Analysis of dexamethasone-stimulated A549 lung adenocarcinoma epithelial cells treated with a glucocorticoid response (GR) element (GRE) specific DNA binding polyamide. Polyamide designed to target the sequence 5'-WGWWCW-3' and disrupt GR-mediated gene expression. Effects of the GR antagonist mifepristone also examined.
Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression.
Cell line
View SamplesAML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a later onset, a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p and 7q, as well as fast progression of the disease with extremely poor prognosis. We and other have shown that the MLL gene is over expressed in amplified cases, however, in most of the cases the amplified region is not restricted to the MLL locus. In the present study we investigated 19 patients with AML/MDS and MLL gain/amplification [15 AML (two secondary, following MDS and PV, and three therapy related) and 4 MDS cases (two therapy related)]. By means of array CGH performed in 12 patients (GSE9928) we were able to delineate the minimal deleted regions within 5q, 17p and 7q and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases were used to define the candidate genes within these regions. Interestingly, analysis of our data suggests an interdependency of genes influenced by losses of 5q and 17p and expression of genes present in 11q23-25. Additionally, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from all other types of AML, thus, indicating specific pathogenesis present in this entity.
AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA copy number changes.
Sex, Age, Specimen part, Disease
View SamplesNeurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth cause progressive hearing loss, and the standard treatment including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allows hearing test. Here we developed a cerebellopontine angle (CPA) schwannomas model that faithfully recapitulates the tumor-induced hearing loss. Using this model we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor HGF levels. cMET gene knockdown study independently confirmed the role of cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared to normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in NF2 patients.
Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesCNS-delivery of Interleukin 4 (IL-4) - via a lentiviral-mediated gene therapy strategy - skews microglia to proliferate, inducing these cells to adopt the phenotype of slowly proliferating cells. Transcriptome analysis revealed that IL-4-treated microglia express a broad number of genes normally encoded by embryonic microglia. Overall design: RNAseq analysis of sorted microglia from mice receiving IL-4 gene therapy
Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis.
Specimen part, Cell line, Subject
View SamplesHeritable differences in gene expression between individuals are an important source of phenotypic variation. The question of how closely the effects of genetic variation on protein levels mirror those on mRNA levels remains open. Here, we addressed this question by using ribosomal footprinting to examine how genetic differences between two strains of the yeast S. cerevisiae affect translation. Strain differences in translation were observed for hundreds of genes, more than half as many as showed genetic differences in mRNA levels. Similarly, allele specific measurements in the diploid hybrid between the two strains found roughly half as many cis-acting effects on translation as were observed for mRNA levels. In both the parents and the hybrid, strong effects on translation were rare, such that the direction of an mRNA difference was typically reflected in a concordant footprint difference. The relative importance of cis and trans acting variation on footprint levels was similar to that for mRNA levels. Across all expressed genes, there was a tendency for translation to more often reinforce than buffer mRNA differences, resulting in footprint differences with greater magnitudes than the mRNA differences. Finally, we catalogued instances of premature translation termination in the two yeast strains. Overall, genetic variation clearly influences translation, but primarily does so by subtly modulating differences in mRNA levels. Translation does not appear to create strong discrepancies between genetic influences on mRNA and protein levels. Overall design: Ribsosomal footprinting and RNASeq in the two yeast strains BY and RM as well as their diploid hybrid. We generated one library each for the BY and RM parents, and two libraries (biological replicates) for the hybrid data.
Genetic influences on translation in yeast.
Cell line, Subject
View SamplesBehavioral transitions Young infant rats paradoxically prefer odors paired with shock but older pups learn aversions. This transition is amygdala- and corticosterone-dependent.
Transitions in infant learning are modulated by dopamine in the amygdala.
No sample metadata fields
View SamplesCharacterization of colon CD11chigh/MHCII+ myeloid cell subsets
Intestinal CD103(+)CD11b(-) dendritic cells restrain colitis via IFN-γ-induced anti-inflammatory response in epithelial cells.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.
Sex, Specimen part
View SamplesOral cavity squamous cell carcinoma (OSCC) is a disease with extensive morbidity and mortality and few useful molecular targets.
Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.
Sex, Specimen part
View SamplesWe elucidate a neurological syndrome affecting both the PNS and CNS defined by CLP1 mutations that impair tRNA splicing Overall design: Identification and biochemical characterization of mutant CLP1 in human patients
Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.
No sample metadata fields
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