prescribing costs and patterns using regression models. Models were adjusted for potential physician-level confounding features, including sex, geographic region, and practice size. Results Among 725,169 individuals with Medicare prescribing data, 341,644 had documented payments in the OPP data (47.1%). Among all physicians receiving funds, mean payment was $1750 (SD $28336); median was $138 (IQR $48-$394). Across the 12 specialties examined, a dose-response relationship was observed in which greater payments were associated with greater prescribing costs per patient. In adjusted regression models, being in the top quintile of payment receipt was associated with incremental prescribing cost per patient ranging from $27 (general surgery) to $2931 (neurology). Similar associations were observed with proportion of branded prescriptions written. Conclusions While distribution and amount of payments differed widely across medical specialties, for each of the 12 specialties examined the receipt of payments was associated with greater prescribing costs per patient, and greater proportion of branded medication prescribing. We cannot infer a causal relationship, but interventions aimed at those physicians receiving the most payments may present an opportunity to address prescribing costs in the US. C1 [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Perlis, Clifford S.] Temple Univ Hlth Syst, Dept Dermatol, Philadelphia, PA USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. EM rperlis@mgh.harvard.edu NR 19 TC 3 Z9 4 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 16 PY 2016 VL 11 IS 5 AR e0155474 DI 10.1371/journal.pone.0155474 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM3XH UT WOS:000376279500042 PM 27183221 ER PT J AU Lin, PY Hagan, K Fenoglio, A Grant, PE Franceschini, MA AF Lin, Pei-Yi Hagan, Katherine Fenoglio, Angela Grant, P. Ellen Franceschini, Maria Angela TI Reduced cerebral blood flow and oxygen metabolism in extremely preterm neonates with low-grade germinal matrix-intraventricular hemorrhage SO SCIENTIFIC REPORTS LA English DT Article ID BIRTH-WEIGHT INFANTS; NEAR-INFRARED SPECTROSCOPY; HUMAN GANGLIONIC EMINENCE; ULTRASOUND ABNORMALITIES; PREMATURE-INFANTS; PERIINTRAVENTRICULAR HEMORRHAGE; NEURODEVELOPMENTAL OUTCOMES; OPTICAL MEASUREMENT; CRANIAL ULTRASOUND; GESTATIONAL-AGE AB Low-grade germinal matrix-intraventricular hemorrhage (GM-IVH) is the most common complication in extremely premature neonates. The occurrence of GM-IVH is highly associated with hemodynamic instability in the premature brain, yet the long-term impact of low-grade GM-IVH on cerebral blood flow and neuronal health have not been fully investigated. We used an innovative combination of frequency-domain near infrared spectroscopy and diffuse correlation spectroscopy (FDNIRS-DCS) to measure cerebral oxygen saturation (SO2) and an index of cerebral blood flow (CBFi) at the infant's bedside and compute an index of cerebral oxygen metabolism (CMRO2i). We enrolled twenty extremely low gestational age (ELGA) neonates (seven with low-grade GM-IVH) and monitored them weekly until they reached full-term equivalent age. During their hospital stay, we observed consistently lower CBFi and CMRO2i in ELGA neonates with low-grade GM-IVH compared to neonates without hemorrhages. Furthermore, lower CBFi and CMRO2i in the former group persists even after the resolution of the hemorrhage. In contrast, SO2 does not differ between groups. Thus, CBFi and CMRO2i may have better sensitivity than SO2 in detecting GM-IVH-related effects on infant brain development. FDNIRS-DCS methods may have clinical benefit for monitoring the evolution of GM-IVH, evaluating treatment response, and potentially predicting neurodevelopmental outcome. C1 [Lin, Pei-Yi; Hagan, Katherine; Franceschini, Maria Angela] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Fenoglio, Angela] Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. [Fenoglio, Angela; Grant, P. Ellen] Harvard Univ, Boston Childrens Hosp, Sch Med, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. RP Lin, PY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM ivylin@nmr.mgh.harvard.edu FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCRR) [UL1 TR001102]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCATS, NIH) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers; American Heart Association [K99HD083512, R21HD072505, R01HD042908] FX We thank Dr. Mark Vangel for his assistance in statistical analysis, which is supported by Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NCRR and NCATS, NIH Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. We thank Drs Erin Buckley and Mathieu Dehaes for their support with the data analysis. We also thank all the families of the participating infants, without whom the study would not be possible, as well as the staff of the participating neonatal intensive care units who contributed their help and support to the project. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. This study was funded by the American Heart Association (P.-Y.L.) K99HD083512 (P.-Y.L.), R21HD072505 (P.E.G.), and R01HD042908 (M.A.F). None of the funders are involved in study design, data collection, data analysis, and manuscript preparation and publication decisions. NR 64 TC 1 Z9 1 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 MAY 16 PY 2016 VL 6 AR 25903 DI 10.1038/srep25903 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL8ON UT WOS:000375901400001 PM 27181339 ER PT J AU Horikoshi, M Pasquali, L Wiltshire, S Huyghe, JR Mahajan, A Asimit, JL Ferreira, T Locke, AE Robertson, NR Wang, X Sim, XL Fujita, H Hara, K Young, R Zhang, WH Choi, S Chen, H Kaur, I Takeuchi, F Fontanillas, P Thuillier, D Yengo, L Below, JE Tam, CHT Wu, Y Abecasis, G Altshuler, D Bell, GI Blangero, J Burtt, NP Duggirala, R Florez, JC Hanis, CL Seielstad, M Atzmon, G Chan, JCN Ma, RCW Froguel, P Wilson, JG Bharadwaj, D Dupuis, J Meigs, JB Cho, YS Park, T Kooner, JS Chambers, JC Saleheen, D Kadowaki, T Tai, ES Mohlke, KL Cox, NJ Ferrer, J Zeggini, E Kato, N Teo, YY Boehnke, M McCarthy, MI Morris, AP AF Horikoshi, Momoko Pasquali, Lorenzo Wiltshire, Steven Huyghe, Jeroen R. Mahajan, Anubha Asimit, Jennifer L. Ferreira, Teresa Locke, Adam E. Robertson, Neil R. Wang, Xu Sim, Xueling Fujita, Hayato Hara, Kazuo Young, Robin Zhang, Weihua Choi, Sungkyoung Chen, Han Kaur, Ismeet Takeuchi, Fumihiko Fontanillas, Pierre Thuillier, Dorothee Yengo, Loic Below, Jennifer E. Tam, Claudia H. T. Wu, Ying Abecasis, Goncalo Altshuler, David Bell, Graeme I. Blangero, John Burtt, Noel P. Duggirala, Ravindranath Florez, Jose C. Hanis, Craig L. Seielstad, Mark Atzmon, Gil Chan, Juliana C. N. Ma, Ronald C. W. Froguel, Philippe Wilson, James G. Bharadwaj, Dwaipayan Dupuis, Josee Meigs, James B. Cho, Yoon Shin Park, Taesung Kooner, Jaspal S. Chambers, John C. Saleheen, Danish Kadowaki, Takashi Tai, E. Shyong Mohlke, Karen L. Cox, Nancy J. Ferrer, Jorge Zeggini, Eleftheria Kato, Norihiro Teo, Yik Ying Boehnke, Michael McCarthy, Mark I. Morris, Andrew P. CA T2D-GENES Consortium TI Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENETIC ARCHITECTURE; BETA-CELLS; METAANALYSIS; VARIANTS; KCNQ1; POPULATIONS; SNPS AB To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci. C1 [Horikoshi, Momoko; Wiltshire, Steven; Mahajan, Anubha; Ferreira, Teresa; Robertson, Neil R.; McCarthy, Mark I.; Morris, Andrew P.] Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England. [Horikoshi, Momoko; Wiltshire, Steven; Robertson, Neil R.; McCarthy, Mark I.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Pasquali, Lorenzo] Germans Trias & Pujol Univ Hosp & Res Inst, PMPPC, Badalona, Spain. [Pasquali, Lorenzo] Josep Carreras Leukaemia Res Inst, Badalona, Spain. [Pasquali, Lorenzo; Ferrer, Jorge] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Barcelona, Spain. [Huyghe, Jeroen R.; Locke, Adam E.; Sim, Xueling; Abecasis, Goncalo; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Huyghe, Jeroen R.; Locke, Adam E.; Sim, Xueling; Abecasis, Goncalo; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Asimit, Jennifer L.; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England. [Wang, Xu; Sim, Xueling; Tai, E. Shyong; Teo, Yik Ying] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore. [Fujita, Hayato] JR Tokyo Gen Hosp, Dept Diabet & Endocrinol, Tokyo, Japan. [Hara, Kazuo; Kadowaki, Takashi] Univ Tokyo, 22nd Century Med & Res Ctr, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo, Japan. [Kadowaki, Takashi] Univ Tokyo, 22nd Century Med & Res Ctr, Dept Integrated Mol Sci Metab Dis, Tokyo, Japan. [Young, Robin] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Zhang, Weihua; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England. [Zhang, Weihua; Chambers, John C.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Froguel, Philippe] Imperial Coll London, Dept Genom Common Dis, Sch Publ Hlth, London, England. [Kooner, Jaspal S.] Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, Hammersmith Campus, London, England. [Kooner, Jaspal S.; Chambers, John C.] Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England. [Ferrer, Jorge] Imperial Coll London, Dept Med, London, England. [Choi, Sungkyoung; Park, Taesung] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea. [Park, Taesung] Seoul Natl Univ, Dept Stat, Seoul, South Korea. [Chen, Han] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Chen, Han; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kaur, Ismeet; Bharadwaj, Dwaipayan] CSIR Inst Genom & Integrat Biol, Genom & Mol Med, New Delhi, India. [Takeuchi, Fumihiko; Kato, Norihiro] Natl Ctr Global Hlth & Med, Res Inst, Dept Gene Diagnost & Therapeut, Tokyo, Japan. [Fontanillas, Pierre; Altshuler, David; Burtt, Noel P.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Thuillier, Dorothee; Yengo, Loic; Froguel, Philippe] EGID FR3508 European Genom Inst Diabet, Lille Inst Biol, Integrat Genom & Modelizat Metab Dis CNRS UMR8199, Lille, France. [Below, Jennifer E.; Hanis, Craig L.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Tam, Claudia H. T.; Chan, Juliana C. N.; Ma, Ronald C. W.] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Chan, Juliana C. N.; Ma, Ronald C. W.] Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China. [Chan, Juliana C. N.; Ma, Ronald C. W.] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Altshuler, David] MIT, Dept Biol, Cambridge, MA USA. [Altshuler, David] Harvard Med Sch, Dept Genet, Boston, MA USA. [Altshuler, David; Florez, Jose C.; Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA. [Bell, Graeme I.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Bell, Graeme I.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Blangero, John; Duggirala, Ravindranath] Texas Biomed Res Inst, Dept Genet, Houston, TX USA. [Seielstad, Mark] Blood Syst Res Inst, San Francisco, CA USA. [Seielstad, Mark] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Atzmon, Gil] Univ Haifa, Dept Nat Sci, Haifa, Israel. [Atzmon, Gil] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Atzmon, Gil] Albert Einstein Coll Med, Dept Genet, New York, NY USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Bharadwaj, Dwaipayan] Jawaharlal Nehru Univ, Sch Biotechnol, New Delhi, India. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cho, Yoon Shin] Hallym Univ, Dept Biomed Sci, Chunchon, South Korea. [Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, Ctr Noncommunicable Dis, Philadelphia, PA 19104 USA. [Tai, E. Shyong] Duke NUS Grad Med Sch Singapore, Cardiovasc & Metab Disorders Program, Singapore, Singapore. [Cox, Nancy J.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ferrer, Jorge] Inst Invest August Pi & Sunyer IDIBAPS, Gen Programming Beta Cells Lab, Barcelona, Spain. [Teo, Yik Ying] Natl Univ Singapore, Inst Life Sci, Singapore, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore. [McCarthy, Mark I.] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Block F,Waterhouse Bldg,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England. RP Morris, AP (reprint author), Univ Liverpool, Dept Biostat, Block F,Waterhouse Bldg,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England. EM a.p.morris@liverpool.ac.uk RI Chan, Juliana /B-7918-2016; Ma, Ronald/C-2788-2009; Yengo, Loic/D-2692-2017; OI Chan, Juliana /0000-0003-1325-1194; Ma, Ronald/0000-0002-1227-803X; Yengo, Loic/0000-0002-4272-9305; Chen, Han/0000-0002-9510-4923; Tai, E Shyong/0000-0003-2929-8966 FU Action on Hearing Loss [G51]; American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation [SP/04/002]; CARDIOMED-CSIR, India [BSC0122(6)]; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant) [279143]; Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; Genome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme [CUHK 1/04C]; Innovation and Technology Fund [ITS/487/09FP, ITS/130/11]; Research Grants Council Theme-based Research Scheme [T12-402/13N]; Japan Society for the Promotion of Science [KAKENHI 23710228]; Medical Research Council [G0601966, G0700931]; Ministerio de Economia y Competitividad [BFU2014-58150-R]; Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging [PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872]; National Institutes of Health [K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535]; National Institute for Health Research [RP-PG-0407-10371]; National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea [NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906]; Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust [WT084723, WT090532, WT098017, WT098051]; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; Wellcome Trust FX This work was supported by Action on Hearing Loss (G51); American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation (SP/04/002); CARDIOMED BSC0122(6)-CSIR, India; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant, 279143); Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; Genome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme (CUHK 1/04C), Innovation and Technology Fund (ITS/487/09FP and ITS/130/11), and the Research Grants Council Theme-based Research Scheme (T12-402/13N); Japan Society for the Promotion of Science (KAKENHI 23710228); Medical Research Council (G0601966, G0700931); Ministerio de Economia y Competitividad (BFU2014-58150-R); Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging (PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872); National Institutes of Health (K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HL102830, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535); National Institute for Health Research (RP-PG-0407-10371); National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea (NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906); Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust (WT084723, WT090532, WT098017, WT098051). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 45 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 2070 EP 2081 DI 10.1093/hmg/ddw048 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100015 PM 26911676 ER PT J AU Lessard, S Manning, AK Low-Kam, C Auer, PL Giri, A Graff, M Schurmann, C Yaghootkar, H Luan, JA Esko, T Karaderi, T Bottinger, EP Lu, YC Carlson, C Caulfield, M Dube, MP Jackson, RD Kooperberg, C McKnight, B Mongrain, I Peters, U Reiner, AP Rhainds, D Sotoodehnia, N Hirschhorn, JN Scott, RA Munroe, PB Frayling, TM Loos, RJF North, KE Edwards, TL Tardif, JC Lindgren, CM Lettre, G AF Lessard, Samuel Manning, Alisa K. Low-Kam, Cecile Auer, Paul L. Giri, Ayush Graff, Mariaelisa Schurmann, Claudia Yaghootkar, Hanieh Luan, Jian'an Esko, Tonu Karaderi, Tugce Bottinger, Erwin P. Lu, Yingchang Carlson, Chris Caulfield, Mark Dube, Marie-Pierre Jackson, Rebecca D. Kooperberg, Charles McKnight, Barbara Mongrain, Ian Peters, Ulrike Reiner, Alex P. Rhainds, David Sotoodehnia, Nona Hirschhorn, Joel N. Scott, Robert A. Munroe, Patricia B. Frayling, Timothy M. Loos, Ruth J. F. North, Kari E. Edwards, Todd L. Tardif, Jean-Claude Lindgren, Cecilia M. Lettre, Guillaume CA NHLBI Go Exome Sequence Project GOT2D T2D-GENES GIANT Consortium TI Testing the role of predicted gene knockouts in human anthropometric trait variation SO HUMAN MOLECULAR GENETICS LA English DT Article ID OF-FUNCTION VARIANTS; PRIMARY HYPEROXALURIA; RECEPTOR GENE; ASSOCIATION; DISEASE; DYSFUNCTION; DISORDERS; DATABASE; GROWTH; EXOMES AB Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (> 100x), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7x), and > 100 000 participants from the Genetic Investigation of ANthropometric Traits (GIANT) Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population. C1 [Lessard, Samuel; Low-Kam, Cecile; Dube, Marie-Pierre; Mongrain, Ian; Rhainds, David; Tardif, Jean-Claude; Lettre, Guillaume] Montreal Heart Inst, 5000 Belanger St, Montreal, PQ H1T 1C8, Canada. [Lessard, Samuel; Low-Kam, Cecile; Dube, Marie-Pierre; Tardif, Jean-Claude; Lettre, Guillaume] Univ Montreal, Fac Med, Montreal, PQ H3T 1J4, Canada. [Manning, Alisa K.; Esko, Tonu; Hirschhorn, Joel N.; Lindgren, Cecilia M.] Broad Inst, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Manning, Alisa K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Manning, Alisa K.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Giri, Ayush; Edwards, Todd L.] Vanderbilt Univ, Med Ctr, Div Epidemiol, Inst Med & Publ Hlth,Vanderbilt Genet Inst, Nashville, TN 37203 USA. [Edwards, Todd L.] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Dept Med, Nashville, TN 37203 USA. [Graff, Mariaelisa; North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Schurmann, Claudia; Bottinger, Erwin P.; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Schurmann, Claudia; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Yaghootkar, Hanieh; Frayling, Timothy M.] Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX2 5DW, Devon, England. [Luan, Jian'an; Scott, Robert A.] Univ Cambridge, Med Res Council Epidemiol Unit, Cambridge CB2 0QQ, England. [Esko, Tonu] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Esko, Tonu; Hirschhorn, Joel N.] Childrens Hosp Boston, Div Endocrinol Genet & Basic & Translat Obes Res, Boston, MA 02115 USA. [Karaderi, Tugce; Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Carlson, Chris; Kooperberg, Charles; Peters, Ulrike; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Caulfield, Mark; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, Clin Pharmacol, William Harvey Res Inst, London EC1M 6BQ, England. [Caulfield, Mark; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, NIHR Barts Cardiovasc Biomed Res Unit, London EC1M 6BQ, England. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Oxford, England. RP Lettre, G (reprint author), Montreal Heart Inst, 5000 Belanger St, Montreal, PQ H1T 1C8, Canada. EM guillaume.lettre@umontreal.ca RI Dube, Marie-Pierre/B-9364-2008; Hrabe de Angelis, Martin/F-5531-2012 OI Dube, Marie-Pierre/0000-0001-8442-4393; Hrabe de Angelis, Martin/0000-0002-7898-2353 FU National Heart, Lung, and Blood Institute (NHLBI); Canadian Institutes of Health Research Banting doctoral scholarship; Genome Canada; Genome Quebec; Canada Research Chairs program; Montreal Heart Institute Foundation; Wellcome Trust [086596/Z/08/Z, 086596/Z/08/A]; Li Ka Shing Foundation; National Institutes of Health [HL088456, HL111089, HL116747]; Andrea and Charles Bronfman Philanthropies; NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924]; Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education [SF0180142s08]; Development Fund of the University of Tartu [SP1GVARENG]; European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) [3.2.0304.11-0312]; FP7 [313010]; US National Institute of Health [R01DK075787]; American Diabetes Association Mentor-Based Postdoctoral Fellowship [7-12-MN-02]; Vanderbilt CTSA from NCATS/NIH [ULTR000445]; NIH from NIGMS/OD [RC2GM092618]; NIH from NHGRI/NIGMS [U01HG004603]; Research Councils UK FX The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. S.L. is funded by a Canadian Institutes of Health Research Banting doctoral scholarship. G.L. is funded by Genome Canada and Genome Quebec; the Canada Research Chairs program; and the Montreal Heart Institute Foundation. C.M.L. is supported by Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A); and the Li Ka Shing Foundation. N.S. is funded by National Institutes of Health (grant numbers HL088456, HL111089, HL116747). The Mount Sinai BioMe Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. GO ESP is supported by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO, RC2 HL-102924 to WHISP). The ESP exome sequencing was performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL-102926 to SeattleGO). EGCUT work was supported through the Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education (grant number SF0180142s08); the Development Fund of the University of Tartu (grant number SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and through FP7 (grant number 313010). EGCUT were further supported by the US National Institute of Health (grant number R01DK075787). A.K.M. was supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship (#7-12-MN-02). The BioVU dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access publication charges for this article was provided by a block grant from Research Councils UK to the University of Cambridge. NR 31 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 2082 EP 2092 DI 10.1093/hmg/ddw055 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100016 PM 26908616 ER PT J AU Verweij, N Leach, IM Isaacs, A Arking, DE Bis, JC Pers, TH Van den Berg, ME Lyytikainen, LP Barnett, P Wang, XC Soliman, EZ Van Duijn, CM Kahonen, M Van Veldhuisen, DJ Kors, JA Raitakari, OT Silva, CT Lehtimaki, T Hillege, HL Hirschhorn, JN Boyer, LA Van Gilst, WH Alonso, A Sotoodehnia, N Eijgelsheim, M De Boer, RA De Bakker, PIW Franke, L Van der Harst, P AF Verweij, Niek Leach, Irene Mateo Isaacs, Aaron Arking, Dan E. Bis, Joshua C. Pers, Tune H. Van den Berg, Marten E. Lyytikainen, Leo-Pekka Barnett, Phil Wang, Xinchen Soliman, Elsayed Z. Van Duijn, Cornelia M. Kahonen, Mika Van Veldhuisen, Dirk J. Kors, Jan A. Raitakari, Olli T. Silva, Claudia T. Lehtimaki, Terho Hillege, Hans L. Hirschhorn, Joel N. Boyer, Laurie A. Van Gilst, Wiek H. Alonso, Alvaro Sotoodehnia, Nona Eijgelsheim, Mark De Boer, Rudolf A. De Bakker, Paul I. W. Franke, Lude Van der Harst, Pim CA LifeLines Cohort Study TI Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUDDEN CARDIAC-ARREST; EARLY REPOLARIZATION; LEAD AVR; PROGNOSTIC VALUE; BRUGADA SYNDROME; COMMON VARIANTS; HEART-FAILURE; INTERVAL; DISEASE AB The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up. C1 [Verweij, Niek; Leach, Irene Mateo; Van Veldhuisen, Dirk J.; Hillege, Hans L.; Van Gilst, Wiek H.; De Boer, Rudolf A.; Van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. [Hillege, Hans L.] Univ Groningen, Univ Med Ctr Groningen, Trial Coordinat Ctr, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. [Franke, Lude; Van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. [Isaacs, Aaron; Van Duijn, Cornelia M.; Silva, Claudia T.] Erasmus Univ, Med Ctr, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands. [Van den Berg, Marten E.; Kors, Jan A.; Eijgelsheim, Mark] Erasmus Univ, Med Ctr, Dept Med Informat, Rotterdam, Netherlands. