Study Assessing Potential Predictive Tumor Markers in Metastatic Colorectal Cancer
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ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Pacientes Con Cáncer Colorrectal Metastásico Y Tumor Con Kras No Mutado Tratados Con Folfox6m Y Panitumumab Como Tratamiento De Primera Línea,Colorectal Neoplasms
PROVIDER: 2101702 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Sub-optimal fetal development is associated with an increased risk of developing cardiovascular disease, type 2 diabetes (T2D) and adiposity later in life. However, definitions of intrauterine growth restriction (IUGR) and small for gestational age (SGA) are based on simple statistical approaches that may misclassify infants with a normal developmental profile and vice versa. We used an unbiased global profiling approach to identify gene expression patterns in umbilical cord tissue from 38 infants and identified a set of 466 genes which separated the subjects into 2 distinct groups – one biased towards lower birth weight and one biased towards normal birth weight. The data suggest that approximately 30% of children of normal size have a molecular profile more typical of impaired fetal development and who may be on a programmed trajectory. Differences in expression between the two groups encompassed 384 upregulated and 82 downregulated genes. Molecular profiling at birth may have utility in identifying markers that potentially reflect antenatal developmental and may be predictive of future phenotypic development after birth. Importantly, it may provide an alternative to the current classification of infants using birth weights.
2011-10-21 | GSE24818 | GEO
Project description:Treatment-selection markers are biological molecules or patient characteristics associated with one's response to treatment. They can be used to predict treatment effects for individual subjects and subsequently help deliver treatment to those most likely to benefit from it. Statistical tools are needed to evaluate a marker's capacity to help with treatment selection. The commonly adopted criterion for a good treatment-selection marker has been the interaction between marker and treatment. While a strong interaction is important, it is, however, not sufficient for good marker performance. In this article, we develop novel measures for assessing a continuous treatment-selection marker, based on a potential outcomes framework. Under a set of assumptions, we derive the optimal decision rule based on the marker to classify individuals according to treatment benefit, and characterize the marker's performance using the corresponding classification accuracy as well as the overall distribution of the classifier. We develop a constrained maximum-likelihood method for estimation and testing in a randomized trial setting. Simulation studies are conducted to demonstrate the performance of our methods. Finally, we illustrate the methods using an HIV vaccine trial where we explore the value of the level of preexisting immunity to adenovirus serotype 5 for predicting a vaccine-induced increase in the risk of HIV acquisition.
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Project description:Primary objectives: The primary objectives are:
• To characterize the safety and tolerability profile of repeated administration of different EMD 525797 dose levels in combination with cetuximab and irinotecan in subjects with k-ras WT mCRC after failure of first-line therapy with an oxaliplatin-containing regimen (Safety Part);
• To assess the anti-cancer activity of 2 EMD 525797 doses in terms progression-free
survival time in subjects with k-ras WT mCRC after failure of first-line therapy with an
oxaliplatin-containing regimen (Randomized Part).
Primary endpoints: Safety Part:
• To characterize the safety and tolerability profile of repeated administration of different EMD 525797 dose levels in combination with cetuximab and irinotecan in subjects with k-ras WT mCRC after failure of first-line therapy with an oxaliplatin-containing regimen.
Randomized Part:
• To assess the anti-cancer activity of 2 EMD 525797 doses in terms of progression-free survival time in subjects with k-ras WT mCRC after failure of first-line therapy with an oxaliplatin-containing regimen.
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Project description:Sub-optimal fetal development is associated with an increased risk of developing cardiovascular disease, type 2 diabetes (T2D) and adiposity later in life. However, definitions of intrauterine growth restriction (IUGR) and small for gestational age (SGA) are based on simple statistical approaches that may misclassify infants with a normal developmental profile and vice versa. We used an unbiased global profiling approach to identify gene expression patterns in umbilical cord tissue from 38 infants and identified a set of 466 genes which separated the subjects into 2 distinct groups – one biased towards lower birth weight and one biased towards normal birth weight. The data suggest that approximately 30% of children of normal size have a molecular profile more typical of impaired fetal development and who may be on a programmed trajectory. Differences in expression between the two groups encompassed 384 upregulated and 82 downregulated genes. Molecular profiling at birth may have utility in identifying markers that potentially reflect antenatal developmental and may be predictive of future phenotypic development after birth. Importantly, it may provide an alternative to the current classification of infants using birth weights. RNA from umbilical cord tissue from full term neonates was extracted and hybridized. Separation into 2 distinct groups, independent of birth weight, but based solely on gene expression levels was analysed by Genespring. After appropriate statistical analysis, one group was keenly associated with a higher birth weight (22 samples) while the other was associated with a lower birth-weight (18 samples). Technical replicates were included for all 40 samples.
