Six1 is a developmental transcriptional regulator frequently overexpressed in human tumors. Recent results also show that SIX1 acts as a repressor of cell senescence, an antiproliferative response with key roles in tumor suppression, among other physiological and pathological settings. Here, we set to study the impact of SIX1 gain of function in transformation and tumorigenesis of fibroblasts, in connection with senescence. Using transcriptomic, histological, and functional analyses in murine cells and tumors of fibroblast origin, we show that SIX1 has a strong pro-tumorigenic action in this model, linked to the repression of a senescence-related gene signature and the activation of cellular plasticity, mediated at least in part by direct transcriptional regulation of the stemness factor Sox2. Moreover, functional analyses with human glioma cell lines also show that SIX1 controls SOX2 expression, senescence and self-renewal in this model. Collectively, our results support a general link of SIX1 with senescence and SOX2-mediated cell plasticity in tumors. Overall design: mRNA profiles were obtained from SIX1-overexpressing tumors and controls in triplicate by RNA-Seq using Illumina HiSeq.
SIX1 represses senescence and promotes SOX2-mediated cellular plasticity during tumorigenesis.
Specimen part, Subject
View SamplesCombination of GSI with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
Specimen part
View SamplesPrecursor T-cell lymphoblastic neoplasms are aggressive haematological neoplasm that most often manifest with extensive marrow and blood affectation (T-cell acute lymphoblastic leukaemia or T-ALL) or less commonly as a thymic mass with limited bone marrow infiltration (T-cell lymphoblastic lymphoma or T-LBL). Here we show data from RNA-Seq in a sample series of T-LBL from Spanish patients.The goal was to determine the levels of expression of coding genes and microRNAs, and to identify all genetic variants including SNVs, indels, and fusion transcripts. Overall design: Expression data were determined by comparson of each tumour sample with two control thymuses (404 and 405). Genetic variants were determined by comparison of tumour sequences with canonical ENSEMBL normal-references of each gene.
RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas.
Specimen part, Subject
View SamplesTrastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab.
The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.
Age, Disease
View SamplesHutchinson-Gilford Progeria Syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. We report herein a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. By using this animal model, we have developed an antisense morpholinobased therapy that prevents the pathogenic Lmna splicing, dramatically reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotidebased therapies for treating human diseases of accelerated aging.
Splicing-directed therapy in a new mouse model of human accelerated aging.
Sex, Age, Specimen part
View SamplesUnderstanding the underlying mechanisms of the well-established platelet hyporeactivity in neonates, would be of great relevance for both improving the clinical management of neonates, a population with a higher bleeding risk than adults (especially among sick and preterm infants), and getting new insights onto the regulatory mechanisms of platelet biology. Transcriptome analysis is a useful tool to identify mRNA signature affecting platelet function. However, human fetal/neonatal platelet transcriptome analysis has never been reported. Here, we used, for the first time, mRNA expression array to compare the platelet transcriptome changes during development. Microarray analysis was performed in pure platelet RNA obtained from adult and cord blood, using the same platform in two independent laboratories.
Comprehensive comparison of neonate and adult human platelet transcriptomes.
Specimen part
View SamplesTo study the effects of previous exposure to mechanical ventilation may modify the development of Ventilator-induced lung injury, preconditioning was induced by low-pressure ventilation for 90 minutes. After 1 week, intact (sham) and preconditioned mice were sacrificed, the lungs extracted and gene expression measured in order to identify differences responsible for the observed tolerance to ventilator-induced lung injury observed in preconditioned animals.
Exposure to mechanical ventilation promotes tolerance to ventilator-induced lung injury by Ccl3 downregulation.
Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Estrogen receptor subtype beta2 is involved in neuromast development in zebrafish (Danio rerio) larvae.
No sample metadata fields
View SamplesThe role of ERbeta2 in zebrafish larvae was investigated by injection of a Morpholino against ERbeta2. After 72hpf, the morphants showed a strong disruption in their sensory systems. ERbeta2 has been shown to be needed for the normal functioning of the sensory system organs, the neuromasts. The mechanisms involved in the neuromast disruption in ERbeta2 morphants was identified by microarrays gene screening. After comparison of two screening with low and hign concentration of Morpholinos, genes that were present in the two microarrays screening were selected. The genes were then chosen by relevance for the mechanisms involved in the role of ERbeta2 in neuromast development. The ngn1 transcription factor, Notch3 and Notch1a showed to be up-regulated, also confirmed by in situ hybridization. The Notch signaling is known to be involved in cell fate in developing neuromasts. The overall conclusion is that ERbeta2 by interacting with the notch signaling pathways is critical for normal development of the neuromast of the lateral line in zebrafish.
Estrogen receptor subtype beta2 is involved in neuromast development in zebrafish (Danio rerio) larvae.
No sample metadata fields
View SamplesThe role of ERbeta2 in zebrafish larvae was investigated by injection of a Morpholino against ERbeta2. After 72hpf, the morphants showed a strong disruption in their sensory systems. ERbeta2 has been shown to be needed for the normal functioning of the sensory system organs, the neuromasts. The mechanisms involved in the neuromast disruption in ERbeta2 morphants was identified by microarrays gene screening. After comparison of two screening with low and high concentration of Morpholinos, genes that were present in the two microarrays screening were selected. The genes were then chosen by relevance for the mechanisms involved in the role of ERbeta2 in neuromast development. The ngn1 transcription factor, Notch3 and Notch1a showed to be up-regulated, also confirmed by in situ hybridization. The Notch signaling is known to be involved in cell fate in developing neuromasts. The overall conclusion is that ERbeta2 by interacting with the notch signaling pathways is critical for normal development of the neuromast of the lateral line in zebrafish.
Estrogen receptor subtype beta2 is involved in neuromast development in zebrafish (Danio rerio) larvae.
No sample metadata fields
View Samples