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GSE31264
Homo sapiens
17 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders.
Publication Title
HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders.
Publication Title
HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.
Sample Metadata Fields
Specimen part, Time
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Human mononuclear cells were cultured in 2 phases. In the 1st phase the culture medium contained cyclosporine A the 2nd phase contained SCF and erythropoietin. Cells were collected at 3 stages of differentiation; on day 6, 10, 12 and represented early erythroblasts, medium stage and normoblasts.
Publication Title
Identification of gene networks associated with erythroid differentiation.
Sample Metadata Fields
No sample metadata fields
View Samples- Drosophila melanogaster
- 19 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
We profiled the transcriptome of Drosophila melanogaster embryos in ttk2D50 embryos or after over-expression using btl-GAL4; UAS-ttk, respectively. We further isolated cells that express btl-enh-RFPmoe (Cabernard and Affolter 2005) and FACS sorting, and profiled their transcriptomes in the same genetic backgrounds.
Publication Title
Tramtrack is genetically upstream of genes controlling tracheal tube size in Drosophila.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 52 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background/Aims: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Methods: 70 treatment-nave patients were randomized to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFN alfa-2a and ribavirin at standard doses and durations. Patients were randomized to undergo a liver biopsy either 24 hours before, or 6 hours after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by the nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results: After four weeks of ribavirin monotherapy, HCV levels decreased by 0.50.5 log10 (p=0.009 vs. controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting the induction of ISGs by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs. 22% non-responders, p=0.01; early virological response, 100% vs. 68%, p=0.03, sustained virological response 83% vs. 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusion: Ribavirin is a weak antiviral but its clinical effect in combination with PEG-IFN seems to be mediated by a separate, indirect mechanism, which may act to reset the interferon responsiveness in HCV-infected liver. Ribavirin pretreatment does not alter the clinical outcome of subsequent combination therapy.
Publication Title
Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment
View Samples- Homo sapiens
- 167 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Using a dataset of 54 pregnant and 113 age/stage-matched non-pregnant breast cancer patients with complete clinical and survival data; we evaluated the pattern of hot spot somatic mutations and performed transcriptomic profiling using Sequenom and Affymetrix, respectively. Breast cancer molecular subtypes were defined using PAM50 and 3-Gene classifiers. We performed Gene set enrichment analysis (GSEA) to evaluate pathways associated with diagnosis during pregnancy. We investigated the differential expression of cancer-related genes and published gene sets according to pregnancy. We finally investigated genes associated with disease-free survival.
Publication Title
Biology of breast cancer during pregnancy using genomic profiling.
Sample Metadata Fields
Age, Disease stage
View Samples- Mus musculus
- 17 Downloadable Samples
Illumina HiSeq 2500
Description
We show that mesenchymal CSC-like cells express an embryonic stem cell signature that is mutant p53 dependent Overall design: Examination of three p53 mutant mesenchymal stem cells and ten derived CSC-like cell lines and 2 derived p53 mutant KO clones compared to control clones
Publication Title
A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Safety sciences and the identification chemical hazard have been seen as one of the most immediate practical applications of human pluripotent stem cell technology. Protocols for the generation of many desirable human cell types have been developed, but optimization of neuronal models for toxicological use has been astonishingly slow, and the wide, clinically- important field of peripheral neurotoxicity is still largely unexplored. Here, a 2-step protocol to generate large lots of identical peripheral human neuronal precursors was characterized and adapted to the measurement of peripheral neurotoxicity. High content imaging allowed an unbiased assessment of cell morphology and viability. The computational quantification of neurite growth as functional parameter highly sensitive to disturbances by toxicants was used as endpoint reflecting specific neurotoxicity. The differentiation of cells towards dorsal root ganglia neurons was tracked in relation to a large background data set based on gene expression microarrays. On this basis, a peripheral neurotoxicity (PeriTox) test was developed as first toxicological assay that harnesses the potential of human pluripotent stem cells to generate cell types/tissues that are not otherwise available for prediction of human systemic organ toxicity. Testing of more than 30 chemicals showed that human neurotoxicants, as well as neurite growth enhancers, were correctly identified. Various classes of chemotherapeutics causing human peripheral neuropathies were identified, while they were missed when tested on human central neurons. The PeriTox-test established here shows the potential of human stem cells for clinically-relevant safety testing of drugs in use and of new emerging candidates.
Publication Title
Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants.
Sample Metadata Fields
Sex, Specimen part, Cell line
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Monocyte chemoattractant protein 1 (MCP-1/CCL2) is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive MCP-1 secretion has been linked to many (auto)inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that the atypical inhibitor of NF-B (IB), a transcriptional co-activator required for the selective expression of a subset of NF-B target genes, is a key activator of the Ccl2 gene. IB-deficient macrophages exhibited impaired secretion of MCP-1 when challenged with diverse inflammatory stimuli, such as lipopolysaccharide or peptidoglycan. These findings were reflected at the level of Ccl2 gene expression, which was tightly coupled to the presence of IB. Moreover, mechanistic insights acquired by chromatin immunoprecipitation demonstrate that IB is directly recruited to the proximal promoter region of the Ccl2 gene and required for histone H3K9 trimethylation. Finally, IB-deficient mice showed significantly impaired MCP-1 secretion and monocyte infiltration in an experimental model of peritonitis. Together, these findings suggest a distinguished role of IB in mediating the targeted recruitment of monocytes in response to local inflammatory events.
Publication Title
IκBζ is a transcriptional key regulator of CCL2/MCP-1.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 91 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. Twelve patients with plaque psoriasis were randomized (3:1) to receive 10mg of tofacitinib or placebo twice daily for 12weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67+ keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT]+ nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1day of tofacitinib (baseline, median of 1290 pSTAT1+ cells/?m2; day 1, median of 332 pSTAT1+ cells/?m2; and nonlesional, median of 155 pSTAT1+ cells/?m2). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P=.016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC andT-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.
Publication Title
Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study.
Sample Metadata Fields
Specimen part, Disease, Treatment, Subject, Time
View Samples