ABSTRACT: Efficacy and safety of eltrombopag in combination with dexamethasone as first-line treatment in adult patients with newly diagnosed immune thrombocytopenia (ITP)
Project description:Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children the disease resolves but in some it becomes chronic. To investigate whether the two forms of the disease are similar or separate entities we performed DNA microarray analysis of T-cells from newly diagnosed children and children with chronic ITP. We found complete separation of the expression files between the two forms of the disease. Furthermore, the gene expression of several cytokines differed between the two forms of the disease. This was also reflected in plasma with increased levels of IL-16 and TWEAK and lower levels of IL-4 in newly diagnosed compared with chronic ITP. Thus, our data indicate that the two forms of the disease may be separate entities. Microarray expression analysis of mRNA in peripheral blood T-cell of Newly diagnosed ITP vs Chronic ITP
Project description:Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children the disease resolves but in some it becomes chronic. To investigate whether the two forms of the disease are similar or separate entities we performed DNA microarray analysis of T-cells from newly diagnosed children and children with chronic ITP. We found complete separation of the expression files between the two forms of the disease. Furthermore, the gene expression of several cytokines differed between the two forms of the disease. This was also reflected in plasma with increased levels of IL-16 and TWEAK and lower levels of IL-4 in newly diagnosed compared with chronic ITP. Thus, our data indicate that the two forms of the disease may be separate entities.
Project description:We evaluated the longitudinal effect of eltrombopag, a thrombopoietin receptor agonist, on gene expression in heavily pretreated patients with chronic immune thrombocytopenia (ITP) using blood transcriptome analysis on pretreatment, and following 1 week and 1 month of treatment samples. A strong stimulation of 208 eltrombopag-induced genes was identified in responders at 1-week time point. 90% of these genes are present in platelets, with GATA1, THPO, VIPAS39 and TGFB1 as top upstream regulators. Subsequently, despite a continued increase in platelet in responders, the eltrombopag-induced gene expression decreased at 1 month compared with the level at 1-week time point. This novel observation of the longitudinal effect of eltrombopag therapy over time suggests different stages of eltrombopag response. Non-responders did not exhibit eltrombopag-induced gene expression changes. This study provides novel insights into the mechanisms of eltrombopag response and nonresponse.
Project description:Children with newly diagnosed ITP that after 12 month enter remission, shows molecular separate entities. The molecular basis for remission and tolerance induction is characterized by gene transcriptional profiling Global gene expression profile in isolated T-cells from 6 children with newly diagnosed ITP and after 12 month when they enter remission
Project description:Children with newly diagnosed ITP that after 12 month enter remission, shows molecular separate entities. The molecular basis for remission and tolerance induction is characterized by gene transcriptional profiling
Project description:Rituximab (RTX) is widely used as a first-line therapeutic strategy for patients affected by immune thrombocytopenia (ITP). However, a large proportion of patients relapse after successful treatment. The present NGS assay was done to help find the cause for this relapse on the immune repertoire level. Therefore, we performed antibody repertoire sequencing for three RTX relapse patients with subsequent mutation and clonal analysis, as well as for two patients with ongoing ITP and two healthy donors (HD) with subsequent mutation analysis.
Project description:Multiple myeloma (MM) is a neoplastic plasma cell (PC) disorder, characterized by clonal proliferation of malignant PC. Despite extensive research, disease heterogeneity within and between treatment resistant patients is poorly characterized. Here, we conduct a prospective multi-center single-arm clinical trial (NCT04065789), combined with longitudinal single cell RNA-seq to study the molecular dynamics of MM resistance mechanisms. Forty-one newly diagnosed MM patients who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab/carfilzomib/lenalidomide/dexamethasone combination. Primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate; progression free survival, and overall survival. Treatment was safe and well-tolerated, deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary-refractory and early-relapsed patients with 11 healthy subjects and 15 newly diagnosed MM patients revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding, and mitochondria respiration, that generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central gene in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR/Cas9 deletion of PPIA or inhibition of PPIA with cyclosporin A significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.
Project description:Early chemotherapy for advanced/metastatic non-castration resistant prostate cancer (PCa) may improve overall patient survival. We studied the safety, tolerability and early efficacy of up-front docetaxel chemotherapy and androgen deprivation therapy (ADT) versus ADT alone for patients with newly-diagnosed advanced/metastatic PCa. As proof of concept, we undertook in vivo gene expression profiling by next generation RNA sequencing (RNA-Seq). Tumour biposies from 6 patients were taken before and after treatment with combined ADT and docetaxcel for 6 weeks
Project description:Early chemotherapy for advanced/metastatic non-castration resistant prostate cancer (PCa) may improve overall patient survival. We studied the safety, tolerability and early efficacy of up-front docetaxel chemotherapy and androgen deprivation therapy (ADT) versus ADT alone for patients with newly-diagnosed advanced/metastatic PCa. As proof of concept, we undertook in vivo gene expression profiling by next generation RNA sequencing (RNA-Seq).
