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GSE63790
Homo sapiens
20 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.
Publication Title
BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Nrf2 is an important therapeutic target as activation of this pathway detoxifies harmful insults and reduces oxidative stress. However, the role of Nrf2 in cancer biology is controversial. Protection against oxidative stress and inflammation can confer a survival advantage to tumor cells, leading to a poor prognosis, and constitutive activation of Nrf2 has been detected in numerous tumors. In our study, we examined the role of two clinically relevant classes of Nrf2 activators, the synthetic triterpenoids (CDDO-Im and CDDO-Me) and dimethyl fumarate (DMF) in lung cancer.
Publication Title
Dimethyl fumarate and the oleanane triterpenoids, CDDO-imidazolide and CDDO-methyl ester, both activate the Nrf2 pathway but have opposite effects in the A/J model of lung carcinogenesis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To compare hepatic gene expression in conditional Keap1 knockout (Alb-Cre:Keap1(flox/-)) and genetic control mice. Disruption of Keap1-mediated repression of Nrf2 signaling was expected to result in increased expression of Nrf2-regulated genes.
Publication Title
Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 21 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease that is difficult to diagnose and follows an unpredictable clinical course. The object of this study was to develop a predictive gene signature model of IPF from whole lung tissue. We collected whole lung samples from 11 IPF patients undergoing diagnostic surgical biopsy or transplantation. Whenever possible, samples were obtained from different lobes. Normals consisted of healthy organs donated for transplantation. We measured gene expression on microarrays. Data were analyzed by hierarchical clustering and Principal Component Analysis. By this approach, we found that gene expression was similar in the upper and lower lobes of individuals with IPF. We also found that biopsied and explanted specimens contained different patterns of gene expression; therefore, we analyzed biopsies and explants separately. Signatures were derived by fitting top genes to a Bayesian probit regression model. We developed a 153-gene signature that discriminates IPF biopsies from normal. We also developed a 70-gene signature that discriminates IPF explants from normal. Both signatures were validated on an independent cohort. The IPF Biopsy signature correctly diagnosed 76% of the validation cases (p < 0.01), while IPF Explant correctly diagnosed 78% (p < 0.001). Examination of differentially expressed genes revealed partial overlap between IPF Biopsy and IPF Explant and almost no overlap with previously reported IPF gene lists. However, several overlapping genes may provide a basis for developing therapeutic targets.
Publication Title
Bayesian probit regression model for the diagnosis of pulmonary fibrosis: proof-of-principle.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hypercapnia, the elevation of CO2 in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases, and is associated with increased risk of mortality. Recent studies have shown that hypercapnia adversely affects innate immunity, host defense, lung edema clearance, and cell proliferation. Airway epithelial dysfunction is a feature of advanced lung disease, but the effect of hypercapnia on airway epithelium is unknown. Thus, in the current study we examined the effect of normoxic hypercapnia (20% CO2 for 24 h) vs normocapnia (5% CO2), on global gene expression in differentiated normal human airway epithelial cells. Gene expression was assessed on Affymetrix microarrays, and subjected to gene ontology analysis for biological process and cluster-network representation. We found that hypercapnia downregulated the expression of 183 genes and upregulated 126. Among these, major gene clusters linked to immune responses and nucleosome assembly were largely downregulated, while lipid metabolism genes were largely upregulated. The overwhelming majority of these genes were not previously known to be regulated by CO2. These changes in gene expression indicate the potential for hypercapnia to impact bronchial epithelial cell function in ways that may contribute to poor clinical outcomes in patients with severe acute or advanced chronic lung diseases.
Publication Title
Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Gut microbes elicit specific changes in gene expression in the colon of mice. We colonized germ-free mice with microbial communities from the guts of humans, zebrafish and termites, human skin and tongue, soil and estuarine microbial mats.
Publication Title
Bacteria from diverse habitats colonize and compete in the mouse gut.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 484 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Homo sapiens
- 249 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Purpose: The primary objective of the current study was to validate biomarkers to identify the 10% to 27% of patients with stage I and 35% of patients with stage IIA squamous cell carcinoma of lung (SC) who are likely to recur following surgical resection, so that these patients may be offered enrollment in clinical trials evaluating directed ACT. A secondary objective was to identify patients with stage IIB SC who are unlikely to develop recurrences and might thereby be spared the potential significant toxicity and expense of ACT.
Publication Title
Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Homo sapiens
- 235 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Purpose: The primary objective of the current study was to validate biomarkers to identify the 10% to 27% of patients with stage I and 35% of patients with stage IIA squamous cell carcinoma of lung (SC) who are likely to recur following surgical resection, so that these patients may be offered enrollment in clinical trials evaluating directed ACT. A secondary objective was to identify patients with stage IIB SC who are unlikely to develop recurrences and might thereby be spared the potential significant toxicity and expense of ACT.
Publication Title
Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Homo sapiens
- 16 Downloadable Samples
IlluminaHiSeq2000
Description
Staphylococcus aureus can cause serious skin, respiratory, and other life-threatening invasive infections in humans, and methicillin-resistant S. aureus (MRSA) strains have been acquiring increasing antibiotic resistance. While MRSA was once mainly considered a hospital-acquired infection, the emergence of new strains, some of which are pandemic, has resulted in community-acquired MRSA infections that often present as serious skin infections in otherwise healthy individuals. Accordingly, defining the mechanisms that govern the activation and regulation of the immune response to MRSA is clinically important and could lead to the discovery of much needed rational targets for therapeutic intervention. Because the cytokine thymic stromal lymphopoetin (TSLP) is highly expressed by keratinocytes of the skin3, we investigated its role in host-defense against MRSA. Here we demonstrate that TSLP acts on neutrophils to increase their killing of MRSA. In particular, we show that both mouse and human neutrophils express functional TSLP receptors. Strikingly, TSLP enhances mouse neutrophil killing of MRSA in both an in vitro whole blood killing assay and an in vivo skin infection model. Similarly, TSLP acts directly on purified human blood neutrophils to reduce MRSA burden. Unexpectedly, we demonstrate that TSLP mediates these effects both in vivo and in vitro by engaging the complement C5 system. Thus, TSLP increases MRSA killing in a neutrophil- and complement-dependent manner, revealing a key connection between TSLP and the innate complement system, with potentially important therapeutic implications for control of MRSA infection. Overall design: mRNA expression analysis. 16 samples are from 2 donors, 8 samples per donor, 2 time points (4hr and 16 hr), and 4 conditions (control, TSLP treated, Heat Killed MRSA treated, and TSLP+HKM treated) .
Publication Title
A TSLP-complement axis mediates neutrophil killing of methicillin-resistant <i>Staphylococcus aureus</i>.
Sample Metadata Fields
No sample metadata fields
View Samples