Report on ISCTM consensus meeting on clinical assessment of response to treatment of cognitive impairment in schizophrenia

Funding for this manuscript was provided by the International Society for CNS Clinical Trials and Methodology.Dr Keefe currently or in the past 3 years has received investigator-initiated research funding support from the Department of Veteran's Affair, Feinstein Institute for Medical Research, GlaxoSmithKline, National Institute of Mental Health, Novartis, Psychogenics, Research Foundation for Mental Hygiene, Inc., and the Singapore National Medical Research Council. He currently or in the past 3 years has received honoraria, served as a consultant, or advisory board member for Abbvie, Akebia, Amgen, Asubio, AviNeuro/ChemRar, BiolineRx, Biogen Idec, Biomarin, Boehringer-Ingelheim, Eli Lilly, EnVivo/FORUM, GW Pharmaceuticals, Janssen, Lundbeck, Merck, Minerva Neurosciences, Inc., Mitsubishi, Novartis, NY State Office of Mental Health, Otsuka, Pfizer, Reviva, Roche, Sanofi/Aventis, Shire, Sunovion, Takeda, Targacept, and the University of Texas South West Medical Center. Dr Keefe receives royalties from the BACS testing battery, the MATRICS battery (BACS Symbol Coding), and the Virtual Reality Functional Capacity Assessment Tool. He is also a shareholder in NeuroCog Trials, Inc. and Sengenix. Dr Haig is a full-time employee of Abbvie. Dr Marder has received consulting fees from Abbvie, Genentech, Roche, Lundbeck, Pfizer, Otsuka, Takeda, and Boeringer Ingelheim. He has received research support from Amgen, Sunovion, and Synchroneuron. Dr Harvey has received consulting fees from Abbvie, Boehringer Ingelheim, Forest Labs, Forum Pharma, Genentech, Otsuka America, Roche Pharma, Sunovion Pharma, and Takeda Pharma during the past year. He also received contract research support from Genentech. Dr Dunayevich for the past 3 years has been a full-time employee and stockholder of Amgen. Dr Medalia in the past 3 years has received research funding support from Sunovion. Dr Medalia has also currently or in the past 3 years received honoraria or served as consultant for Dainippon Sumitomo Pharma Co., Ltd., Otsuka, and Takeda Pharmaceuticals U.S.A., Inc. Dr Davidson has received research grant support and/or travel support and/or speaker fees and/or consultancy fees from Lundbeck, Eli Lilly, Servier, Abbott, Minerva and holds stocks in CTR and BiolineRx. Dr Lombardo is a full-time employee of FORUM Pharmaceuticals. Dr Bowie reports receiving grant support from Pfizer. He has also been a consultant for Lundbeck, Otsuka, Abbvie, and Takeda. Dr Buchanan reports: Advisory Board: Abbvie, Amgen, EnVivo, Roche; Consultant: Abbvie, Amgen, Bristol Myers Squibb, EnVivo, Omeros; DSMB member: Pfizer. Dr Bugarski -Kirola is a full-time employee of Hoffmann-La Roche Ltd. Dr Carpenter in the past 2 years has been a consultant to Roche/Genetech. Dr Dago in the last 3 years has received honoraria from Lundbeck, Forest Pharmaceuticals, Otsuka, Pam Labs, and Astra Zeneca for lectures given in promotion of their psychotropic medications. Dr Durand in the past year has been a consultant and received honoraria from Teva Pharmaceuticals. Dr Gold receives royalty payments from the BACS. He also has served as a consultant for Amgen, Hoffman LaRoche, and Lundbeck. Dr Hooker has served as a consultant and is currently a Co-Investigator on an NIH SBIR grant with PositScience Corporation. Dr Loebel is an employee of Sunovion Pharmaceuticals. Dr McGurk reports receiving consulting fees from Abbvie and EnVivo Pharmaceuticals. Dr Pinkham in the past year has received consulting fees from Otsuka America Pharmaceutical, Inc.The following authors have declared that there are no conflicts of interest in relation to the subject of this study: Drs Csernansky, Frese, Goff, Kopelowic, Opler, and Stern. (International Society for CNS Clinical Trials and Methodology; Department of Veteran's Affair; Feinstein Institute for Medical Research; GlaxoSmithKline; National Institute of Mental Health; Novartis; Psychogenics; Research Foundation for Mental Hygiene, Inc.; Singapore National Medical Research Council; Abbvie; Genentech; Roche; Lundbeck; Pfizer; Otsuka; Takeda; Boeringer Ingelheim; Amgen; Sunovion; Synchroneuron; Boehringer Ingelheim; Forest Labs; Forum Pharma; Otsuka America; Roche Pharma; Sunovion Pharma; Takeda Pharma; Eli Lilly; Servier; Abbott; Minerva; BACS; EnVivo Pharmaceuticals; Otsuka America Pharmaceutical, Inc.)Published versio

Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis

Background/Introduction: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. Aim: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. Design: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. Methods: Cohorts of Irish sarcoidosis patients (n=228), healthy Irish controls (n=263) and a secondary cohort of American sarcoidosis patients (n=123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. Results: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 Fhomozygous pulmonary sarcoidosis patients resulted in reduced IFN-? and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. Discussion/Conclusion: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarke