Therapy in combination with capecitabine, cetuximab and oxaliplatin
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,This Study Is Designed As A Multicentre, Parallel Group Phase Ii Trial With 24 First-line Patients With Metastatic K-ras Wild Type Crc. The Objective Of This Pharmacokinetic Study Is To Exclude A...,This Study Is Designed As A Multicentre, Parallel Group Phase Ii Trial With 24 First-line Patients With Metastatic K-ras Wild Type Crc. the Objective Of This Pharmacokinetic Study Is To Exclude A Probable Influence Of Cetux On The Plasma Disposition And Metabolic Activation Of Ccb And When This Regimen Is Given Combined With Oxpt.,Colorectal Cancer Metastatic
PROVIDER: 2529757 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The objective of this pharmacokinetic study is to exclude a possible influence of CETUX on the plasma disposition and metabolic activation of Capecitabine (CCB) and when this regimen is given combined with Oxaliplatin (OxPt).
| 2123891 | ecrin-mdr-crc
Project description:Inappropriate or sustained activation of innate immunity is a pathologic feature of several common cardio-metabolic disorders. Little is known, however, about transcriptomic modulation during inflammatory stress in disease-relevant human tissues. We applied deep RNA sequencing (RNA-seq) during low-dose experimental endotoxemia (LPS) in healthy humans to interrogate, in an unbiased manner, inflammatory tissue-level transcriptome responses of relevance to complex cardio-metabolic diseases. We utilized adipose and blood samples from three individuals who underwent a standardized inpatient endotoxemia protocol. Our comprehensive analysis revealed substantial, highly tissue- and subject-specific LPS-modulated changes in the expression of protein-coding genes and linc-RNAs as well as alternative splicing (AS). We also confirmed adipocytes and macrophages as potential cell sources of selective LPS-modulated linc-RNAs and AS events. Finally, we defined disease relevance of a subset of findings in obese adipose tissue and through interrogation of overlap with genome-wide association study loci for cardio-metabolic traits. Our findings provide novel insights into tissue-level genomic regulation, not detectable through analysis of DNA variations alone, of relevance to common cardio-metabolic diseases. Using RNA-seq data to study LPS-modulated changes in lincRNA expression for adipose and blood of a healthy individual.
2014-01-02 | E-GEOD-50792 | biostudies-arrayexpress
Project description:Purpose: Evaluate the effect of terbinafine in T. rubrum gene expression using a co-culture model in conjunction with RNA-seq Methods: T. rubrum and HaCat cells line were co-cultured in RPMI medium supplemented with 5% of fetal bovine serum and treated with 0.0162 µM of terbinafine.The co-culture was incubated for 24 h at 37ºC in a humidified atmosphere containing 5% CO2 , followed RNA by extraction of both organisms, libraries construction and sequence. Results: Our data demonstrated the modulation of several T. rubrum genes involved in the biosynthesis of ergosterol in addition to the target gene of terbinafine that is already known, genes encoding MFS- and ABC-type membrane transporters that are associated with the phenomenon of multidrug resistance, genes that have been discussed in the literature as possible novel targets for antifungal compounds and genes which do not have a known function in T. rubrum yet, but have been modulated in response to the drug. Conclusions: RNA-seq sequencing of the T. rubrum co-culture in the presence of terbinafine showed that several genes of the ergosterol biosynthesis cascade were repressed. We highlight the induction of transmembrane transporters, which may be associated with the efflux of this allylamine. In addition, other genes that could be involved in the pathogenicity of T. rubrum were also modulated in the presence of the drug. In addition, we observed the modulation of hypothetical genes with still unknown functions in T. rubrum but that possess orthologs in other dermatophytes.
2019-11-28 | GSE135095 | GEO
Project description:Detection of the abnormal phosphatidylcholine (PtdCho) metabolism in EOC by analysis of magnetic resonance profile (MRS), showed a significant increase of PCho content in EOC cells as compared with non tumoral counterparts associated with activation of choline kinase (ChoK), the enzyme responsible for PCho production following choline phosphorylation in the PtdCho biosynthetic pathway (Kennedy’s pathway). The α-isoform of ChoK has an essential role in growth control and signal transduction and it has been implicated in the carcinogenic process. Aim of the study is the evaluation of the biological relevance of ChoK expression and activity to define its possible role as a non-invasively detectable EOC biomarker and druggable target. We specifically silenced ChoKα expression by transient RNA interference in two different EOC cell lines and evaluated the biological effects related to metabolic profiles, cell proliferation, cell cycle regulation and alteration of global gene expression to possibly identify new pathways implicated in altered choline metabolism. Following ChoKα silencing we observed a 70% reduction of mRNA and protein expression with a similar reduction in PCho accumulation as assessed by HMRS analysis. The ChoKα silencing was accompanied by 20% inhibition of cell growth and similar percentage of cells blocked in the G1-phase of cell cycle. No alteration in cell morphology and modulation of the main survival signaling pathways (PI3K and MAPK-related signaling) were observed. By gene expression analysis we found 476 differentially expressed genes (p< 0.01; FDR 25%) in silenced cells. By transcriptome analysis of CHKA silenced cells as compared to controls, among the most relevant co-repressed genes we found CyclinA, related to regulation of cell cycle progression, and cytokines genes (IL-6 and IL-8) related to inflammation and EOC aggressiveness. Acyl-CoA synthetase medium-chain family member 3 (ACSM3), phosphatidic acid phosphatase type 2 (PPAP2A) and Osteoprotegerin were among the most up-regulated genes. All co-modulated genes have been validated by RTqPCR also in independent biological replicates. Ingenuity System Pathways Analysis (IPA) identified a network of molecules most significantly affected by CHKA silencing whose main functions is related to cell morphology cellular assembly and organization, cellular function and maintenance. Also, the cellular functions predicted to be mostly affected by silencing were cellular movement and cell death that are expected to be respectively decreased and increased in silenced cells. a total of 12 samples were analyzed: Two EOC cell line SKOV3 and INTOV11 were transiently silenced with unrelated or CHKA-specific siRNA pool. Three independent experiment were run for each cell line.
2014-01-23 | E-GEOD-39943 | biostudies-arrayexpress
Project description:A comparative transcriptomic analysis of the responses arising 24 hours after infection of the susceptible T. aestivum variety ‘Fielder’, by Fg with co-application of either abscisic acid (ABA), gibberellic acid (GA) or the ABA-signaling inhibitor AS6, compared to stand-alone treatments is reported. Relevance of transcriptomic responses were assessed by differential expression feature evaluations (DEFE), highlighting that co-applied GA elicits a relatively strong opposing influence on Fg modulated genes, while co-applied ABA elicits similar responses to Fg. Co-applied AS6 elicited an opposing effect on gene regulation compared to co-applied ABA, and based on its lack of biological effect, was instrumental in reducing the identity of genes relevant to eliciting ABA and GA effects, to a subset of genes, largely defined within four DEFE patterns. A more targeted investigation of the impact of the co-applied conditions with respect to plant phytohormone biosynthesis and signaling pathways, correlated with select phytohormone profiles, confirmed activation of the ABA and GA pathways. Further analyses highlighted a novel interaction, potentially representing cross-talk, between co-applied ABA and the brassinosteroid signaling pathway. Additional responses within the classical defense hormone pathways as well as auxin and cytokinin pathways were found to correlate with expected defense responses. Togther these results yield insight into a range of mechanisms potentially underlying the observed contributions of ABA and GA to wheat susceptibility and resistance respectively to Fg, raising novel hypotheses for consideration in the development of FHB resistant wheat lines and agronomic practices in the longer term.
