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McGill University1, Montreal Neurological Institute and Hospital2, Concordia University3, University of Paris4, University of Oxford5, University of Montpellier6, Innsbruck Medical University7, University of Lille Nord de France8, University of Bologna9, Vita-Salute San Raffaele University10, University of Münster11, Genzyme12, Tel Aviv University13, Sheba Medical Center14, Columbia University Medical Center15, Sacred Heart Hospital16, Université du Québec à Montréal17, Université de Montréal18, Laval University19
TL;DR: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome‐wide association studies of Parkinson disease (PD) and specific disease‐associated variants in this locus are identified and their potential implications are identified.
Abstract: Objective The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.
62 citations
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28 May 1997TL;DR: A method for forming a graft in heart tissue which comprises the transplantation of cells chosen from cardiomyocytes, fibroblasts, smooth muscle cells, endothelial cells and skeletal myoblasts is provided in this paper.
Abstract: A method is provided for forming a graft in heart tissue which comprises the transplantation of cells chosen from cardiomyocytes, fibroblasts, smooth muscle cells, endothelial cells and skeletal myoblasts. The grafts are especially useful in treating scar tissue on the heart. Also provided is a method of isolating and culturing cardiomyocytes for use in such grafts.
62 citations
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TL;DR: It is shown that patients with metastatic melanoma are not tolerant to gp100 Ag based on the detection of CD8+ T cells specific for multiple HLA-A*0201-restricted, gp100-derived epitopes.
Abstract: Replication-deficient recombinant adenovirus (Ad) encoding human gp100 or MART-1 melanoma Ag was used to transduce human dendritic cells (DC) ex vivo as a model system for cancer vaccine therapy. A second generation E1/E4 region deleted Ad which harbors the CMV immediate-early promoter/enhancer and a unique E4-ORF6/pIX chimeric gene was employed as the backbone vector. We demonstrate that human monocyte-derived DC are permissive to Ad infection at multiplicity of infection between 100 and 500 and occurs independent of the coxsackie Ad receptor. Fluorescent-labeled Ad was used to assess the kinetics and distribution of viral vector within DC. Ad-transduced DC show peak transgene expression at 24-48 h and expression remains detectable for at least 7 days. DC transduced with replication-deficient Ad do not exhibit any unusual phenotypic characteristics or cytopathic effects. DC transduced with Ad2/gp100v2 can elicit tumor-specific CTL in vitro from patients bearing gp100+ metastatic melanoma. Using a panel of gp100-derived synthetic peptides, we show that Ad2/gp100v2-transduced DC elicit Ag-specific CTL that recognize only the G209 and G280 epitopes, both of which display relatively short half-lives ( approximately 7-8 h) on the surface of HLA-A*0201+ cells. Thus, patients with metastatic melanoma are not tolerant to gp100 Ag based on the detection of CD8+ T cells specific for multiple HLA-A*0201-restricted, gp100-derived epitopes.
62 citations
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TL;DR: By increasing the iodine excretion, rhTSH allows a shorter hospitalization length, which partially compensates its acquisition cost.
Abstract: Purpose
Treatment of thyroid cancer consists of thyroidectomy and radioiodine ablation following thyroid-stimulating hormone (TSH) stimulation. Similar ablation rates were obtained with either thyroid hormone withdrawal (THW) or rhTSH. But with rhTSH, the elimination of radioiodine is more rapid, thus reducing its whole-body retention and potentially resulting in a shorter hospital stay. The aim of this study was to assess the financial impact of a reduced length of hospital stay with the use of rhTSH.
62 citations
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TL;DR: The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.
Abstract: Purpose: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when adminis- tered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. Experimental Design: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m 2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. Results: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m 2 . At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non ^ small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11months. Conclusions: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m 2 . The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.
62 citations
Authors
Showing all 3085 results
Name | H-index | Papers | Citations |
---|---|---|---|
George M. Whitesides | 240 | 1739 | 269833 |
Stephen J. O'Brien | 153 | 1062 | 93025 |
Robert B. Jackson | 132 | 458 | 91332 |
Glenn M. Chertow | 128 | 764 | 82401 |
Jon Clardy | 116 | 983 | 56617 |
John J. Fung | 115 | 1011 | 52924 |
Robert B. Colvin | 111 | 556 | 52034 |
Sergio Giralt | 109 | 1024 | 48513 |
Paul Saftig | 107 | 356 | 49929 |
Robert J. Desnick | 102 | 694 | 39698 |
Robert A. Soslow | 87 | 427 | 29014 |
Richard J. Roman | 84 | 461 | 23760 |
Diana W. Bianchi | 81 | 405 | 24554 |
Paolo Raggi | 80 | 439 | 33332 |
Helmut G. Rennke | 77 | 256 | 33959 |