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Bis, Joshua C.; Sotoodehnia, Nona] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Sotoodehnia, Nona] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. [Pers, Tune H.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Div Cardiol, Boston, MA USA. [Verweij, Niek; Pers, Tune H.; Hirschhorn, Joel N.; De Bakker, Paul I. W.] Broad Inst MIT & Harvard, Program Med & Populat Genet, 301 Binney St, Cambridge, MA 02142 USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere 33520, Finland. [Barnett, Phil] Univ Amsterdam, Acad Med Ctr, Dept Anat Embryol & Physiol, NL-1105 AZ Amsterdam, Netherlands. [Wang, Xinchen; Boyer, Laurie A.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Tampere 33521, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Hirschhorn, Joel N.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [De Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Univ Weg 100, NL-3584 CG Utrecht, Netherlands. [Van der Harst, Pim] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3511 GC Utrecht, Netherlands. [Verweij, Niek] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Verweij, Niek] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Isaacs, Aaron] Maastricht Univ, Maastricht Ctr Syst Biol MaCSBio, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands. [Isaacs, Aaron] Maastricht Univ, Dept Biochem, Maastricht, Netherlands. RP Van der Harst, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. EM p.van.der.harst@umcg.nl RI Alonso, Alvaro/A-4917-2010; Verweij, Niek/A-4499-2017; OI Alonso, Alvaro/0000-0002-2225-8323; Silva, Claudia T./0000-0001-8172-5860 FU Dutch Kidney Foundation [E033]; EU Project grant GENECURE [FP-6 LSHM CT 2006 037697]; National Institutes of Health [2R01LM010098, HHSN268200625226C, UL1RR025005]; Netherlands Organization for Health Research and Development (NWO-Groot grant) [175.010.2007.006]; Netherlands Organization for Health Research and Development (NWO VENI) [916.761.70]; Netherlands Organization for Health Research and Development (ZonMw) [90.700.441]; Dutch Inter University Cardiology Institute Netherlands (ICIN); Netherlands Heart Foundation [NHS2010B280]; Netherlands Organization of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University Medical Center Groningen; University of Groningen; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Netherlands Organization for Scientific Research (NWO VENI grant) [916.10.135]; Horizon Breakthrough grant from the Netherlands Genomics Initiative [92519031]; European Community's Health Seventh Framework Programme (FP7) [259867]; Netherlands Organization for Scientific Research (NWO; Pioneer grant); Erasmus Medical Center; Centre for Medical Systems Biology (CMSB); Netherlands Kidney Foundation; National Heart, Lung and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756, HL103612, HL120393]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Advancing Translational Sciences; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Academy of Finland [286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]; Social Insurance Institution of Finland; Kuopio, Tampere and Turku University Hospital Medical Funds [X51001]; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjo Jahnsson Foundation; Marie Sklodowska-Curie GF grant [661395] FX PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (grant E033), the EU Project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441) and the Dutch Inter University Cardiology Institute Netherlands (ICIN). N.V. is supported by the Netherlands Heart Foundation (grant NHS2010B280). LifeLines: The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. L.F. is supported by the Netherlands Organization for Scientific Research (NWO VENI grant 916.10.135) and a Horizon Breakthrough grant from the Netherlands Genomics Initiative (grant 92519031. The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. RS I, II and III: Akzo Nobel, Alzheimer's Association, Astra Pharmaceutial N.V., AstraZeneca, Bayer AG, Blinden-penning Foundation, Amsterdam, Brain Foundation of the Netherlands, Bristol-Myers Squibb, Center of Medical Systems Biology (CMSB), Dutch Diabetes Research Foundation, Dutch Kidney Foundation, Dutch Arthritis Association, Elise Mathilde Foundation, Maarn, Erasmus Medical Center, Erasmus University Rotterdam, European Commission, Foundation for Helping the Blind, The Hague, Foundation for the Ophthalmic Diseased, Rotterdam, Foundation G. Ph. Verhagen, General Electric Healthcare, Glaxo Smith Kline, International Foundation Alzheimer's Research, Inspectorate for Healthcare, Janivo Foundation, K.F. Hein Foundation, Merck Sharp and Dohme, Haarlem, Municipality of City of Rotterdam, National Epilepsy Fund, National Health Fundraising Foundation, National Institute on Aging, NIH, Bethesda, MD, USA, National Society for the Blind and Visually Impaired (LSBS), Netherlands Foundation for the Blind and Visually Handicapped, Netherlands Heart Foundation, Netherlands Institute for Health Sciences (Nihes), Netherlands Ophthalmic Research Institute, Netherlands Organisation for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Netherlands Society for the Prevention of Blindness, Netherlands Thrombosis Foundation, Novo Nordisk, Numico Research B.V., OOG Foundation, The Hague, N.V. Organon, Oxagen, Optimix Foundation, Amsterdam, Physicotherapeutic Institute, Prinses Beatrix Foundation, Procter and Gamble, Research Institute for Diseases in the Elderly (RIDE), Rotterdam Foundation for Ophthalmic Research, Rotterdam Foundation for the Interests of the Blind, St Laurens Institute, Rotterdam, Topcon Europe B.V., Trust Fund Erasmus University Rotterdam, Unilever, Van Leeuwen Van Lignac Foundation, Rotterdam. ERF: The ERF study was supported by grants from the Netherlands Organization for Scientific Research (NWO; Pioneer grant), Erasmus Medical Center, the Centre for Medical Systems Biology (CMSB) and the Netherlands Kidney Foundation.; We are grateful to all patients and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402 and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CHS: Cardiovascular Health Study: this CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and NHLBI grants HL080295, HL087652, HL105756, HL103612 and HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org/. