Here we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with different statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, increases sensitivity to the drug.
Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer.
Specimen part, Cell line
View SamplesThe origin and function of human double negative (DN) TCR-alpha/beta T cells is unknown. They are thought to contribute to the pathogenesis of systemic lupus erythematosus because they expand and accumulate in inflamed organs. Here we provide evidence that human TCR-alpha/beta CD4- CD8- DN T cells derive exclusively from activated CD8+ T cells. Freshly isolated TCR-alpha/beta DN T cells display a distinct gene expression and cytokine production profile. DN cells isolated from peripheral blood as well as DN cells derived in vitro from CD8+ T cells, produce a defined array of pro-inflammatory mediators that includes IL-1, IL-17, IFN-gama, CXCL3, and CXCL2. These results indicate that, upon activation, CD8+ T cells have the capacity to acquire a distinct phenotype that grants them inflammatory capacity.
Human TCR-alpha beta+ CD4- CD8- T cells can derive from CD8+ T cells and display an inflammatory effector phenotype.
Specimen part
View SamplesA transgenic mouse was generated using a CD2-driven transgene containing the cDNA of Ppp2ca to achieve over-expression of PP2Ac in T cells. Nave CD4 T cells were isolated and lysed at times 0, 6, and 24 hours after stimulation with anti-CD3 and anti-CD28
Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression.
Specimen part, Cell line
View SamplesThe transcriptional activiy of GATA1s was compared to GATA1 through gene expression analysis in a cell line model with both erythroid and megakaryocyte differentiation.
Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression.
Specimen part, Cell line
View SamplesSome infectious agents are associated with non-Hodgkin lymphoma development. Here we have used p53-deficient mice chronically injected with Streptococcus pneumoniae (Spn) with the aim to develop an animal model of infection-associated lymphomagenesis. We show that repeated stimulations with heat-killed Spn significantly enhanced the incidence of peripheral T-cell lymphoma (PTCL) in these mice. Phenotypic studies and gene expression profile analyses indicate that these PTCL arose from chronically stimulated natural killer T (NKT) cells, a T cell lineage that exhibits unique properties. Furthermore, lymphoma development was blocked when these PTCL were transferred to recipients lacking CD1d expression or treated with blocking CD1d mAbs, thus demonstrating that in vivo TCR/CD1d interactions are required for these PTCL survival. In conclusion, we have identified a new entity of peripheral T-cell lymphoma that originates from CD1d-restricted natural killer T (NKT) cells. Our results could refine the classification of PTCL and pave the way for the development of new immunotherapeutic approaches.
CD1d-restricted peripheral T cell lymphoma in mice and humans.
Age, Specimen part
View SamplesThe homeobox containing gene Arx is expressed during ventral telencephalon development and it is required for correct GABAergic interneuron tangential migration from the ganglionic eminences to the olfactory bulbs, cerebral cortex and striatum. Its human ortholog is associated with a variety of neurological clinical manifestations whose syntoms are compatible with a loss of cortical interneurons and altered basal ganglia related-activities in humans. Herein, we reported the identification by global expression profiling of a group of genes whose expression is consistently altered in Arx mutant ganglionic eminences. Following analysis revealed the striking ectopic expression in the ganglionic eminences of a number of genes normally not, or only marginally, expressed in the ventral telencephalon. Among them, we functionally analyzed Ebf3, whose ectopic expression in ventral telencephalon is preventingneuronal tangential migration. Further, we showed that Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissue might marginally rescue tangential cell movements. Together, these data provide an initial analysis of the molecular pathways regulated by Arx and how their networking might regulate those specific cellular processes during telencephalon development strongly altered by loss of Arx.
Arx acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity.
No sample metadata fields
View SamplesWe performed RNA sequencing in isogenic models of COX-1 proficient (OV3/SCR) and COX-1 deficient (OV3/COX1KD) OVCAR-3 ovarian cancer cells. COX-1 knockdown was associated with a coordinated anti-oncogenic phenotype, with growth, angiogenesis, migration/invasion, and epithelial-mesenchymal transition among the pathways down-regulated. Overall design: RNA sequencing was performed at Vanderbilt Technologies for Advanced Genomics (VANTAGE) using Illumina HiSeq 2500.
Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer.
No sample metadata fields
View SamplesT-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. To address its incomplete molecular concept, we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identified novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor / cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM towards a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.
Specimen part
View SamplesEndometriosis is a complex pathological condition in which multiple components are involved in the disease development and clinical outcome. Endometriosis is mainly an inflammatory codition estrogen-dependent, with unknown pathogenesis, that is characterized by dissemination of edometrium tissue in ectopic position (ovary or pelvic peritoneum). Two main theories rise the pathologic onset: the presence of retrograde menstruation and celomic metaplasia in the pelvic peritoneum, that can occur for development defects. Endometriosis is related not only to genetic or immunological changes and to environmental pollution factors, as the endocrine interferents. The disease phenotype results from multiple events (genetics and enviromental), thus it is difficult to find a single gene as causative while is more probable that a gene network/s might involved in the onset and mantainement of the disease state. The peculiarity of endometriosis rely on the tissue speificity manteinance in the ectopic position, where it responds to the hormone stimuli as the tissue in the eutopic position.
Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects.
Specimen part, Disease, Disease stage, Subject
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