Alternative processing of pre-mRNA transcripts is a major source of protein diversity in eukaryotes and has been implicated in several disease processes including cancer. In this study we have performed a genome wide analysis of alternative splicing events with the GeneChip Human Exon 1.0 ST Array from Affymetrix in lung adenocarcinoma. We found that ~13.3% of the 17800 core Refseq genes appear to have alternative transcripts that are differentially expressed in lung adenocarcinoma versus normal. According to their known functions the largest subset of these genes (30.8%) is believed to be cancer related. Detailed analysis was performed for several genes using PCR, quantitative RT-PCR and DNA sequencing. We found overexpression of ERG variant 2 but not variant 1 in lung tumors and overexpression of CEACAM1 variant 1 but not variant 2 in lung tumors but not in breast or colon tumors. We also identified a novel, overexpressed variant of CDH3 and verified the overexpression of a novel variant of P16. These findings demonstrate how analysis of alternative pre-mRNA processing can shed additional light on differences between tumors and normal tissues as well as between different tumor types. Such studies may lead to the development of additional tools for tumor diagnosis, prognosis and therapy.
Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer.
Sex, Age, Race, Subject
View SamplesWe sequenced liver biopsy tissue from healthy, patients with NAFLD and patients with NASH Overall design: 3 patients either healthy, presenting with NAFLD or NASH
Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?
Sex, Age, Subject
View SamplesThe effects of mercury (HgCl2) on barley (Hordeum vulgare L.) growth, physiological traits and gene expression profiles were studied. The shoot to root ratio was decreased in the two levels of HgCl2 (500 and 1000 M) assayed, which was related primarily with decreases in shoot dry weight. Moreover stomatal conductance was limited and leaf carbon isotope discrimination decreased. Therefore water uptake limitations seem to be an important component of barley responses to HgCl2. Evidences for decreased stomatal conductance and water uptake limitations were further confirmed by the over expression of ABA related transcripts and down regulation of an aquaporin in roots. Root dry weight was only affected at 1000 M HgCl2 and root browning was observed, while several transcripts for lignin biosynthesis were up regulated in HgCl2. Microarray analysis further revealed that growth inhibition in HgCl2 was related to increased expression of genes participating in ethylene biosynthesis and down regulation of several genes participating in DNA synthesis, chromatin structure and cell division, cell wall degradation and modification, oxidative pentose phosphate cycle and nitrogen metabolism pathway. Genes involved in detoxification and defence mechanisms were up regulated including several cytochrome P450s, glucosyltransferases and glutathione-s-transferases and amino acid metabolism participatory genes. It is concluded that barley plants survive in the presence of HgCl2 through several mechanisms that include water uptake limitations, shoot and root growth regulation, increased expression of genes involved in the biosynthesis of several plant protection secondary metabolites and finally through detoxification.
Molecular and physiological mechanisms associated with root exposure to mercury in barley.
Specimen part
View SamplesWe have generated transgenic mice expressing constitutively activated aryl hydrocarbon receptor (CA-AhR) to examine the biological consequences of AhR activation..
A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis.
Specimen part
View SamplesWe are examining the genes that control initiation and progression of murine medulloblastomas that result from loss of patched. Approximately 25% of human medulloblastomas have mutations in patched or in other elements of the sonic hedgehog pathway. However, the cells from which these tumors originate (neural progenitors or stem cells), the cells that are responsible for tumor propagation (cancer stem cells), and the genes that are required for tumor progression are poorly understood. To address these questions, we have developed conditional patched knockout mice in which the gene is deleted in neural stem cells or progenitors. In addition, we have isolated a population of tumor-propagating cells from these tumors. By studying these models we will gain insight into the mechanisms of tumorigenesis and identify new targets for therapy.
Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma.
No sample metadata fields
View SamplesGrowth hormone signaling in hepatocytes is fundamentally important. Disruptions in this pathway have led to fatty liver and other metabolic abnormalities. Growth hormone signals through the JAK2/STAT5 pathway. Mice with hepatocyte specific deletion of STAT5 were previously shown to develop fatty liver. Our aim in this study was to determine the effect of deleting JAK2 in hepatocytes on liver gene expression. To do so, we generated animals with hepatocyte specific deletion of JAK2.
Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2.
Sex, Age, Specimen part
View SamplesGene expression profiles were collected from HEK-HT cells expressing H-Ras with Ras-activating (G12V), Raf-activating (G12V,T35S), RalGEF-activating (G12V,E37G), or PI3K-activating (G12V,Y40C) mutations.
A genomic strategy to elucidate modules of oncogenic pathway signaling networks.
Specimen part
View SamplesDuring chronic stimulation T cells acquire an exhausted phenotype characterized by expression of multiple inhibitory receptors and down-modulation of effector function. While this is required for the protection of the organism from excessive immunopathology, it also prevents successful immunity against persistent viruses or tumor cells. Here we demonstrate that CD8+ T cell exhaustion is characterized by a progressive decline in cellular metabolism. Exhausted T cells exhibit reduced metabolic reserve, impaired fatty acid oxidation and production of mitochondrial reactive oxygen species (ROS). Blockade of inhibitory PD-1/PD-L1 signaling rescued mitochondrial biogenesis, oxidative phosphorylation and ROS production, which was required for efficient restoration of cellular expansion and effector function. Expression of inhibitory receptors and impaired metabolic function was fuled by high amounts of IRF4, BATF and NFAT, which formed a TCR-responsive transcriptional circuit that sustained the transcriptional network responsible for T cell exhaustion. Overall design: Transcriptional profiling of T cells in mice with chronic and acute infections using RNA sequencing
Transcription Factor IRF4 Promotes CD8<sup>+</sup> T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection.
Specimen part, Cell line, Subject, Time
View SamplesDespite advances in contemporary chemotherapeutic strategies, long term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. In order to validate our oxaliplatin sensitivity signature, Patient-Derived Colorectal Cancer Explants (PDCCEs) were developed in NOD-SCID mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (Sensitivity=87.5%; Specificity=100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.
Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer.
No sample metadata fields
View SamplesTransgenic (Probasin driven Myr-AKT)or wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 hours following the beginning of treatment
mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.
No sample metadata fields
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