Project description:Primary objectives: The primary objective is to investigate circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Primary endpoints: circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Project description:DNA methylation (DNAm) influences when and where genes are expressed or repressed during growth and development. Recently, patterns of DNAm at conserved genomic sites have been discovered that predict chronological age in all mammals. Deviations from these ‘epigenetic clocks’ have been used to identify factors that alter the aging process. In this study, we profile DNAm with a custom microarray for over 330 wild Phyllostomus hastatus, a highly polygynous bat in which unrelated females form long-lasting associations and larger males compete aggressively to control mating access to female groups. DNAm age estimates reveal that females can live more than 1.5 times as long as males. After fitting linear models for age, sex and their interaction we find that DNAm changes 1.4 times faster in males than females at thousands of sites. Therefore, even though age of either sex can be predicted by a common set of sites, the methylome of males is more dynamic than that of females. Sites associated with differences in the rate of change between males and females are sensitive to androgens and enriched on the X chromosome. Those that gain methylation with age in both sexes are associated with active and repressive chromatin states in blood and are enriched in promoters of genes involved in regulation of metabolic processes. In contrast, few sites differ in DNAm rate between males of different reproductive status, though subordinate males exhibit faster DNAm change than dominant males. Thus, males have accelerated physiological processes in comparison to females that likely increase mating success but reduce survival.
