Dual IRE1 RNase functions dictate glioblastoma development
Ontology highlight
ABSTRACT: The transcriptome dataset has been used to validate on a GBM patient cohort (n=117) the IRE1-dependent gene expression signature identified in U87 cell line.
Project description:We investigated differential gene expression in response to treatment of multiple myeloma cells with EZH2 inhibitor RNA-seq in two cell lines
Project description:We assayed leukocyte global gene expression for a prospective discovery cohort of 106 adult patients admitted to UK intensive care units with sepsis due to community acquired pneumonia or faecal peritonitis. We assigned all samples to sepsis response signature groups after performing unsupervised analysis of the transcriptomic data.
Project description:Glioblastoma (GBM) is the most common and devastating malignant brain tumor in adults. The mortality rate is very high despite different treatments. New therapeutic targets are therefore highly needed to improve patient care. Cell-surface proteins represent attractive targets due to their accessibility, their involvement in essential signaling pathways, and their dysregulated expression in cancer. Moreover, they are potential targets for CA-based immunotherapy or mRNA vaccine strategies. However, cell-surface proteins are often underrepresented in standard proteomic data sets, due to their poor solubility and lower expression levels compared to intracellular proteins. In this context, we investigated GBM-associated surfaceome by comparison to healthy astrocytes surfaceome to identify new specific targets to GBM. For this purpose, biotinylation of cell surface proteins has been carried out in GBM and healthy astrocytes cell lines. Biotinylated proteins were purified on streptavidin beads and analyzed by shotgun proteomics. After filtering our data with Cell Surface Proteins Atlas (CSPA) and Gene Ontology, 78 overexpressed or exclusive in GBM have been identified. Validation has been performed using Human Protein Atlas. In this context, we identified 21 specific potential targets for GBM including 5 mutated proteins (RELL1, CYBA, EGFR, and MHC I proteins). Taken together, we identified potential targets for immune therapy strategies in GBM.
Project description:We assayed leukocyte global gene expression for a prospective validation cohort of 106 adult patients admitted to UK intensive care units with severe sepsis due to community acquired pneumonia.
Project description:Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Comprehensively capturing the host physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index and APACHE II score were poor predictors of survival. Instead, using plasma proteomes quantifying 302 plasma protein groups at 387 timepoints in 57 critically ill patients on invasive mechanical ventilation, we found 14 proteins that showed trajectories different between survivors and non-survivors. A proteomic predictor trained on single samples obtained at the first time point at maximum treatment level (i.e. WHO grade 7) and weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81, n=49). We tested the established predictor on an independent validation cohort (AUROC of 1.0, n=24). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that predictors derived from plasma protein levels have the potential to substantially outperform current prognostic markers in intensive care.
Project description:We performed longitudinal blood sampling of end-stage kidney disease (ESKD) patients with COVID-19, collecting samples pre-infection and serially during infection. SomaLogic proteomics data were generated for two cohorts. The Wave 1 cohort consists of samples collected from ESKD patients during the first wave of COVID-19 in early 2020, while samples were collected for the Wave 2 cohort in the following year. A full analysis of the dataset is presented in the Nature Communications manuscript (https://doi.org/10.1038/s41467-022-35454-4).
Project description:This SuperSeries is composed of the following subset Series: GSE23105: Postnatal Growth Restriction and Gene Expression Changes in a Mouse Model of Fetal Alcohol Syndrome (Kidney) GSE23106: Postnatal Growth Restriction and Gene Expression Changes in a Mouse Model of Fetal Alcohol Syndrome (Liver) Refer to individual Series
Project description:Growth restriction, craniofacial dysmorphology and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal and/or postnatal, but the underlying mechanisms remain unknown. We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome, e.g. craniofacial changes and growth restriction in adolescent mice. Here we further characterize the growth restriction phenotype by measuring body weight at gestational day 16.5, cross-fostering from birth to weaning, and extending our observations into adulthood. Furthermore, in an attempt to unravel the molecular events contributing to the growth phenotype, we have compared gene expression patterns in the liver and kidney of non-fostered ethanol-exposed and control mice at postnatal day 28. We find that the ethanol-induced growth phenotype is not detectable prior to birth, but is present at weaning, even in mice that have been cross-fostered to unexposed dams. This suggests a postnatal growth restriction phenotype that is not due to deficient postpartum care by dams that drank ethanol, but rather a physiological result of ethanol exposure in utero. We also find that, despite some catch-up growth after five weeks of age, the effect extends into adulthood, consistent with longitudinal studies in humans. Genome-wide gene expression analysis revealed interesting ethanol-induced changes in the liver, including genes involved in the metabolism of exogenous and endogenous compounds, iron homeostasis and lipid metabolism. Gene expression changes in the livers of offspring exposed to alcohol in utero compared to controls.
Project description:Growth restriction, craniofacial dysmorphology and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal and/or postnatal, but the underlying mechanisms remain unknown. We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome, e.g. craniofacial changes and growth restriction in adolescent mice. Here we further characterize the growth restriction phenotype by measuring body weight at gestational day 16.5, cross-fostering from birth to weaning, and extending our observations into adulthood. Furthermore, in an attempt to unravel the molecular events contributing to the growth phenotype, we have compared gene expression patterns in the liver and kidney of non-fostered ethanol-exposed and control mice at postnatal day 28. We find that the ethanol-induced growth phenotype is not detectable prior to birth, but is present at weaning, even in mice that have been cross-fostered to unexposed dams. This suggests a postnatal growth restriction phenotype that is not due to deficient postpartum care by dams that drank ethanol, but rather a physiological result of ethanol exposure in utero. We also find that, despite some catch-up growth after five weeks of age, the effect extends into adulthood, consistent with longitudinal studies in humans. Genome-wide gene expression analysis revealed interesting ethanol-induced changes in the liver, including genes involved in the metabolism of exogenous and endogenous compounds, iron homeostasis and lipid metabolism. Gene expression changes in the kidneys of offspring exposed to alcohol in utero compared to controls.
Project description:Formalin-fixed paraffin embedded (FFPE) tissues are routinely prepared and collected for diagnostics in pathology departments. Therefore, FFPE tissues are the most accessible research sources in pathology archives. In this study we investigated whether we can apply a targeted and quantitative parallel reaction monitoring (PRM) method for FFPE tissue samples in a sensitive and reproducible way. Normal brain and glioblastoma multiforme (GBM) tissues were used to demonstrate the feasibility of our approach. Two analytical methods (or workflows) were used: PRM measurement of a tryptic digest without phosphopeptide enrichment (Direct-PRM) and after Fe-NTA phosphopeptide enrichment (Fe-NTA-PRM). Applying these two methods, the phosphorylation ratio could be determined for selected four peptide pairs that originate from Neuroblast differentiation-associated protein (AHNAK S5448-p), Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D T337-p), Eukaryotic translation initiation factor 4B (EIF4B S93-p) and Epidermal growth factor receptor (EGFR S1166-p). In normal brain FFPE tissues, using the Fe-NTA-PRM method, we were able to quantify the targeted phosphorylated peptides with a high degree of reproducibility (CV = 14%). Our results indicate that formalin fixation does not impede relative quantification of a phosphosite and its phosphorylation ratio in FFPE tissues. The developed methods open ways to study archival FFPE tissues.