Chemotherapy With DNA Damaging Agents In Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2114543 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Cardiac surgery and cardiopulmonary bypass induce a substantial immune and inflammatory response, the overactivation of which is associated with significant complications. Longitudinal DNA methylation profiling allows the potential to identify changes in gene regulatory mechanisms that are secondary to surgery and to identify molecular processes that predict and/or cause postoperative complications. In this study, we measure DNA methylation in preoperative and postoperative whole blood samples from 96 patients undergoing cardiac surgery on cardiopulmonary bypass. We identify several loci with statistically significant postoperative changes in methylation. Additionally, two of these loci are associated with new-onset postoperative atrial fibrillation, a significant complication after cardiac surgery. This research establishes that there are statistically significant changes in DNA methylation that occur immediately after cardiac surgery and that these acute alterations in DNA methylation have the granularity to identify processes associated with major postoperative complications.
2023-01-09 | GSE215937 | GEO
Project description:The inflammatory response to surgery is essential for healing and recovery, however hyperinflammation and altered immune competence increases the risk of inflammation mediated complications. We hypothesised that, in some patients, a state of postoperative systemic inflammatory dysregulation (PSID) exists increasing the risk or infection and sepsis, and that this will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. In this study we utilised phenotypic extremes of postoperative plasma C-reactive protein levels to define PSID, which manifested clinically in significantly higher rates of sepsis, complications and longer hospital stays following major abdominal surgery. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression confirms that dysregulation is mediated at multiple levels within specific gene sets and hence, non-specific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.
2021-09-17 | GSE184047 | GEO
Project description:The inflammatory response to surgery is essential for healing and recovery, however hyperinflammation and altered immune competence increases the risk of inflammation mediated complications. We hypothesised that, in some patients, a state of postoperative systemic inflammatory dysregulation (PSID) exists increasing the risk or infection and sepsis, and that this will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. In this study we utilised phenotypic extremes of postoperative plasma C-reactive protein levels to define PSID, which manifested clinically in significantly higher rates of sepsis, complications and longer hospital stays following major abdominal surgery. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression confirms that dysregulation is mediated at multiple levels within specific gene sets and hence, non-specific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.
2021-09-17 | GSE184039 | GEO
Project description:DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (NtAI) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of NtAI forecast a better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair.
2012-03-22 | GSE28330 | GEO
Project description:Tyrosyl DNA phosphodiesterase 1 (TDP1) and DNA Ligase III (LigIII) are key enzymes in nuclear and mitochondrial single-strand break (SSB) repair pathways whereby TDP1 removes the 3-tyrosine residue remaining after degradation of a trapped DNA topoisomerase 1. Here we define a direct interaction between TDP1 catalytic domain and LigIII DNA binding domain (DBD) that is regulated by conformational changes in the unstructured TDP1 N-terminal region induced by phosphorylation and/or alterations in amino acid sequence. Full-length and N-terminally truncated TDP1 are more effective at correcting the defect in SSB repair of TDP1 null cells compared with full-length TDP1 with amino acid substitutions of an N-terminal serine residue that is phosphorylated in response to DNA damage. TDP1 forms a stable complex with LigIII170-755, full-length LigIII as well as full-length LigIII alone and in complex with XRCC1. Homodimerization of LigIII BRCT domains links two LigIII-TDP1 heterodimers. Small angle X-ray scattering and negative stain electron microscopy combined with mapping of the interacting regions, identify a TDP1/LigIII compact dimer of heterodimers in which the two LigIII catalytic cores are positioned in the center, whereas two TDP1 molecules are located at the edges of the core complex formed by the LigIII DBD and the TDP1 catalytic domain flanked by highly flexible regions that can interact with other repair proteins and the SSB. As TDP1- LigIII repairs adducts caused by TOP1 cancer chemotherapy inhibitors, the defined interaction architecture and regulation informs on how this enzyme complex functions and is regulated in non-malignant and cancer cells.
2021-04-12 | MSV000087179 | MassIVE
Project description:DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (NtAI) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of NtAI forecast a better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair. SNP data from 27 and 40 primary triple negative breast cancer tumor samples from two clinical trials treated with cisplatin and cisplatin + bevacizumab. Labeling, hybridization and data processing was performed by Affymetrix using 70k MIP arrays and 330k MIP arrays. In the cisplatin trial, matched normal samples based on blood from all patients and an additional three samples based on FFPE negative lymph nodes were used as references (30 normal references in total). In the cisplatin+bevacizumab trial, mathed normal samples based on blood from 10 patients were used as references.
