Objective : To study molecular changes in the articular cartilage and subchondral bone of the tibial plateau from mice deficient in frizzled related protein (Frzb) compared to wild-type mice by transcriptome analysis.
Tight regulation of wingless-type signaling in the articular cartilage - subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice.
Sex, Age, Specimen part
View SamplesRheumatoid arthritis (RA) is an inflammatory joint disorder that results in progressive joint damage when insufficiently treated. In order to prevent joint destruction and functional disability in RA, early diagnosis and initiation of appropriate treatment with Disease-Modifying Antirheumatic Drugs (DMARDs) is needed. However, in daily clinical practice, patients may initially display symptoms of arthritis that do not fulfil the classification criteria for a definite diagnosis of RA, or any other joint disease, a situation called Undifferentiated Arthritis (UA). Out of the patients with UA, 30 to 50% usually develop RA, and early identification of these remains a challenge.
Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus.
Sex, Age, Specimen part, Disease, Treatment
View SamplesObjective: Rituximab displays therapeutic benefits in the treatment of rheumatoid arthritis (RA) patients resistant to TNF blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. In this study we investigated the global molecular effects of rituximab in synovial biopsies obtained from anti-TNF resistant RA patients before and after administration of the drug.
Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium.
Sex, Specimen part, Disease, Disease stage, Treatment
View SamplesInsulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting.
IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy.
Specimen part, Treatment
View SamplesA genetic association between the ANP32A gene and osteoarthritis has been suggested. We compared transcriptome profiles of the articular cartilage and subchondral bone from mice deficient in ANP32A with wild-type mice to get insights into the role of ANP32A in the pathogenesis of ostearthritis.
ANP32A regulates ATM expression and prevents oxidative stress in cartilage, brain, and bone.
Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
RNA expression profiling of human iPSC-derived cardiomyocytes in a cardiac hypertrophy model.
Specimen part
View SamplesCardiac hypertrophy is an independent risk factor for cardiovascular disease and heart failure. There is increasing evidence that microRNAs (miRNAs) play an important role in the regulation of messenger RNA (mRNA) and the pathogenesis of various cardiovascular diseases. However, the ability to comprehensively study cardiac hypertrophy on a gene regulatory level is impacted by the limited availability of human cardiomyocytes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer the opportunity for disease modeling.
RNA expression profiling of human iPSC-derived cardiomyocytes in a cardiac hypertrophy model.
Specimen part
View SamplesWe investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays.
Posttranscriptional regulation of PER1 underlies the oncogenic function of IREα.
Cell line, Treatment
View SamplesTo assess the effects of histone deacetylase (HDAC) inhibitor, HDACi 4b, treatment on muscle function on a molecular level, we performed microarray analysis on skeletal muscle (gastrocnemius) samples from wt and N17182Q mice treated with the HDAC inhibitor 4b for 3 months (50 mg/kg; s.c. injection 3x weekly; n=4 per group). The transcriptome pattern in N17182Q mice compared to wt controls consisted of deficits in the expression of genes related to mitochondrial function and oxidative metabolism. In addition, we noted that numerous genes associated with basal contractile function were altered in HD N17182Q mice. These include genes related to the muscle contractile complex, Tnnt3 and Myh8, as well as several additional myosin genes: myosin heavy chain genes, Myh10 and Myh4, and myosin light chain genes, Myl1, Mylc2 and Mylk. These findings implicate deficits in the underlying contractile function in skeletal muscle from HD mice. Further, we found robust effects of 4b treatment on the expression of genes in skeletal muscle, with 556 genes showing significantly altered expression, at p<0.005, in 4b-treated N17182Q muscle compared to vehicle-treated control mice.
HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation.
Specimen part, Treatment
View SamplesDEAD-box RNA helicases eIF4A and Ded1 are believed to promote translation initiation by resolving mRNA secondary structures that impede ribosome attachment at the mRNA 5' end or subsequent scanning of the 5'UTR, but whether they perform distinct functions or act redundantly in vivo is poorly understood. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling. Despite similar reductions in bulk translation, inactivation of a cold-sensitive Ded1 mutant substantially reduced the TEs of >600 mRNAs, whereas inactivation of a temperature-sensitive eIF4A mutant yielded <40 similarly impaired mRNAs. The broader requirement for Ded1 did not reflect more pervasive secondary structures at low temperature, as inactivation of temperature-sensitive and cold-sensitive ded1 mutants gave highly correlated results. Interestingly, Ded1-dependent mRNAs exhibit greater than average 5'UTR length and propensity for secondary structure, implicating Ded1 in scanning though structured 5' UTRs. Reporter assays confirmed that cap- distal stem-loop insertions increase dependence on Ded1 but not eIF4A for efficient translation. While only a small fraction of mRNAs is strongly dependent on eIF4A, this dependence is significantly correlated with requirements for Ded1 and 5'UTR features characteristic of Ded1- dependent mRNAs. Our findings suggest that Ded1 is critically required to promote scanning through secondary structures within 5'UTRs; and while eIF4A cooperates with Ded1 in this function, it also promotes a step of initiation common to virtually all yeast mRNAs. Overall design: We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling.The study includes 32 samples, comprised of 16 mRNA-Seq samples and 16 ribosome footprint profiling samples, derived from biological replicates of 3 mutant strains, ded1-cs, ded1-ts and tif1-ts, and the corresponding wild-type strains. The tif1-ts mutant and its wild-type counterpart were analyzed at 30°C and 37°C.
Functional interplay between DEAD-box RNA helicases Ded1 and Dbp1 in preinitiation complex attachment and scanning on structured mRNAs in vivo.
Subject
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