Filters
Technology
Platform
GSE11184
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.
Publication Title
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL.
Publication Title
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 116 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
To identify novel oncogenic pathways in T-cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular cytogenetic analyses including the Chromosome Conformation Capture on Chip (4C) method. Two T-ALL subtypes were identified that lacked rearrangements of known oncogenes. One subtype associated with cortical arrest, expression of cell cycle genes and ectopic NKX2-1 or NKX2-2 expression for which rearrangements were identified. The second subtype associated with immature T-cell development and high expression of the MEF2C transcription factor as consequence of rearrangements of MEF2C, transcription factors that target MEF2C or MEF2C-associated cofactors. We propose NKX2-1, NKX2-2 and MEF2C as T-ALL oncogenes that are activated by various rearrangements.
Publication Title
Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina HiSeq 2000
Description
After induction of ischemic chronic heart failure (CHF), mice exhibited depression-like behavior, in terms of increased anhedonia, and decreased both exploratory activity and interest in novelty. On histology, ischemic CHF mice showed no alterations in overall cerebral morphology. To further evaluate relevant behavioral changes found in CHF mice, RNA-sequencing analysis of prefrontal cortex and hippocampus - the brain regions, whose structural and functional alterations are associated with an increased risk for developing major depressive disorder - and of left myocardial tissue was performed in CHF vs. sham-operated animals. RNA-sequencing revealed relevant changes in hippocampal or prefrontal cortical expression of genes responsible for axonal vesicle transport (Kif5b), signal transduction (Arc, Gabrb2), limitation of inflammation (RORA; Nr4a1) and of hypoxic brain damage (Hif3a). Besides, the actual literature describes some of the genes (RORA, Gabrb2, Npas4, and Junb) being associated with depression-like behavior. Nr4a1 significantly regulated in both brain and heart tissue after induction of ischemic CHF could be a potential link and reveals the central role of inflammation in the interrelation of the brain and the failing heart. Overall design: Heart failure vs. sham-operation were performed in C57BL/6 male mice. After development of chronic heart failure (CHF) 8 weeks after the operation RNA was extracted out of prefrontal cortex, hippocampus and left ventricular myocardium in both groups. RNA of 3 ischemic CHF mice versus 6 sham operated mice was pooled and further subjected to RNA sequencing. To fabricate singular pools each probe of the group equally contributed with the final amount of 2 µg RNA per pool with the result that we had 6 different pools to be further evaluated. The mRNA profile was generated by IGA Technology, Italy (http://www.igatechnology.com/) by deep sequencing, using Illumina HiSeq 2000 platform (HiSeq). CLC-Bio Genomics Workbench software (CLC Bio, Denmark) was used to calculate gene expression levels based on Mortazavi et al. (Nat Methods. 2008;5:621-628) approach.
Publication Title
Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. We identified POTEF-AS1 is an androgen-regulated non-coding RNA gene.
Publication Title
Androgen-induced lncRNA POTEF-AS1 regulates apoptosis-related pathway to facilitate cell survival in prostate cancer cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. We identified androgen-regulated genes, CTBP2, FOXP1 and RUNX1. These factors interact with AR ligand dependently.
Publication Title
CtBP2 modulates the androgen receptor to promote prostate cancer progression.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
To assess the effect of activation of the unfolded protein response (UPR) in colon cancer cell lines, we treated cells with the AB5 subtilase cytotoxin (SubAB). This proteolytically cleaves the 78-kDa glucose-regulated protein (GRP78; also known as HSPA5 or BiP) inside the endoplasmic reticulum. We find that the WNT signaling pathway is highly affected upon treatment with SubAB.
Publication Title
ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 23 Downloadable Samples
- IlluminaGenomeAnalyzerIIx
Description
To define molecular mechanisms underlying rod and cone differentiation, we generated H9 human embryonic stem cell line carrying a GFP reporter that is controlled by the promoter of cone-rod homeobox (CRX) gene, the first known marker of post-mitotic photoreceptor precursors. CRXp-GFP reporter in H9 line replicates endogenous CRX expression when induced to form self-organizing 3-D retina-like tissue. We define temporal transcriptome dynamics of developing photoreceptors during the establishment of cone and rod cell fate. Our studies provide an essential framework for delineating molecules and cellular pathways that guide human photoreceptor development and should assist in chemical screening and cell-based therapies of retinal degeneration. Overall design: Undifferentiated CRXp-GFP HP hES cells and 3D-neural retina were collected at days 37, 47, 67 and 90 and dissociated into single cells. Cells were sorted at 4°C and by FACSAria (Becton Dickinson). GFP+ and GFP- cells were separately collected. Total RNA was extracted by RNA purification kit (Norgen Biotek) and analyzed by 2100 Bioanalyzer (Agilent Technologies Genomics). High quality of total RNA (RIN: 7.7-9.2) was subjected to libraries construction using 40-60 ng of total RNA as input. Libraries were constructed using a stranded modification of the Illumina TruSeq mRNA (Brooks, et al. Meth Mol Biol 2012). Each library was single-end sequenced in an independent lane of a GAIIx at a length of 76 bases. Fastq files were generated from reads passing chastity filter.
Publication Title
Transcriptome Dynamics of Developing Photoreceptors in Three-Dimensional Retina Cultures Recapitulates Temporal Sequence of Human Cone and Rod Differentiation Revealing Cell Surface Markers and Gene Networks.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Androgen-deprivation therapy is the first-line treatment strategy for advanced prostate cancer. However, many tumors develop to castration-resistant prostate cancer (CRPC) and relapse. Thus, analyzing key factors for development of CRPC is important. We found PSF functions as RNA binding protein and transcription factor to promote castration-resistant tumor growth. High expression of PSF in metastatic prostate cancer tissue indicates the clinical relevance.
Publication Title
Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Affymetrix Microarrays were used to analyse gene expression in aortas and circulating CD115+ cells of ApoE- and ApoE/Lymphotoxin beta receptor (LTbR)-double-deficent mice fed a Western diet from 8 to 12 weeks of age in order to identify regulated genes and pathways leading to reduced atherosclerosis in ApoE-/-/LTbR-/- mice compared to ApoE-/- littermate controls.
Publication Title
Deficiency in lymphotoxin β receptor protects from atherosclerosis in apoE-deficient mice.
Sample Metadata Fields
Sex, Age
View Samples