To accelerate the development of disease-modifying therapeutics for Huntingtons disease (HD), a dynamic biomarker of disease activity and treatment response is critically needed.
Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse.
Sex, Specimen part
View SamplesShiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and LPS. Data were analyzed using a rigorous combinatorial approach with three separate statistical algorithms. Thirty-six genes met the criteria of up-regulated expression in response to Stx1 treatment with 14 genes uniquely up-regulated by Stx1. Microarray data were validated by real time RT-PCR for genes encoding Egr-1 (transcriptional regulator), COX-2 (inflammation), and DUSP1, 5 and 10 (regulation of MAPK signaling). Stx1-mediated signaling through ERK1/2 and Egr-1 appears to be involved in the increased expression of the proinflammatory mediator TNF-. Activation of COX-2 expression is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins.
Global transcriptional response of macrophage-like THP-1 cells to Shiga toxin type 1.
Specimen part, Cell line
View SamplesSwiss-Webster female mice (Charles River Laboratories, Wilmington, MA) 5-6 weeks of age were infected intranasally with 5 LD50 of either WT or lpp mutant of Y. pestis CO92. Uninfected mice were used as controls. At either 12 or 48 h post infection (p.i.), 3 mice per group were euthanized and the lungs, livers, and spleens were harvested and homogenized in 1 ml of RNALater (Ambion/Applied Biosystems, Austin, TX) using 50-ml tissue homogenizers (Kendell, Mansfield, MA). RNA was isolated from the tissue homogenates and purified using RNAqueous (Ambion). After an overnight precipitation, the RNA was resuspended in 20 ul of diethylpyrocarbonate (DEPC)-treated water and hybridized to Affymetrix GeneChip Mouse Genome 430 2.0 arrays, performed by the Molecular Genomics Core at UTMB Galveston, Texas, per manufacture protocols. The arrays had 45,000 probe sets representing more than 39,000 transcripts derived from ~34,000 well-substantiated mouse genes. The experiments were performed in triplicate (biological replicates), generating a total of 45 arrays.
Comparative Analyses of Transcriptional Profiles in Mouse Organs Using a Pneumonic Plague Model after Infection with Wild-Type Yersinia pestis CO92 and Its Braun Lipoprotein Mutant.
Sex, Specimen part, Time
View SamplesOur results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of nave CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of nave cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS.
IL-11 Induces Th17 Cell Responses in Patients with Early Relapsing-Remitting Multiple Sclerosis.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Specimen part, Cell line
View SamplesSorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Specimen part, Cell line
View SamplesSorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Specimen part, Cell line
View SamplesSorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Specimen part, Cell line
View SamplesRegulatory T cells (Tregs) are essential for maintaining proper immune homeostasis. Extracellular signals (e.g. TCR, CD28, IL-2R) are necessary for the generation and maintenance of Tregs, but how these signals are integrated to control the gene expression patterns of Tregs is less clear. Here we show that the epigenetic regulator, Ezh2, was induced by CD28 costimulation and Ezh2 activity was elevated in Tregs as compared to conventional CD4+ T cells. Deletion of Ezh2 in mouse Tregs led to a progressive autoimmune disease because Tregs were compromised after activation, losing proper control of essential Treg lineage genes and adopting a gene expression pattern similar to Foxp3-deficient ‘Tregs.’ Lineage-tracing of Ezh2-deficient Tregs in vivo confirmed that the cells were destabilized selectively in activated Treg populations, which led to a significant loss of Tregs in non-lymphoid tissues. These studies reveal an essential role for Ezh2 in the maintenance of Treg “identity” during cellular activation and differentiation. Overall design: RNAseq of sorted populations of CD62Lhi or CD62Llo Tregs for both Ezh2-HET (Foxp3YFP-Cre/Foxp3WT;Ezh2fl/+ female mice) and Ezh2-KO (Foxp3YFP-Cre/Foxp3WT;Ezh2fl/fl female mice) were generated, in triplicate for each condition, using Illumina HiSeq 2500 single-end 50bp sequencing platform.
The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation.
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View SamplesIdentifying the effect of the co-chaperone SGTA on global androgen receptor transcriptional activity in C4-2B prostate cancer cells with view to further elucidating the broader biological role of SGTA on other signaling pathways within prostate cancer cells
Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation.
Specimen part, Treatment
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