2021-10-01 | GSE137895 | GEO
Project description:The current view of cellular transformation and cancer progression supports the notion that cancer cells must reprogram their metabolism in order to survive and progress in different microenvironments. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator PGC1α suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is consistently down-regulated in multiple prostate cancer patient datasets and its alteration is associated with reduced disease-free survival and metastasis. Genetically engineered mouse model studies revealed that compound prostate epithelium-specific deletion of Pgc1a and Pten promotes prostate cancer progression and metastasis, whereas, conversely, PGC1α expression in cell lines inhibits the pre-existing metastatic capacity. Through the application of integrative metabolomics and transcriptomics we demonstrate that PGC1α expression in prostate cancer is sufficient to elicit a global metabolic rewiring that opposes cell growth, consisting of sustained oxidative metabolism at the expense of anabolism. This metabolic program is regulated downstream the Oestrogen-related receptor alpha (ERRα), and PGC1α mutants lacking ERRα activation capacity lack metabolic rewiring capacity and metastasissuppressive function. Importantly, an ERRα signature in prostate cancer recapitulates the prognostic features of PGC1A. Our findings uncover an unprecedented causal contribution of PGC1α to the metabolic switch in prostate cancer and to the suppression of metastatic dissemination. Total RNA was isolated from prostate cancer cell line PC3 expressing or not PGC1a (for induction, cells were treated with doxycycline for 2 passages)
2016-03-16 | E-GEOD-75193 | biostudies-arrayexpress
Project description:Inappropriate or sustained activation of innate immunity is a pathologic feature of several common cardio-metabolic disorders. Little is known, however, about transcriptomic modulation during inflammatory stress in disease-relevant human tissues. We applied deep RNA sequencing (RNA-seq) during low-dose experimental endotoxemia (LPS) in healthy humans to interrogate, in an unbiased manner, inflammatory tissue-level transcriptome responses of relevance to complex cardio-metabolic diseases. We utilized adipose and blood samples from three individuals who underwent a standardized inpatient endotoxemia protocol. Our comprehensive analysis revealed substantial, highly tissue- and subject-specific LPS-modulated changes in the expression of protein-coding genes and linc-RNAs as well as alternative splicing (AS). We also confirmed adipocytes and macrophages as potential cell sources of selective LPS-modulated linc-RNAs and AS events. Finally, we defined disease relevance of a subset of findings in obese adipose tissue and through interrogation of overlap with genome-wide association study loci for cardio-metabolic traits. Our findings provide novel insights into tissue-level genomic regulation, not detectable through analysis of DNA variations alone, of relevance to common cardio-metabolic diseases.
2014-01-02 | GSE50792 | GEO
Project description:Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether “microarray profiles” could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. Six patterns of co-expressed genes were detected at the 1-hour time point which indicate regulatory expression of genes dependent on the order of the administration. When topotecan is given first, several signal transduction transcription factors associated with cancer or inactivation of a tumor suppressor were co-regulating gene expression. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination.
2015-01-21 | GSE63902 | GEO
Project description:The unicellular eukaryote Entamoeba histolytica is a human parasite that causes amebic dysentery and liver abscess. A genome-wide analysis of gene expression modulated by intestinal colonization and invasion identified an up-regulated transcript that encoded a putative high-mobility-group box (HMGB) protein, EhHMGB1. We tested if EhHMGB1 encoded a functional HMGB protein, and determined its role in control of parasite gene expression. Recombinant EhHMGB1 was able to bend DNA in vitro, a characteristic of HMGB proteins. Core conserved residues required for DNA bending activity in other HMGB proteins were demonstrated by mutational analysis to be essential for EhHMGB1 activity. EhHMGB1 was also able to enhance the binding of human p53 to its cognate DNA sequence in vitro, which is expected for an HMGB1 protein. Confocal microscopy, using antibodies against the recombinant protein, confirmed its nuclear localization. Overexpression of EhHMGB1 in HM1: IMSS trophozoites led to modulation of 33 transcripts involved in a variety of cellular functions. Of these, twenty were also modulated at either day one or day 29 in the mouse model of intestinal amebiasis. Notably, four transcripts with known roles in virulence, including two encoding Gal/GalNAc lectin light chains, were modulated in response to EhHMGB1 overexpression. We concluded that EhHMGB1 was a bona fide HMGB protein with the capacity to recapitulate part of the modulation of parasite gene expression seen during adaptation to the host intestine. 6 samples for two groups: 3M and Gir. Each groups contain 3 samples
2008-11-19 | E-GEOD-12204 | biostudies-arrayexpress
Project description:Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether M-bM-^@M-^\microarray profilesM-bM-^@M-^] could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. Six patterns of co-expressed genes were detected at the 1-hour time point which indicate regulatory expression of genes dependent on the order of the administration. When topotecan is given first, several signal transduction transcription factors associated with cancer or inactivation of a tumor suppressor were co-regulating gene expression. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. mRNA responses were compared within bone marrow of Sprague-Dawley rats after a single 30-minute treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control Please note that one of the 'Bone Marrow_Oxaliplatin _Vehicle 1' sample (1344-05H_4M 40) was considered an outlier and thus, was excluded from data analysis and GEO records.
2015-01-21 | E-GEOD-63902 | biostudies-arrayexpress