Dataset Information

OPTIMISTIC DAC for ReCognitION

ABSTRACT: Data Access Committee EGAC00001002434

PROVIDER: EGAC00001002434 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial.

Okkersen Kees K Jimenez-Moreno Cecilia C Wenninger Stephan S Daidj Ferroudja F Glennon Jeffrey J Cumming Sarah S Littleford Roberta R Monckton Darren G DG Lochmüller Hanns H Catt Michael M Faber Catharina G CG Hapca Adrian A Donnan Peter T PT Gorman Gráinne G Bassez Guillaume G Schoser Benedikt B Knoop Hans H Treweek Shaun S van Engelen Baziel G M BGM

The Lancet. Neurology 20180619 8

<h4>Background</h4>Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1.<h4>Methods</h4>We did a multicentre, single-blind, randomised trial, ...[more]

PMID: 29934199

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Project description:Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitor, decitabine (5-aza-2'-deoxycitidine), is proving efficacious for hematological neoplasms especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response seen in patients. Transient exposure of leukemic and solid tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity or apoptosis, produces sustained reduced tumorigenicity, and for leukemia cells, diminished long-term self-renewal. These effects appear triggered by cellular reprogramming and include sustained decreases in promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, most of which are high priority targets for pharmacologic anti-cancer strategies. Thus, low dose decitabine regimens appear to have broad applicability for cancer management. [Gene expression profiling] Leukemia cell lines Kasumi-1 and KG1A are treated with 10nM DAC during 72 hours and gene expression was assayed at day 3, 7 and 14 after the start of the treatment. Appropriate mock treated samples were used as control in each case. In addition, Kasumi-1 cells were also treated with a higher dose of DAC (500nM), 100nM ARA-C and 300 nM TSA, again controlled against mock treated Kasumi-1 cells, to separate dose and agent dependent effects. MCF7 was studied as an example of a solid tumor cell line. Therefore MCF7 cells were treated with 100nM DAC and results were assayed at day 1, day 3 and day 10. [Methylation profiling] The effects of the demethylating agent DAC were studied in the leukemia cell line Kasumi-1 over a 28 day time course. Intermediate time points were studied at days 3, 7, 14 and 21. These results were verfied in KG1A and KG1 leukemia cell lines, at one selected time point. The effects on one primary sample were also studied. Four normal leukemia samples (PL1, 2, 4 and 5) were used as general controls. The effect of DAC was compared to ARA-C, TSA. Both mock treated and day 3 DAC treated Kasumi-1 cells were repeated. These results were verified at one selected time point for the DAC treated MCF7 breast cancer cell line.

Dataset Information

OPTIMISTIC DAC for ReCognitION

Publications

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial.

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