2012-03-22 | E-GEOD-28330 | biostudies-arrayexpress
Project description:Colorectal cancer (CRC) is one of the most frequently diagnosed and lethal malignancy. Several key factors including poor dietary habits, smoking, alcohol consumption, genetic predisposition, obesity, diabetes mellitus, and sedentary lifestyle – all result in a significantly increased risk for developing CRC. Current treatment modalities for patients with CRC include surgery, which is often followed with adjuvant chemotherapy, especially in patients with a stage II and III disease. Most patients with advanced CRC are generally treated with the chemotherapeutic drug, 5-fluorouracil (5-FU) – either given alone or in combination with oxaliplatin and other molecularly-targeted drugs. While such treatment regimens are effective at improving disease outcomes, their clinical usefulness is often hampered due to the considerable toxicity associated with these treatments, which often causes severe nausea, vomiting, weight loss, and risk of infectious complications due to immunosuppression. Furthermore, their therapeutic efficacy is limited due to the emergence of chemotherapeutic drug resistance. In this study we performed genomewide transcriptomic analysis of parental and 5-FU resistant cells to identify differentially expressed genes and its associated pathways in promoting chemoresistance in CRC.
2022-02-19 | GSE196900 | GEO
Project description:This cohort included 118 consecutive and unselected patients who underwent, between September 1998 and September 2010, curative intent surgery for PDA (Brussels Dataset). Archived tumor specimens were available for the entire study population. Exclusion criteria included: preoperative chemotherapy or chemoradiotherapy (n=12), macroscopically incomplete resection (R2) (n=6), or tumor histology other than ductal adenocarcinoma (n=19). We also excluded patients who died of postoperative complications within 30 days following surgery (n=1) because they are non-informative for this kind of translational study.
2018-08-22 | GSE85916 | GEO
Project description:In this study we analyzed gene expression profiles in a well-characterized BL cell line upon treatment with HDACi combined with chemotherapy. The impact on gene expression regulation was broader when HDACi was combined with chemotherapy, than when either therapy was used alone. As expected, treatment interfered in the regulation of cell cycle progression and enhanced cell death. Noteworthy was the effect on members of p53 signaling pathway. The down regulation of PI3KCA and up regulation of p16 were observed at the gene and protein levels, while the inhibition of Akt phosphorylation and the down regulation of c-Myc were confirmed through the analysis of protein levels. As a complementary approach we investigated if HDACi combined with chemotherapy treatment would enhance mir-101, mir-143 and mir-145 levels in BL cell line. This hypothesis was confirmed and we also observed that levels of mir-101, mir-143 and mir-145 were extremely down regulated in BL patients' samples. In this study we demonstrate mechanisms involved in cell cycle arrest upon cell treatment using a combination of HDACi and chemotherapy. We highlight the fact that effective combinations of HDACis with other cytotoxic drugs could improve BL therapy in the future. DNA microarrays were used to access global gene expression modulation upon treatment of Raji BL cell line with VP-16 or NaB and a combination of NaB and VP-16 for 24 hours. Total RNA was extracted using TrizolM-BM-.. Gene expression of treated cells was compared with controls consisting of untreated cells. Microarray analysis was performed using Agilent Whole Human Genome Microarray 4M-CM-^W44K arrays and labeled using the One Color Quick Amp Labeling Kit (Agilent Technologies). Two biological replicates were included for each experimental condition.
2014-06-20 | E-GEOD-48399 | biostudies-arrayexpress
Project description:Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T-cells caused by human T-cell lymphotropic virus type 1 (HTLV-1). Recently, it has been noted that some epigenome abnormalities including DNA methylation and tri-methylation at histone H3Lys27 (H3K27me3) contribute to malignant transformation of ATL. Hence, we investigate the combined effect of DNA demethylating agents and enhancer of zeste homolog 2 (EZH2), which catalyze H3K27me3, inhibitors in ATL. Methylaome analyse revealed that OR21 and the combination changes DNA methylation.
2023-05-03 | GSE189602 | GEO