Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.
Notch signaling functions in retinal pericyte survival.
Sex, Specimen part
View SamplesThe aim of the study was to investigate the activation of human NK cells by IL2 through analyzing the global gene expression at different time points (0, 2, 8 and 24 hours) after culture with the cytokine IL2 at 100 IU/ml. NK cells with the CD56+/CD16+ and CD3- phenotype were negatively selected by immunomagnetic beads and re-examined by flow-cytometry to ensure greater than 90% purity .
Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: gene expression signatures indicative of novel molecular signaling pathways.
No sample metadata fields
View SamplesThis work was designed to determine the role of the vascular endothelial growth factor A (VEGF) isoforms during early neuroepithelial development in the mammalian central nervous system (CNS), specifically in the forebrain. An emerging model of interdependence between neural and vascular systems includes VEGF, with its dual roles as a potent angiogenesis factor and neural regulator. Although a number of studies have implicated VEGF in CNS development, little is known about the role that the different VEGF isoforms play in early neurogenesis. We used a mouse model of disrupted VEGF isoform expression that eliminates the predominant brain isoform, VEGF164, and expresses only the diffusible form, VEGF120. We tested the hypothesis that VEGF164 plays a key role in controlling neural precursor populations in developing cortex. We used microarray analysis to compare gene expression differences between wild type and VEGF120 mice at E9.5, the primitive stem cell stage of the neuroepithelium. We quantified changes in PHH3-positive nuclei, neural stem cell markers (Pax6 and nestin) and the Tbr2-positive intermediate progenitors at E11.5 when the neural precursor population is expanding rapidly. Absence of VEGF164 (and VEGF188) leads to reduced proliferation without an apparent effect on the number of Tbr2-positive cells. There is a corresponding reduction in the number of mitotic spindles that are oriented parallel to the ventricular surface relative to those with a vertical or oblique angle. These results support a role for the VEGF isoforms in supporting the neural precursor population of the early neuroepithelium.
Vascular endothelial growth factor (VEGF) isoform regulation of early forebrain development.
Specimen part
View SamplesAnaplastic large-cell lymphoma (ALCL) makes up approximately 15% of paediatric non-Hodgkin's lymphomas of childhood. The vast majority of them is associated with the t(2;5)(p23;q35) translocation that results in the expression of a hybrid oncogenic tyrosine kinase, NPM-ALK. In order to investigate ALCL biological characteristics we used transcriptional profiling approach. Genome-wide gene expression profiling, performed on 23 paediatric ALCL and 12 reactive lymph nodes specimens, showed two novel ALCL subgroups based on their NPM-ALK expression levels (named (ALK low and ALK high). Gene set enrichment analysis revealed, in ALK low samples, a positive enrichment of genes involved in the Interleukin signaling pathway, whereas we found increased expression of genes related to cell cycle progression and division in ALK high tumour samples, such as Aurora Kinase A (AURKA) and B (AURKB). Growth inhibition was observed upon administration of AURKA and AURKB inhibitors Alisertib and Barasertib and it was associated with perturbation of the cell cycle and induction of apoptosis. In conclusion we identified two novel ALCL subgroups, which display unique biological characteristics suggesting sensitivity to distinct targeted therapies.
NPM-ALK expression levels identify two distinct subtypes of paediatric anaplastic large cell lymphoma.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Integrative miRNA and whole-genome analyses of epicardial adipose tissue in patients with coronary atherosclerosis.
Age, Specimen part, Disease, Disease stage
View SamplesGene expression profiles of Human EAT vs. SAT (CTRL & CAD). The aim of the present study was to assess a gene expression chart characterizing EAT vs. SAT, and CAD vs. CTRL. Results provide the information that EAT is characterized by a differential expression of different genes when compared to its reference tissue (SAT), and that EAT is characterized by specific gene expression changes in patients with CAD.
Integrative miRNA and whole-genome analyses of epicardial adipose tissue in patients with coronary atherosclerosis.
Age, Specimen part, Disease, Disease stage
View SamplesAnaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. While ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. Additionally, DUSP22-rearranged ALCLs minimally expressed PD-L1 compared to other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like, immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.
Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with <i>DUSP22</i> rearrangements.
No sample metadata fields
View SamplesmiRNAs are small non-coding RNAs that inhibit translation and promote mRNA decay. The levels of mature miRNAs are the result of different rates of transcription, processing, and turnover. The non-canonical polymerase Gld2 has been implicated in the stabilization of miR-122 possibly by catalyzing 3’ monoadenylation, however, there is little evidence that this relationship is one of cause and effect. Here, we biochemically characterize Gld2 involvement in miRNA monoadenylation and its effect on miRNA stability. We find that Gld2 directly monoadenylates and stabilizes specific miRNA populations in human fibroblasts and that sensitivity to monoadenylation-induced stability depends on nucleotides in the miRNA 3‘ end. These results establish a novel mechanism of miRNA stability and resulting post-transcriptional gene regulation. Overall design: Sequencing of miRNAs to assess amount and 3'' end monoadenylation state upon Gld2 knock-down.
Specific miRNA stabilization by Gld2-catalyzed monoadenylation.
Specimen part, Subject
View SamplesTo identify novel Nurr1 target genes we have used microarrays strategies in rat midbrain primary cultures, enriched in dopaminergic neurons, by the action of basic fibroblast growth factor (bFGF, 20ng/ml) and Sonic hedgedog (SHH), following upregulation of Nurr1 expression by depolarization.To this aim we have treated the cultures after 9 days in vitro for 2h with high KCl and collected 30 min or 2 h after the end of depolarization (2h + 30 min or 2h + 2h). With this experimental protocol we have identify a putative Nurr1 regulator and Nurr1 target
Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro.
Specimen part
View SamplesIdiopathic 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.
Bayesian probit regression model for the diagnosis of pulmonary fibrosis: proof-of-principle.
Sex, Age, Specimen part
View Samples