2011-10-20 | E-GEOD-24818 | biostudies-arrayexpress
Project description:Heterogeneity in acute myeloid leukemias makes the development of effective therapies challenging. In the current study, we found that mitochondrial membrane potential (MMP) differs as a function of metabolism and stemness of leukemic cells. Mechanistically, MMP is regulated by mitochondrial translation, whose rate is sensitive to the availability of asparagine. Interestingly, this MMP-modulating mechanism is hijacked by leukemic cells, especially leukemic stem cells (LSCs), to elevated MMP to evade chemotherapy and thus depletion of asparagine by asparaginase chemo-sensitizes LSCs. To further evaluate the function of MMP-modulating mechanisms in disease development and drug resistance, we performed a targeted drug screen and identified Alexidine as a strong MMP-lowering agent via repressing mitochondrial translation. We revealed that Alexidine binds to cardiolipin to interfere with the inner membrane localization of mitochondrial ribosomes to inhibit mitochondrial translation. We demonstrated that Alexidine has anti-leukemic effect and is a potent chemo-sensitizer. Together, our study suggests that targeting MMP-modulating machineries is a promising approach to eradicate leukemic cells.
2024-09-01 | GSE266913 | GEO
Project description:BackgroundChemotherapy resistance remains a major obstacle in the treatment of women with ovarian cancer. Establishing predictive markers of chemoresponse would help to individualize therapy and improve survival of ovarian cancer patients. Chemotherapy resistance in ovarian cancer has been studied thoroughly and several non-overlapping single genes, gene profiles and copy number alterations have been suggested as potential markers. The objective of this study was to explore genetic alterations behind chemotherapy resistance in ovarian cancer with the ultimate aim to find potential predictive markers.MethodsTo create the best opportunities for identifying genetic alterations of importance for resistance, we selected a homogenous tumor material concerning histology, stage and chemotherapy. Using high-resolution whole genome array comparative genomic hybridization (CGH), we analyzed the tumor genomes of 40 fresh-frozen stage III ovarian serous carcinomas, all uniformly treated with combination therapy paclitaxel/carboplatin. Fisher's exact test was used to identify significant differences. Subsequently, we examined four genes in the significant regions (EVI1, MDS1, SH3GL2, SH3KBP1) plus the ABCB1 gene with quantitative real-time polymerase chain reaction (QPCR) to evaluate the impact of DNA alterations on the transcriptional level.ResultsWe identified gain in 3q26.2, and losses in 6q11.2-12, 9p22.3, 9p22.2-22.1, 9p22.1-21.3, Xp22.2-22.12, Xp22.11-11.3, and Xp11.23-11.1 to be significantly associated with chemotherapy resistance. In the gene expression analysis, EVI1 expression differed between samples with gain versus without gain, exhibiting higher expression in the gain group.ConclusionIn conclusion, we detected specific genetic alterations associated with resistance, of which some might be potential predictive markers of chemotherapy resistance in advanced ovarian serous carcinomas. Thus, further studies are required to validate these findings in an independent ovarian tumor series.
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Project description:Human bone marrow derived mesenchymal stromal cells (BMSCs) represent a putative cell source candidate for tissue engineering based strategies to repair cartilage and bone. However, traditional isolation of BMSCs by their preference to adhere to plastic leads to very heterogeneous cell populations and may account for high inter-donor variability and unpredictability of chondrogenic differentiation out-come. Identification of a cell fraction with higher chondrogenic capacity and reduced variance in basic chondrogenic differentiation could further aid the process for developing BMSC-based cartilage and bone regeneration approaches. Since single cell derived clones isolated from fresh bone marrow aspirates show a broad range of chondrogenic capacity, we assessed whether the gene expression profile of clones with high and low chondrogenic capacity differs. While a clustering between high and low chondrogenic capacity clones was observed for one donor, donor-to-donor variability drastically hampered the possibility to achieve conclusive results when different donors were considered. NCAM1/CD56 as identified by the transcriptomic analysis of one donor was still up-regulated in clones with higher chondrogenic capacity and we showed that enriching expanded multiclonal BMSCs for CD56+ expression led to an increase in chondrogenic capacity, though still highly affected by donor-to-donor variability. Our study finally suggests that the definition of predictive marker(s) for BMSCs chondrogenesis is challenged by the high donor’s heterogeneity of these cells. Moreover, we hypothesis that multiple pathways may be involved in determining the chondrogenic potential of BMSCs, making the identification of putative markers still an open issue.
2020-01-13 | GSE111822 | GEO
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2010-05-17 | GSE13070 | GEO