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- Kuhle, J, et al.
(författare)
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A 10-year follow-up of the European multicenter trial of interferon β-1b in secondary-progressive multiple sclerosis
- 2016
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 22:4, s. 533-543
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Tidskriftsartikel (refereegranskat)abstract
- To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). Methods: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. Results: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R2: 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited ( R2: 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. Conclusions: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.
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- Kruse, Jacqueline J.C.M., et al.
(författare)
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A portrait of cisplatin-induced transcriptional changes in mouse embryonic stem cells reveals a dominant p53-like response
- 2007
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Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X. ; 617:1-2, s. 58-70
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of damage in undifferentiated cells may threaten homeostasis and regenerative capacity. Remarkably, p53 has been suggested to be transcriptionally inactive in these cells. To gain insight in the kinetics and interplay of the predominant transcriptional responses of DNA damage signalling pathways in undifferentiated cells, mouse embryonic stem cells were exposed to cisplatin at four different time points (2, 4, 8 and 24 h) and concentrations (1, 2, 5 and 10 μM). RNA was isolated and subjected to genome-wide expression profiling. Up to one fourth of the tested genes could be identified as being differentially expressed (false discovery rate = 10%) after the cisplatin treatment. Clustering of the expression changes showed a strong time dependency. To investigate the relationship between affected genes, a gene set analysis method was used. Functionally related gene sets were defined using gene ontologies or transcription factor binding sites and were tested for overrepresentation within the differentially expressed genes. A variety of gene sets were clearly enriched among which 'apoptosis' and 'cell cycle' were the most pronounced. Furthermore, there was a strong enrichment of genes with a p53-binding motif. The involvement of the 'cell cycle' and 'apoptosis' gene sets in the cisplatin response was detected at concentrations and time points where the respective biological assays were still negative. The results reveal novel insights into the mechanisms which maintain the genomic integrity in undifferentiated cells. Additionally the results illustrate that gene set analysis of genome-wide expression changes provides a sensitive instrument to detect cellular stress responses to DNA damage.
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