Project description:Interventions: Radiofrequency ablation will be done after hepatic arterial embolization with degradable starchmicrosphere and mitomycinC. Twenty-five patients with colorectal cancer livr metastasis will be treated and followed for 2 years. Study period will be 36 months.
Primary outcome(s): Local tumo control
Study Design: Single arm Non-randomized
Project description:Extensive epigenetic remodelling takes place during early life; however, the alterations of DNA methylation that occur during this period have not been sufficiently addressed by longitudinal studies. We made use of the most recent Illumina MethylationEPIC Beadchip platform to characterize genome-wide DNA methylation changes observed through the first 10 years of life in longitudinal blood samples of 11 subjects. We described numerous changes during the first 5 years, while many less alterations in the following 5 year period. Interestingly, we identified a subset of persistent DNA methylation changes of considerable magnitude along the first 10 years of life. Moreover, our data demonstrated that genes that suffer simultaneous hyper- and hypomethylation are functionally different from genes that are exclusively hyper- or hypomethylated. Furthermore, our results evidence that enhancer-associated methylation changes are different for the gain or loss of methylation. throughout hematopoietic maturation by analyzing multiple hematopoietic cell types at different developmental stages. We identified a plethora of DNA methylation changes that occur during human hematopoietic differentiation. Interestingly, we observed that T lymphocytes display a substantial enhancement of de novo CpG hypermethylation as compared to other hematopoietic cell populations.
Project description:Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Sixty-five per cent of tumours were poorly differentiated ductal carcinomas and hormonal receptors were present in 47%. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median progression-free survival was 10.6 years after the diagnosis of metastatic disease. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival . Gene ontology analysis demonstrated that genes involved in HIF activation, EGF receptor signalling pathway, PI3 kinase pathway, apoptosis signalling pathway and p53 pathway significantly correlated with response. The PI3K pathway was the most strongly associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. These findings support that trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression to trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy. 53 FFPE samples, which passed the RNA quality control criteria, were analyzed (45 primary tumours and 8 metastases). Among these 53 samples, 35 samples corresponded to long-term responders and 18 to the control group.
Project description:Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Sixty-five per cent of tumours were poorly differentiated ductal carcinomas and hormonal receptors were present in 47%. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median progression-free survival was 10.6 years after the diagnosis of metastatic disease. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival . Gene ontology analysis demonstrated that genes involved in HIF activation, EGF receptor signalling pathway, PI3 kinase pathway, apoptosis signalling pathway and p53 pathway significantly correlated with response. The PI3K pathway was the most strongly associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. These findings support that trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression to trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.
Project description:Analysis of 104 breast cancer biopsies (removed prior to any treatment with tamoxifen or chemotherapeutic agents) from patients aged between 31 years and 89 years at the time of diagnosis (mean age = 58 years). Twenty were less than 50 years and seventy-seven women were 50 years, or older, at diagnosis. The size of the tumours ranged between 0.6 cm and 8.0 cm (mean = 2.79 cm). Eighteen tumours were T1 (<2 cm) in maximal dimension; 83 were T2 (2–5 cm) and 3 tumours were T3 (>5 cm). Eighty-two were invasive ductal carcinoma, 17 were invasive lobular and five were tumours of special type (two tubular and three mucinous). Eleven tumours were grade 1; 40 were grade 2; and 53 were grade 3. Sixty-seven tumours were oestrogen receptor (ER) positive and 34 were ER negative (ER status was determined by Enzyme Immuno-Assay (EIA); a positive result was defined as more than 200 fmol/g protein). ER status was not available for 3 patients. Forty-five tumours had no axillary metastases and 59 tumours had metastasised to axillary lymph nodes. Sixty-nine women were treated with post-operative tamoxifen; 26 did not receive tamoxifen. Fifty patients were treated with adjuvant systemic chemotherapy (CMF +/− adriamycin); 45 patients did not receive chemotherapy. Details regarding tamoxifen and systemic chemotherapy were not available for 9 patients. Maximal follow-up was 3,026 days with a mean follow-up of 1,887 days. 17 normal breast tissues were also assayed.
Project description:The basidiomycete Moniliophthora roreri causes frosty pod rot of cacao (Theobroma cacao) in the Western hemisphere. M. roreri is considered asexual and haploid throughout its hemibiotrophic lifecycle. To understand the processes driving genome modification, using long-read sequencing technology we sequenced and assembled five high quality M. roreri genomes out of a collection of ninety-nine isolates collected throughout the pathogen's range. We obtained chromosome-scale assemblies composed of eleven scaffolds. We used short-read technology to sequence the genomes of twenty-two similarly chosen isolates. Alignments among the five reference assemblies revealed inversions and segmental translocations and duplications between and within scaffolds. Isolates at the front of the pathogens’ expanding range tend to share lineage-specific structural variants, as confirmed by short-read sequencing. We identified, for the first time, three new mating type A locus alleles (five in total) and one new potential mating type B locus allele (three in total). Currently only two mating type combinations, A1B1 and A2B2, are known to exist outside of Colombia. A systematic survey of the M. roreri transcriptome across twenty-two isolates identified an expanded candidate effector pool and provided evidence that effector candidate genes unique to the Moniliophthoras have been selected for preferential expression during the biotrophic phase of disease. Notably, M. roreri isolates in Costa Rica carry a chromosome segment duplication that has doubled the associated gene complement and includes secreted proteins and candidate effectors. Clonal propagation of the haploid M. roreri genome has allowed lineages with unique genome structures and compositions to dominate as it expands its range, displaying a significant founder effect.
Project description:The basidiomycete Moniliophthora roreri causes frosty pod rot of cacao (Theobroma cacao) in the Western hemisphere. M. roreri is considered asexual and haploid throughout its hemibiotrophic lifecycle. To understand the processes driving genome modification, using long-read sequencing technology we sequenced and assembled five high quality M. roreri genomes out of a collection of ninety-nine isolates collected throughout the pathogen's range. We obtained chromosome-scale assemblies composed of eleven scaffolds. We used short-read technology to sequence the genomes of twenty-two similarly chosen isolates. Alignments among the five reference assemblies revealed inversions and segmental translocations and duplications between and within scaffolds. Isolates at the front of the pathogens’ expanding range tend to share lineage-specific structural variants, as confirmed by short-read sequencing. We identified, for the first time, three new mating type A locus alleles (five in total) and one new potential mating type B locus allele (three in total). Currently only two mating type combinations, A1B1 and A2B2, are known to exist outside of Colombia. A systematic survey of the M. roreri transcriptome across twenty-two isolates identified an expanded candidate effector pool and provided evidence that effector candidate genes unique to the Moniliophthoras have been selected for preferential expression during the biotrophic phase of disease. Notably, M. roreri isolates in Costa Rica carry a chromosome segment duplication that has doubled the associated gene complement and includes secreted proteins and candidate effectors. Clonal propagation of the haploid M. roreri genome has allowed lineages with unique genome structures and compositions to dominate as it expands its range, displaying a significant founder effect.
Project description:Analysis of 104 breast cancer biopsies (removed prior to any treatment with tamoxifen or chemotherapeutic agents) from patients aged between 31 years and 89 years at the time of diagnosis (mean age = 58 years). Twenty were less than 50 years and seventy-seven women were 50 years, or older, at diagnosis. The size of the tumours ranged between 0.6 cm and 8.0 cm (mean = 2.79 cm). Eighteen tumours were T1 (<2 cm) in maximal dimension; 83 were T2 (2M-bM-^@M-^S5 cm) and 3 tumours were T3 (>5 cm). Eighty-two were invasive ductal carcinoma, 17 were invasive lobular and five were tumours of special type (two tubular and three mucinous). Eleven tumours were grade 1; 40 were grade 2; and 53 were grade 3. Sixty-seven tumours were oestrogen receptor (ER) positive and 34 were ER negative (ER status was determined by Enzyme Immuno-Assay (EIA); a positive result was defined as more than 200 fmol/g protein). ER status was not available for 3 patients. Forty-five tumours had no axillary metastases and 59 tumours had metastasised to axillary lymph nodes. Sixty-nine women were treated with post-operative tamoxifen; 26 did not receive tamoxifen. Fifty patients were treated with adjuvant systemic chemotherapy (CMF +/M-bM-^HM-^R adriamycin); 45 patients did not receive chemotherapy. Details regarding tamoxifen and systemic chemotherapy were not available for 9 patients. Maximal follow-up was 3,026 days with a mean follow-up of 1,887 days. 17 normal breast tissues were also assayed. Gene expression profiling of 104 breast cancer and 17 normal breast biopsies.