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GSE8252
Rattus norvegicus
6 Downloadable Samples
Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Tienilic acid (TA) was withdrawn from the US market due to numerous cases of liver necrosis. Two major hypotheses currently used to understand the mechanisms of idiosyncratic reactions such as TA-induced hepatotoxicity are the hapten and danger hypotheses. Both human cytochrome (CYP) P450 2C9 and the rat ortholog CYP 2C11 metabolize TA, and it was reported that a reactive metabolite of TA binds almost exclusively to these enzymes, thus acting as a mechanism-based inhibitor. TA-induced liver toxicity is associated with antibodies against CYP 2C9, thus TA appears to act as a hapten. However, if the binding were limited to CYP 2C, it is unlikely that this would lead to significant cell stress. Thus, if TA does not cause cell stress it would suggest that a drug does not have to generate a danger signal in order to cause an idiosyncratic drug reaction and acting as a hapten is sufficient. In order to test whether TA can cause cell stress, male Sprague Dawley rats were orally dosed with TA, and hepatic gene expression was profiled at 6 and 24 h after drug administration.
Publication Title
Changes in gene expression induced by tienilic Acid and sulfamethoxazole: testing the danger hypothesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few studies have focused on critical early stages. Our prior microarray study correlated gene expression in human hippocampus with AD markers. Results suggested a new model of early-stage AD in which pathology spreads along myelinated axons, orchestrated by upregulated transcription and epigenetic factors related to growth and tumor suppression (Blalock et al., 2004). However, the microarray analyses were performed on RNA from fresh frozen hippocampal tissue blocks containing both gray and white matter, potentially obscuring region-specific changes. In the present study, we used laser capture microdissection to exclude major white matter tracts and selectively collect CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippoc ampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many correlations similar to those seen in our prior study, particularly for neuron-related genes. Nonetheless, in the laser-captured tissue, we found a striking paucity of the AD-associated epigenetic and transcription factor genes that had been strongly overrepresented in the prior tissue block study. In addition, we identified novel pathway alterations that may have considerable mechanistic implications, including downregulation of genes stabilizing ryanodine receptor Ca2+ release and upregulation of vascular development genes. We conclude that FFPE tissue can be a reliable resource for microarray studies, that upregulation of growth-related epigenetic/ transcription factors with incipient AD is predominantly localized to white matter, further supporting our prior findings and model, and that alterations in vascular and ryanodine receptor-relat ed pathways in gray matter are closely associated with incipient AD.
Publication Title
Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease.
Sample Metadata Fields
Sex, Age, Disease
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Classically activated (M1) macrophages protect from infection but can cause inflammatory disease and tissue damage while alternatively activated (M2) macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs that control macrophage differentiation. A potential mechanism by which macrophages differentiate may be through microRNA (miRNA), which bind to messenger RNA and post-transcriptionally modify gene expression, cell phenotype and function. The inflammation-associated miRNA, miR-155, was rapidly up-regulated over 100-fold in M1, but not M2, macrophages. Inflammatory M1 genes and proteins iNOS, IL-1b and TNF-a were reduced up to 72% in miR-155 knockout mouse macrophages, but miR-155 deficiency did not affect expression of genes associated with M2 macrophages (e.g., Arginase-1). Additionally, a miR-155 oligonucleotide inhibitor efficiently suppressed iNOS and TNF-a gene expression in wild-type M1 macrophages. Comparative transcriptional profiling of unactivated (M0) and M1 macrophages derived from wild-type and miR-155 knockout (KO) mice revealed an M1 signature of approximately 1300 genes, half of which were dependent on miR-155. Real-Time PCR of independent datasets validated miR-155's contribution to induction of iNOS, IL-1b, TNF-a, IL-6 and IL-12, as well as suppression of miR-155 targets Inpp5d, Tspan14, Ptprj and Mafb. Overall, these data indicate that miR-155 plays an essential role in driving the differentiation and effector potential of inflammatory M1 macrophages.
Publication Title
Control of the Inflammatory Macrophage Transcriptional Signature by miR-155.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Rattus norvegicus
- 12 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Background: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruptions well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleeps relationship to cognitive aging.
