This SuperSeries is composed of the SubSeries listed below.
A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis.
Sex, Specimen part, Disease, Disease stage, Treatment, Subject
View SamplesOBJECTIVE: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. METHODS: Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. RESULTS: Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor (TGF)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. CONCLUSION: These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGF- and IFN-regulated genes
Association of Interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis.
Specimen part, Disease, Disease stage, Subject
View SamplesIn the clinical setting, mutations in the CFTR gene enhance the inflammatory response to P. aeruginosa (PA01) infection, but measurements of the inflammatory response to pathogen stimulation by isolated airway epithelia can yield variable results. In this series, we exposed CFBE41o- cells over-expressing F508/F508 CFTR and CFBE41o- cells rescued with wt-CFTR to P. aeruginosa biofilms. P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL2, CXCL3, CXCR4 and TNF-) in CFBE-wt-CFTR cells compared to CFBE-F508-CFTR cells. These results demonstrate that CFBE41o- cells complemented with wt-CFTR mount a more robust inflammatory response to P. aeruginosa than CFBE41o- F508/F508-CFTR cells.
Does the F508-CFTR mutation induce a proinflammatory response in human airway epithelial cells?
Specimen part
View SamplesThe etiology of autoimmune hepatitis is poorly understood but likely involves Th1 cells producing IFN-. BALB/c background TGF-1-/- mice rapidly develop fulminant Th1-mediated autoimmune hepatitis. Our aims are to profile liver gene expression in TGF-1-/- mice, to identify gene expression pathways dependent on IFN- as possible targets for rational therapy, and to test potential targets directly in vivo in mice.
The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis.
No sample metadata fields
View SamplesNrf2 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.
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.
Sex, Specimen part
View SamplesThe histone methyltransferase mixed lineage leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although Hox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-regulated genes in normal hematopoietic cells remains unknown. Here we identify and characterize part of the Mll-transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll-dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, Prdm16 emerged as a target gene that is uniquely effective at partially rescuing Mll-deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia.
An MLL-dependent network sustains hematopoiesis.
Specimen part
View SamplesTo examine the effects of disrupting the AML1/ETO MYND-SMRT interaction with the W692A substitution on AML1/ETO function, the global gene expression profile of mouse bone marrow LSK cells transduced with GFP was compared to that of cells transduced with either wild-type AML1/ETO or AML1/ETO harboring the W692A substitution in the MYND domain. Three independent biological replicates were assessed for both the control (GFP/MigR1) and AML1/ETO (intact MYND-SMRT interaction) conditions, whereas four independent biological replicates were assessed for the W692A (disrupted MYND-SMRT interaction) condition. The three GFP replicates were used to establish a baseline signal for comparison to both the AML1/ETO and W692A samples.
No associated publication
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
In vitro analysis of tobramycin-treated Pseudomonas aeruginosa biofilms on cystic fibrosis-derived airway epithelial cells.
No sample metadata fields
View SamplesIn order to identify the targets of GATA4-FOG2 action in mammalian heart development we performed Affymetrix microarray comparisons of gene expression in normal and mutant at embryonic (E) day E12.5 hearts. We compared RNA samples from both Fog2-null and Gata4ki/ki mutant E12.5 hearts to the wild-type control E12.5 hearts. We reasoned that as the phenotypes of the Fog2 knockout and Gata4ki/ki mutation (a V217G mutation that specifically cripples the interaction between GATA4 and FOG proteins) are similar, we should expect to identify a similar set of differentially expressed genes in both experiments. As an additional control, we expected to find the Fog2 gene expression absent in the mutant (null) Fog2 cardiac sample, but not Gata4ki/ki sample.
Cardiac expression of Tnnt1 requires the GATA4-FOG2 transcription complex.
Specimen part
View SamplesWe grew Pseudomonas aeruginosa biofilms on CFBE41o- human airway cells in culture, and we treated these biofilms with tobramycin. Microarray analysis was performed to gain an understanding of the global transcriptional changes that occur during antibiotic treatment.
In vitro analysis of tobramycin-treated Pseudomonas aeruginosa biofilms on cystic fibrosis-derived airway epithelial cells.
No sample metadata fields
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