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284 (T.L.), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi); the Social Insurance Institution of Finland; Kuopio, Tampere and Turku University Hospital Medical Funds (grant X51001 for T.L.); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research (T.L.); Finnish Cultural Foundation; Tampere Tuberculosis Foundation (T.L.); Emil Aaltonen Foundation (T.L.) and Yrjo Jahnsson Foundation (T.L.). Funding to pay the Open Access publication charges for this article was provided by the Marie Sklodowska-Curie GF grant (661395) from N. Verweij. NR 45 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2016 VL 25 IS 10 BP 2093 EP 2103 DI 10.1093/hmg/ddw058 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA9JA UT WOS:000386958100017 PM 26962151 ER PT J AU Mabray, MC Talbott, JF Whetstone, WD Dhall, SS Phillips, DB Pan, JZ Manley, GT Bresnahan, JC Beattie, MS Haefeli, J Ferguson, AR AF Mabray, Marc C. Talbott, Jason F. Whetstone, William D. Dhall, Sanjay S. Phillips, David B. Pan, Jonathan Z. Manley, Geoffrey T. Bresnahan, Jacqueline C. Beattie, Michael S. Haefeli, Jenny Ferguson, Adam R. TI Multidimensional Analysis of Magnetic Resonance Imaging Predicts Early Impairment in Thoracic and Thoracolumbar Spinal Cord Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE BASIC; MRI; spinal cord injury; thoracic; T2 hyperintensity; TLICS ID PRINCIPAL-COMPONENTS-ANALYSIS; OPTIMAL RADIOLOGIC METHOD; CANAL COMPROMISE; REPRODUCIBLE METHOD; MOTOR RECOVERY; MR; TRAUMA; CLASSIFICATION; COMPRESSION; SEVERITY AB Literature examining magnetic resonance imaging (MRI) in acute spinal cord injury (SCI) has focused on cervical SCI. Reproducible systems have been developed for MRI- based grading; however, it is unclear how they apply to thoracic SCI. Our hypothesis is that MRI measures will group as coherent multivariate principal component (PC) ensembles, and that distinct PCs and individual variables will show discriminant validity for predicting early impairment in thoracic SCI. We undertook a retrospective cohort study of 25 patients with acute thoracic SCI who underwent MRI on admission and had American Spinal Injury Association Impairment Scale (AIS) assessment at hospital discharge. Imaging variables of axial grade, sagittal grade, length of injury, thoracolumbar injury classification system (TLICS), maximum canal compromise (MCC), and maximum spinal cord compression (MSCC) were collected. We performed an analytical workflow to detect multivariate PC patterns followed by explicit hypothesis testing to predict AIS at discharge. All imaging variables loaded positively on PC1 (64.3% of variance), which was highly related to AIS at discharge. MCC, MSCC, and TLICS also loaded positively on PC2 (22.7% of variance), while variables concerning cord signal abnormality loaded negatively on PC2.PC2 was highly related to the patient undergoing surgical decompression. Variables of signal abnormality were all negatively correlated with AIS at discharge with the highest level of correlation for axial grade as assessed with the Brain and Spinal Injury Center (BASIC) score. A multiple variable model identified BASIC as the only statistically significant predictor of AIS at discharge, signifying that BASIC best captured the variance in AIS within our study population. Our study provides evidence of convergent validity, construct validity, and clinical predictive validity for the sampled MRI measures of SCI when applied in acute thoracic and thoracolumbar SCI. C1 [Mabray, Marc C.; Talbott, Jason F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Whetstone, William D.] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. [Dhall, Sanjay S.; Phillips, David B.; Manley, Geoffrey T.; Bresnahan, Jacqueline C.; Beattie, Michael S.; Haefeli, Jenny; Ferguson, Adam R.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Pan, Jonathan Z.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Talbott, Jason F.; Whetstone, William D.; Dhall, Sanjay S.; Phillips, David B.; Pan, Jonathan Z.; Manley, Geoffrey T.; Bresnahan, Jacqueline C.; Beattie, Michael S.; Haefeli, Jenny; Ferguson, Adam R.] San Francisco Gen Hosp, Brain & Spinal Injury Ctr, San Francisco, CA 94110 USA. [Ferguson, Adam R.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Talbott, JF (reprint author), San Francisco Gen Hosp, Dept Radiol, 1001 Potrero Ave,Room 1X57C, San Francisco, CA 94110 USA.; Ferguson, AR (reprint author), Univ Calif San Francisco, Brain & Spinal Injury Ctr, Neurol Surg, Box 0899,1001 Potrero Ave,Bldg 1,Room 101, San Francisco, CA 94143 USA. EM Jason.talbott@ucsf.edu; adam.ferguson@ucsf.edu FU Craig H. Neilsen Foundation; Wings for Life Foundation; DOD grant CDMRP SCIRP [120559 (W81XWH-13-1-0297)]; NIH [5T32EB001631-10]; Craig H. Neilsen Foundation [313739]; [R01NS067092] FX This work was supported by R01NS067092 (ARF), the Craig H. Neilsen Foundation (ARF; JCB), Wings for Life Foundation (ARF), DOD grant CDMRP SCIRP 120559 (W81XWH-13-1-0297) (MSB and JCB). MCM was supported by an NIH T32 Fellowship, 5T32EB001631-10. JH was supported by a Craig H. Neilsen Foundation fellowship (313739). NR 59 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD MAY 15 PY 2016 VL 33 IS 10 BP 954 EP 962 DI 10.1089/neu.2015.4093 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DN3TC UT WOS:000376985400005 PM 26414451 ER PT J AU Birket, SE Chu, KK Houser, GH Liu, LB Fernandez, CM Solomon, GM Lin, V Shastry, S Mazur, M Sloane, PA Hanes, J Grizzle, WE Sorscher, EJ Tearney, GJ Rowe, SM AF Birket, Susan E. Chu, Kengyeh K. Houser, Grace H. Liu, Linbo Fernandez, Courtney M. Solomon, George M. Lin, Vivian Shastry, Suresh Mazur, Marina Sloane, Peter A. Hanes, Justin Grizzle, William E. Sorscher, Eric J. Tearney, Guillermo J. Rowe, Steven M. TI Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE mucociliary transport ID CFTR POTENTIATOR; BICARBONATE SECRETION; MUCOCILIARY TRANSPORT; PRIMARY CULTURES; PHE508DEL CFTR; SWEAT CHLORIDE; IN-VITRO; MUCUS; IVACAFTOR; MUTATION AB Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies. C1 [Birket, Susan E.; Fernandez, Courtney M.; Solomon, George M.; Lin, Vivian; Shastry, Suresh; Sloane, Peter A.; Sorscher, Eric J.; Rowe, Steven M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Chu, Kengyeh K.; Liu, Linbo; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Chu, Kengyeh K.; Liu, Linbo] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA USA. [Houser, Grace H.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Tearney, Guillermo J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Mazur, Marina; Sorscher, Eric J.; Rowe, Steven M.] Univ Alabama Birmingham, Cyst Fibrosis Res Ctr, Birmingham, AL USA. [Grizzle, William E.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Rowe, Steven M.] Univ Alabama Birmingham, Dept Cellular Dev & Integrat Biol, Birmingham, AL USA. [Chu, Kengyeh K.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hanes, Justin] Johns Hopkins Univ Hosp, Dept Ophthalmol, Ctr Nanomed, Baltimore, MD 21287 USA. [Hanes, Justin] Johns Hopkins Univ Hosp, Dept Neurosurg, Baltimore, MD 21287 USA. RP Rowe, SM (reprint author), 1702 2nd Ave South,MCLM 702, Birmingham, AL 35294 USA. EM smrowe@uab.edu FU National Heart, Lung, and Blood Institute [R01-HL-116213, 5T32-HL-105346-04]; National Institute of Diabetes and Digestive and Kidney Diseases [P30-DK-072482]; Research Development Program [R464-CF]; Mucociliary Clearance Consortium of the Cystic Fibrosis Foundation; Flatley Foundation; Dixon Foundation FX This work was supported by the National Heart, Lung, and Blood Institute [R01-HL-116213 (G. J. Tearney and S. M. Rowe) and 5T32-HL-105346-04 (S. E. Birket)] and the National Institute of Diabetes and Digestive and Kidney Diseases [P30-DK-072482 (E. J. Sorscher)], the Research Development Program (R464-CF), the Mucociliary Clearance Consortium (G. J. Tearney and S. M. Rowe) of the Cystic Fibrosis Foundation, the Flatley Foundation (K. K. Chu, G. J. Tearney, and S. M. Rowe), and the Dixon Foundation (G. H. Houser). NR 48 TC 3 Z9 3 U1 3 U2 5 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 MAY 15 PY 2016 VL 310 IS 10 BP L928 EP L939 DI 10.1152/ajplung.00395.2015 PG 12 WC Physiology; Respiratory System SC Physiology; Respiratory System GA DM6LR UT WOS:000376464500005 PM 26968770 ER PT J AU Walensky, RP Jacobsen, MM Bekker, LG Parker, RA Wood, R Resch, SC Horstman, NK Freedberg, KA Paltiel, AD AF Walensky, Rochelle P. Jacobsen, Margo M. Bekker, Linda-Gail Parker, Robert A. Wood, Robin Resch, Stephen C. Horstman, N. Kaye Freedberg, Kenneth A. Paltiel, A. David TI Potential Clinical and Economic Value of Long-Acting Preexposure Prophylaxis for South African Women at High-Risk for HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; preexposure prophylaxis; cost-effectiveness; South