Publication Title
Deep sleep and parietal cortex gene expression changes are related to cognitive deficits with age.
Sample Metadata Fields
Sex, Age, Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Classically (M1) and alternatively activated (M2) macrophages play distinct roles in various physiological and disease processes. Understanding the gene transcription programs that contribute to macrophage polarization along the M1/M2 spectrum may lead to new tools to detect and therapeutically manipulate macrophage phenotype. Here, we define the M1 and M2 macrophage signature through mRNA microarray. The M1 macrophage signature was defined by 629 up-regulated and 732 down-regulated genes while the M2 macrophage signature was formed by 388 up-regulated and 425 down-regulated genes. While a subset of probes was common to both M1 and M2 cells, others were exclusive to each macrophage subset. The common M1/M2 pathways were characterized by changes in various transcriptional regulators and signaling partners, including increases in Kruppel-like Factor (Klf) 4, but decreases in Klf2. To identify M1 and M2 biomarkers that help discriminate these populations, we selected genes that were increased during M1 or M2 differentiation but decreased in the opposite population. Among top novel M1-distinct genes, we identified CD38, G-protein coupled receptor 18 (Gpr18) and Formyl peptide receptor 2 (Fpr2). Among top M2 genes, we found early growth response protein 2 (Egr2) and Myc. We validated these genes by Real-Time PCR and developed a CD38/Egr2-based flow cytometry assay that discriminates between M1 and M2 macrophages. Overall, this work defines the M1 and M2 signature and identifies several novel M1 and M2 genes that may be used to distinguish and manipulate M1 and M2 macrophages.
Publication Title
Novel Markers to Delineate Murine M1 and M2 Macrophages.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 28 Downloadable Samples
- Affymetrix Genome-Wide Human SNP 6.0 Array (genomewidesnp6), Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Metaplastic breast carcinomas display genomic and transcriptomic heterogeneity [corrected]. .
Sample Metadata Fields
Disease
View Samples- Homo sapiens
- 28 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Expression profiling of metaplastic carcinoma of the breast
Publication Title
Metaplastic breast carcinomas display genomic and transcriptomic heterogeneity [corrected]. .
Sample Metadata Fields
Disease
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The goal of the study was to identify the effects of TGF-beta on primary human macrophages maturated under different conditions.
Publication Title
Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The functionality of dendritic cells might be influenced by alterations of their biophysic microenvironment, e.g. changes in salt concentration. Microarray analysis aims to evaluate whether dendritic cells cultured in medium containing different salt concentrations modulate their gene expression profile.
Publication Title
The renal microenvironment modifies dendritic cell phenotype.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 384 Downloadable Samples
Illumina HiSeq 2500
Description
Cellular dormancy and heterogeneous cell cycle lengths provide important explanations for treatment failure following adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC) yet the molecular control of the dormant versus cycling state remains unknown. In CRCs dormant cells are found to be highly clonogenic and resistant to chemotherapies. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumour cells. Overall design: Six colorectal cancer cell lines (DLD1, HCT15, HT55, SW948, RKO and SW48) were labelled with the cell permeable dye CFSE and then grown in non-adherent spheroid culture for 6 days to enable identification of dormant cells that retain CFSE (LRC) and cycling cells (BULK). LRCs and BULK populations were then FACS sorted from each cell line in quadruplicate. As a control experiment, to identify off-target effects of the CFSE dye and culture artefacts, BULK populations from DLD1 cells at d1 and d6 after seeding both with and without CFSE labelling were included in the RNAseq analysis. RNA was extracted using the RNAeasy Micro Plus kit (Qiagen) and quantified using the Qubit RNA Assay Kit (Thermo Fisher Scientific). RNA quality was assessed using the Agilent Bioanalyser system as per manufacturer's instructions. Following normalisation and sample randomisation, Truseq library (Illumina) preparation was carried out at the CRUK CI genomics facility and subsequent single end, 50bp sequencing using the HiSeq system (Illumina). Following human genome alignment (hg19), read counts were normalised and differential expression tested using the DEseq protocol.
Publication Title
Itraconazole targets cell cycle heterogeneity in colorectal cancer.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples