Project description:Giant cell lesions of the jaws are aggressive proliferative conditions that affect young and adult patients. The genetic profile of the tumour has not been established yet. In this project we performed whole exome sequencing of 18 samples and RNAseq (n=6) of giant cell lesions of the jaws. All the tumours are sporadic and only non-syndromic patients were included.
Project description:Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable with few means to predict which patients will benefit. To develop a molecular means of predicting response at diagnosis, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients responsive and resistant to decitabine (DAC). While somatic mutations did not differentiate responders and non-responders, we were able to identify for the first time 158 differentially methylated regions (DMRs) at baseline between responders and non-responders using next-generation sequencing. These DMRs were primarily localized to non-promoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. We also found 53 differentially expressed genes between responders and non-responders. Genes up-regulated in responders were enriched in the cell cycle, potentially contributing to effective DAC incorporation. Two chemokines overexpressed in non-responders -- CXCL4 and CXCL7 -- were able to block the effect of DAC on normal CD34+ and primary CMML cells in vitro, suggesting their up-regulation contributes to primary DAC resistance. DNA methylation profiling in bone marrow mononuclear cells (BM MNC) from 39 CMML patients (19 decitabine responders vs. 20 non-responders).
Project description:Interventions: 1. Clinical data registration;
2. Molecular analysis of polypoid vs. flat colorectal lesions.
Primary outcome(s): 1. Prevalence of flat colorectal lesions in a Dutch population;
2. Clinical characteristics (e.g. location of lesions, percentage of high-grade dysplasia or early cancer);
3. Molecular charcteristics (epigenetic: methylation status and genetic) of flat vs. polypoid colorectal lesions;
4. Prevalence of flat advanced colorectal cancers vs. polypoid advanced colorecal cancers: clinical features of these lesions (e.g. tumor stage);
5. Relation between serrated and adenomatous polyps.
Study Design: Non-randomized controlled trial, Open (masking not used), N/A , unknown, Factorial
Project description:To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA).Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification.Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ?55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA.Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.
Project description:The impact of drugs inhibiting DNA methylation (5-aza-2'-deoxycytodine, DAC) and EZH2 (EPZ-6438) on H3K27me3 coverage was analyzed in two neuroblastoma cell lines. Parallel analyses investigated associated changes in RNA expression and DNA methylation. The neuroblastoma cell lines Be(2)-C and IMR5-75 were treated with a combination of DAC and EPZ-6438. Controls were treated with solvent (DMSO). H3K27me3 ChIP seq was done to investigate treatment-related changes of this mark. In addition, H3K4me3 and H3K27ac ChIP seq was done in DMSO treated samples to identify putative regulatory regions.
Project description:Recently, the H3K4 demethylase, KDM5B, was shown to be amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins, either alone, or in combination with the DNA demethylating agent 5-aza-2’ deoxycytidine (DAC). Alone, the KDM5 inhibitor (KDM5i) increased expression of a small number of genes, but when combined with DAC, the drug enhanced the effects of the latter for increasing expression of hundreds of DAC responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing, and creation of thousands of new H3K4me3 domains. When compared to DAC alone, increased promoter and gene body H3K4me3 occupancy at DAC responsive genes was observed in cells treated with the drug combination. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. Finally, we found that KDM5i could synergize with DAC to reduce the viability of luminal breast cancer cells in in-vitro assays. Our study provides the first look into the molecular effects of novel KDM5i compounds and suggests that combining these with DAC may represent an exciting new approach to epigenetic therapy.
Project description:We profiled trophoblast stem cell replication-timing in order to compare these data to our data on underrepresented (UR) domainss in trophoblast giant cells (polyploid cells derived from 2N trophoblast stem cells). We found that UR domains are formed from late-replicating regions in tropoblast stem cells.