Africa; long-acting agents ID ANTIRETROVIRAL THERAPY; COST-EFFECTIVENESS; DRUG-RESISTANCE; RILPIVIRINE; PREVENTION; TENOFOVIR; TRIAL AB Background. For young South African women at risk for human immunodeficiency virus (HIV) infection, preexposure prophylaxis (PrEP) is one of the few effective prevention options available. Long-acting injectable PrEP, which is in development, may be associated with greater adherence, compared with that for existing standard oral PrEP formulations, but its likely clinical benefits and additional costs are unknown. Methods.aEuro integral Using a computer simulation, we compared the following 3 PrEP strategies: no PrEP, standard PrEP (effectiveness, 62%; cost per patient, $150/year), and long-acting PrEP (effectiveness, 75%; cost per patient, $220/year) in South African women at high risk for HIV infection (incidence of HIV infection, 5%/year). We examined the sensitivity of the strategies to changes in key input parameters among several outcome measures, including deaths averted and program cost over a 5-year period; lifetime HIV infection risk, survival rate, and program cost and cost-effectiveness; and budget impact. Results.aEuro integral Compared with no PrEP, standard PrEP and long-acting PrEP cost $580 and $870 more per woman, respectively, and averted 15 and 16 deaths per 1000 women at high risk for infection, respectively, over 5 years. Measured on a lifetime basis, both standard PrEP and long-acting PrEP were cost saving, compared with no PrEP. Compared with standard PrEP, long-acting PrEP was very cost-effective ($150/life-year saved) except under the most pessimistic assumptions. Over 5 years, long-acting PrEP cost $1.6 billion when provided to 50% of eligible women. Conclusions.aEuro integral Currently available standard PrEP is a cost-saving intervention whose delivery should be expanded and optimized. Long-acting PrEP will likely be a very cost-effective improvement over standard PrEP but may require novel financing mechanisms that bring short-term fiscal planning efforts into closer alignment with longer-term societal objectives. C1 [Walensky, Rochelle P.; Jacobsen, Margo M.; Parker, Robert A.; Horstman, N. Kaye; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Flr, Boston, MA 02114 USA. [Walensky, Rochelle P.; Jacobsen, Margo M.; Parker, Robert A.; Horstman, N. Kaye; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Parker, Robert A.] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Walensky, Rochelle P.; Parker, Robert A.; Freedberg, Kenneth A.] Harvard Univ, Harvard Med Sch, Ctr AIDS Res, Cambridge, MA 02138 USA. [Resch, Stephen C.] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Hlth Decis Sci, Cambridge, MA 02138 USA. [Freedberg, Kenneth A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Cambridge, MA 02138 USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Paltiel, A. David] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Bekker, Linda-Gail; Wood, Robin] Univ Cape Town, Fac Med, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7700 Rondebosch, South Africa. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Flr, Boston, MA 02114 USA. EM rwalensky@partners.org FU National Institute of Allergy and Infectious Diseases [R01 AI058736, AI093269]; National Institute of Mental Health [R01 MH105203]; Massachusetts General Hospital FX This work was supported by the National Institute of Allergy and Infectious Diseases (grants R01 AI058736 and AI093269), the National Institute of Mental Health (grant R01 MH105203), and Massachusetts General Hospital (Research Scholars Award to R. P. W.). NR 47 TC 1 Z9 1 U1 0 U2 4 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 MAY 15 PY 2016 VL 213 IS 10 BP 1523 EP 1531 DI 10.1093/infdis/jiv523 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DM8XX UT WOS:000376648900003 PM 26681778 ER PT J AU Vapnik, JS Kim, JB Isselbacher, EM Ghoshhajra, BB Cheng, YS Sundt, TM MacGillivray, TE Cambria, RP Lindsay, ME AF Vapnik, Joshua S. Kim, Joon. Bum Isselbacher, Eric M. Ghoshhajra, Brian B. Cheng, Yisha Sundt, Thoralf M., III MacGillivray, Thomas E. Cambria, Richard P. Lindsay, Mark E. TI Characteristics and Outcomes of Ascending Versus Descending Thoracic Aortic Aneurysms SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID E-DEFICIENT MICE; CANINE ATHEROSCLEROSIS; INTERNATIONAL REGISTRY; SEQUENCE VARIANT; DISSECTION IRAD; SUSCEPTIBILITY; HOMOGRAFTS; PREDICTOR; DIAMETER; IMPLANTS AB Thoracic aortic aneurysms (TAs) occur in reproducible patterns, but etiologic factors determining the anatomic distribution of these aneurysms are not well understood. This study sought to gain insight into etiologic differences and clinical outcomes associated with repetitive anatomic distributions of TAs. From 3,247 patients registered in an institutional Thoracic Aortic Center database from July 1992 to August 2013, we identified 844 patients with full aortic dimensional imaging by computerized axial tomography or magnetic resonance imaging scan (mean age 62.8 +/- 14 years, 37% women, median follow-up 40 months) with TA diameter >4.0 cm and without evidence of previous aortic dissection. Patient demographic and imaging data were analyzed in 3 groups: isolated ascending thoracic aortic aneurysms (AAs; n = 628), isolated descending TAs (DTAs; n = 130), and combined AA and DTA (mixed thoracic aortic aneurysm, MTA; n = 86). Patients with DTA had more hypertension (82% vs 59%, p <0.001) and a higher burden of atherosclerosis (88% vs 9%, p <0.001) than AA. Conversely, patients with isolated AA were younger (59.5 +/- 13.5 vs 71.0 +/- 11.8 years, p <0.001) and contained almost every case of overt, genetically triggered TA. Patients with isolated DTA were demographically indistinguishable from patients with MTA. In follow-up, patients with DTA/MTA experienced more aortic events (aortic dissection/rupture) and had higher mortality than patients with isolated AA. In multivariate analysis, aneurysm size (odds ratio 1.1, 95% CI 1.07 to 1.16, p <0.001) and the presence of atherosclerosis (odds ratio 5.7, 95% CI 2.02 to 16.15, p <0.001) independently predicted adverse aortic events. We find that DTA with or without associated AA appears to be a disease more highly associated with atherosclerosis, hypertension, and advanced age. In contrast, isolated AA appears to be a clinically distinct entity with a greater burden of genetically triggered disease. (C) 2016 Elsevier Inc. All rights reserved. C1 [Vapnik, Joshua S.; Kim, Joon. Bum; Isselbacher, Eric M.; Cheng, Yisha; Sundt, Thoralf M., III; MacGillivray, Thomas E.; Cambria, Richard P.; Lindsay, Mark E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thorac Aort Ctr, Boston, MA USA. [Vapnik, Joshua S.; Isselbacher, Eric M.; Cheng, Yisha; Lindsay, Mark E.] Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. [Kim, Joon. Bum; Sundt, Thoralf M., III; MacGillivray, Thomas E.] Harvard Univ, Sch Med, Div Cardiac Surg, Boston, MA USA. [Ghoshhajra, Brian B.] Harvard Univ, Sch Med, Div Radiol, Boston, MA USA. [Cambria, Richard P.] Harvard Univ, Sch Med, Div Vasc & Endovasc Surg, Boston, MA USA. [Kim, Joon. Bum] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Thorac & Cardiovasc Surg, Seoul, South Korea. RP Lindsay, ME (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thorac Aort Ctr, Boston, MA USA.; Lindsay, ME (reprint author), Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. EM Lindsay.Mark@MGH.Harvard.edu RI Ghoshhajra, Brian/J-2114-2016; OI Ghoshhajra, Brian/0000-0002-3865-3432; Kim, Joon Bum/0000-0001-5801-2395 FU AATS Graham Traveling Fellowship; Fredman Fellowship in Aortic Disease Research; Toomey fund for Aortic Dissection FX Dr. Kim is supported by the AATS Graham Traveling Fellowship. Dr. Lindsay is supported by the Fredman Fellowship in Aortic Disease Research and the Toomey fund for Aortic Dissection. NR 30 TC 1 Z9 1 U1 0 U2 0 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 MAY 15 PY 2016 VL 117 IS 10 BP 1683 EP 1690 DI 10.1016/j.amjcard.2016.02.048 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM3AN UT WOS:000376219300023 PM 27015890 ER PT J AU Carmody, JS Munoz, R Yin, HL Kaplan, LM AF Carmody, Jill S. Munoz, Rodrigo Yin, Huali Kaplan, Lee M. TI Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE glucagon-like peptide-1; Roux-en-Y gastric bypass; glucose tolerance; obesity; central regulation ID GLUCAGON-LIKE PEPTIDE-1; VERTICAL SLEEVE GASTRECTOMY; HIGH-FAT DIET; WEIGHT-LOSS; INSULIN-RESISTANCE; BARIATRIC SURGERY; MOUSE MODELS; FOOD-INTAKE; HOMEOSTASIS; OBESITY AB Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9-39) (2 pmol.kg(-1).min(-1) peripherally; 0.5 pmol.kg(-1).min(-1) centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation. C1 [Carmody, Jill S.; Munoz, Rodrigo; Yin, Huali; Kaplan, Lee M.] Massachusetts Gen Hosp, Obes Metab & Nutr Inst, Boston, MA 02114 USA. [Carmody, Jill S.; Munoz, Rodrigo; Yin, Huali; Kaplan, Lee M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Carmody, Jill S.; Munoz, Rodrigo; Yin, Huali; Kaplan, Lee M.] Harvard Univ, Sch Med, Boston, MA USA. [Munoz, Rodrigo] Pontificia Univ Catolica Chile, Fac Med, Dept Cirugia Digest, Alameda 340, Santiago, Chile. RP Kaplan, LM (reprint author), Massachusetts Gen Hosp, Obes Metab & Nutr Inst, 149 13th St,Rm 8219, Charlestown, MA 02129 USA. EM LMKaplan@partners.org FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-095567, DK-088661, DK-090956]; Ethicon FX This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-095567 (J.S. Carmody), DK-088661, and DK-090956 (L.M. Kaplan) and a research grant from Ethicon. NR 34 TC 2 Z9 2 U1 5 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAY 15 PY 2016 VL 310 IS 10 BP E855 EP E861 DI 10.1152/ajpendo.00412.2015 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA DM2DH UT WOS:000376156000007 PM 27026085 ER PT J AU Wang, H Akkin, T Magnain, C Wang, RP Dubb, J Kostis, WJ Yaseen, MA Cramer, A Sakadzic, S Boas, D AF Wang, Hui Akkin, Taner Magnain, Caroline Wang, Ruopeng Dubb, Jay Kostis, William J. Yaseen, Mohammad A. Cramer, Avilash Sakadzic, Sava Boas, David TI Polarization sensitive optical coherence microscopy for brain imaging SO OPTICS LETTERS LA English DT Article ID SPECTRAL-DOMAIN; TOMOGRAPHY; CONTRAST; RESOLUTION; TISSUE AB Optical coherence tomography (OCT) and optical coherence microscopy (OCM) have demonstrated the ability to investigate cyto- and myelo-architecture in the brain. Polarization-sensitive OCT provides sensitivity to additional contrast mechanisms, specifically the birefringence of myelination and, therefore, is advantageous for investigating white matter fiber tracts. In this Letter, we developed a polarization-sensitive optical coherence microscope (PS-OCM) with a 3.5 mu m axial and 1.3 mu m transverse resolution to investigate fiber organization and orientation at a finer scale than previously demonstrated with PS-OCT. In a reconstructed mouse brain section, we showed that at the focal depths of 20-70 mu m, the PS-OCM reliably identifies the neuronal fibers and quantifies the in-plane orientation. (C) 2016 Optical Society of America C1 [Wang, Hui; Magnain, Caroline; Wang, Ruopeng; Dubb, Jay; Kostis, William J.; Yaseen, Mohammad A.; Cramer, Avilash; Sakadzic, Sava; Boas, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Akkin, Taner] Univ Minnesota, Dept Biomed Engn, Minneapolis, MN 55455 USA. RP Wang, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM hwang47@mgh.harvard.edu FU National Institutes of Health (NIH) [EB015896, EB021018, NS055104, NS091230, EB018464, AG042026]; National Science Foundation (NSF) [1510674] FX National Institutes of Health (NIH) (EB015896, EB021018, NS055104, NS091230, EB018464, AG042026); National Science Foundation (NSF) (1510674). NR 16 TC 3 Z9 3 U1 3 U2 11 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 EI 1539-4794 J9 OPT LETT JI Opt. Lett. PD MAY 15 PY 2016 VL 41 IS 10 BP 2213 EP 2216 DI 10.1364/OL.41.002213 PG 4 WC Optics SC Optics GA DL6KH UT WOS:000375747600021 PM 27176965 ER PT J AU Ware, NC Pisarski, EE Tam, M Wyatt, MA Atukunda, E Musiimenta, A Bangsberg, DR Haberer, JE AF Ware, Norma C. Pisarski, Emily E. Tam, Melanie Wyatt, Monique A. Atukunda, Esther Musiimenta, Angella Bangsberg, David R. Haberer, Jessica E. TI The Meanings in the messages: how SMS reminders and real-time adherence monitoring improve antiretroviral therapy adherence in rural Uganda SO AIDS LA English DT Article DE antiretroviral therapy; mechanisms of effect; real-time adherence monitoring; SMS ID RANDOMIZED CONTROLLED-TRIAL; QUALITATIVE CONTENT-ANALYSIS; HEALTH INTERVENTIONS; WORKERS; CARE AB Objective:To understand how a pilot intervention combining SMS reminders with real-time adherence monitoring improved adherence to HIV antiretroviral therapy (ART) for adults initiating treatment in rural Uganda.Design:Qualitative study, conducted with a pilot randomized controlled trial.Methods:Sixty-two pilot intervention study participants took part in qualitative interviews on: preferences for content; frequency and timing of SMS adherence reminders; understandings and experiences of SMS reminders; and understandings and experiences of real-time adherence monitoring. Analysis of interview data was inductive and derived categories describing how participants experienced the intervention, and what it meant to them.Results:SMS reminders prompted taking individual doses of antiretroviral therapy, and helped to develop a habit' of adherence. Real-time adherence monitoring was experienced as being seen'; participants interpreted being seen' as an opportunity to demonstrate seriousness of commitment to treatment and taking responsibility' for adherence. Both SMS reminders and real-time monitoring were interpreted as signs of caring' by the healthcare system. Feeling cared about' offset depressed mood and invigorated adherence.Conclusion:Although serving as reminders, SMS messages and real-time adherence monitoring also had larger emotional and moral meanings for participants that they felt improved their adherence. Understanding the larger meanings in the messages,' as well as their more literal content and function, will be central in delineating how SMS reminders and other adherence interventions using cellular technology work or do not work in varying contexts. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Ware, Norma C.; Pisarski, Emily E.; Tam, Melanie; Wyatt, Monique A.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. [Ware, Norma C.] Brigham & Womens Hosp, Dept Med, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. [Atukunda, Esther; Musiimenta, Angella] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Bangsberg, David R.; Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.; Haberer, Jessica E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Ware, NC (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. EM norma_ware@hms.harvard.edu FU US National Institute of Mental Health [R34MH100940] FX financial support for the research was provided by a grant from the US National Institute of Mental Health to J.E.H. (R34MH100940). NR 30 TC 10 Z9 10 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAY 15 PY 2016 VL 30 IS 8 BP 1287 EP 1293 DI 10.1097/QAD.0000000000001035 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DL6WR UT WOS:000375781200014 PM 26807967 ER PT J AU Haberer, JE Musiimenta, A Atukunda, EC Musinguzi, N Wyatt, MA Ware, NC Bangsberg, DR AF Haberer, Jessica E. Musiimenta, Angella Atukunda, Esther C. Musinguzi, Nicholas Wyatt, Monique A. Ware, Norma C. Bangsberg, David R. TI Short message service (SMS) reminders and real-time adherence monitoring improve antiretroviral therapy adherence in rural Uganda SO AIDS LA English DT Article DE antiretroviral therapy; real-time adherence monitoring; short message service (SMS) ID RANDOMIZED CONTROLLED-TRIAL; SOCIAL SUPPORT; HIV/AIDS; INTERVENTION; DEPRESSION AB Objective:To explore the effects of four types of short message service (SMS) plus real-time adherence monitoring on antiretroviral therapy (ART) adherence: daily reminders, weekly reminders, reminders triggered after a late or missed dose (delivered to patients), and notifications triggered by sustained adherence lapses (delivered to patient-nominated social supporters).Design:Pilot randomized controlled trial.Methods:Sixty-three individuals initiating ART received a real-time adherence monitor and were randomized (1:1:1):(1) Scheduled SMS reminders (daily for 1 month, weekly for 2 months), then SMS reminders triggered by a late or missed dose (no monitoring signal within 2h of expected dosing); SMS notifications to social supporters for sustained adherence lapses (no monitoring signal for >48h) added after 3 months. (2) Triggered SMS reminders starting at enrolment; SMS notifications to social supporters added after 3 months. (3) Control: No SMS. HIV RNA was determined at 9 months. Percentage adherence and adherence lapses were compared by linear generalized estimating equations and Poisson regression, respectively.Results:Median age was 31 years, 65% were women, and median enrolment CD4(+) cell count was 322cells/l 97% took once daily tenofovir/emtricitabine/efavirenz. Compared to control, adherence was 11.1% higher (P=0.04) and more than 48-h lapses were less frequent (IRR 0.6, P=0.02) in the scheduled SMS arm. Adherence and more than 48-h lapses were similar in the triggered SMS arm and control. No differences in HIV RNA were seen.Conclusion:Scheduled SMS reminders improved ART in the context of real-time monitoring. Larger studies are needed to determine the impact of triggered reminders and role of social supporters in improving adherence. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Haberer, Jessica E.; Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haberer, Jessica E.; Wyatt, Monique A.; Ware, Norma C.; Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Musiimenta, Angella; Atukunda, Esther C.; Musinguzi, Nicholas; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Bangsberg, David R.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Haberer, JE (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 125 Nashua St,Suite 722, Boston, MA 02114 USA. EM jhaberer@mgh.harvard.edu FU US National Institutes of Health [R34MH100940] FX The study was funded by a grant from the US National Institutes of Health (R34MH100940). The study was registered with ClinicalTrials.gov (NCT01957865). NR 18 TC 11 Z9 11 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 MAY 15 PY 2016 VL 30 IS 8 BP 1294 EP 1298 DI 10.1097/QAD.0000000000001021 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DL6WR UT WOS:000375781200015 PM 26760452 ER PT J AU Skrypnyk, NI Siskind, LJ Faubel, S de Caestecker, MP AF Skrypnyk, Nataliya I. Siskind, Leah J. Faubel, Sarah de Caestecker, Mark P. TI Bridging translation for acute kidney injury with better preclinical modeling of human disease SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE acute kidney injury; animal models; human disease; preclinical research; drug discovery ID ACUTE-RENAL-FAILURE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; CISPLATIN-INDUCED NEPHROTOXICITY; CONTRAST-INDUCED NEPHROPATHY; RANDOMIZED CONTROLLED-TRIAL; ISCHEMIA-REPERFUSION INJURY; CRITICALLY-ILL PATIENTS; TUMOR-NECROSIS-FACTOR; SODIUM-BICARBONATE INFUSION; ACUTE TUBULAR-NECROSIS AB The current lack of effective therapeutics for patients with acute kidney injury (AKI) represents an important and unmet medical need. Given the importance of the clinical problem, it is time for us to take a few steps back and reexamine current practices. The focus of this review is to explore the extent to which failure of therapeutic translation from animal studies to human studies stems from deficiencies in the preclinical models of AKI. We will evaluate whether the preclinical models of AKI that are commonly used recapitulate the known pathophysiologies of AKI that are being modeled in humans, focusing on four common scenarios that are studied in clinical therapeutic intervention trials: cardiac surgery-induced AKI; contrast-induced AKI; cisplatin-induced AKI; and sepsis associated AKI. Based on our observations, we have identified a number of common limitations in current preclinical modeling of AKI that could be addressed. In the long term, we suggest that progress in developing better preclinical models of AKI will depend on developing a better understanding of human AKI. To this this end, we suggest that there is a need to develop greater in-depth molecular analyses of kidney biopsy tissues coupled with improved clinical and molecular classification of patients with AKI. C1 [Skrypnyk, Nataliya I.; de Caestecker, Mark P.] Vanderbilt Univ, Med Ctr, Div Nephrol & Hypertens, Nashville, TN USA. [Siskind, Leah J.] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Siskind, Leah J.] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. [Faubel, Sarah] Univ Colorado Denver, Div Renal, Aurora, CO USA. [Faubel, Sarah] Denver Vet Affairs Med Ctr, Aurora, CO USA. RP de Caestecker, MP (reprint author), Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, 1161 21st Ave South,S3223 Med Ctr North, Nashville, TN 37232 USA. EM mark.de.caestecker@vanderbilt.edu FU National Institutes of Health (NIH) [1RC4DK090770, VUMC44339-0R/P30DK079307-007, VUMC43321/U24 DK076169, 2R01 DK069403]; Vanderbilt Center for Kidney Disease (VCKD); NephroGenex, Inc.; NIH Grant [R01DK093462]; Veterans Afairs Merit Review Grants [I01 BX001498, R56 HL095363] FX This work was supported by National Institutes of Health (NIH) Grants 1RC4DK090770, VUMC44339-0R/P30DK079307-007, VUMC43321/U24 DK076169, and 2R01 DK069403, and the Vanderbilt Center for Kidney Disease (VCKD). A research grant from NephroGenex, Inc. supported M. P. de Caestecker; NIH Grant R01DK093462 supported L. J. Siskind; and S. Faubel was supported by Veterans Afairs Merit Review Grants I01 BX001498 and R56 HL095363. NR 178 TC 0 Z9 0 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAY 15 PY 2016 VL 310 IS 10 BP P972 EP P984 DI 10.1152/ajprenal.00552.2015 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA DL7TG UT WOS:000375842400005 ER PT J AU Roberts, DA Kantarjian, HM Steensma, DP AF Roberts, Daniel A. Kantarjian, Hagop M. Steensma, David P. TI Contract Research Organizations in Oncology Clinical Research: Challenges and Opportunities SO CANCER LA English DT Editorial Material DE clinical trial; contract research organizations; drug trial; ethics ID CANCER-RESEARCH; SPONSORSHIP; IMPACT; COSTS AB Contract research organizations (CROs) represent a multibillion dollar industry that is firmly embedded in the contemporary clinical trial process. Over the past 30 years, and especially within the last decade, the reach of CROs has extended to service all phases of drug trials in an increasingly global research environment. The presence of CROs is particularly noticeable in medical oncology because of the large number of investigational compounds developed to treat cancer that are currently undergoing testing in human subjects. Although limited data are available with which to objectively define the effects that CROs