Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.
Project description:To determine whether gene expression profiles from peripheral whole blood could be used to determine therapeutic outcome in a cohort of children with newly diagnosed polyarticular JIA.
Project description:Glioblastoma multiforme(GBM) is the most common and lethal malignant primary brain tumor. Temozolomide (TMZ) is a promising chemo-therapeutic agent to treat GBM. However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells’ resistance to TMZ are not fully understood. Non-coding RNAs are aberrantly expressed in many cancers and are highly involved in their pathogenesis including drug-resistence. In order to systematically study the role of miRNAs in GBM cells' resistence to TMZ , we built gene expression profiles of TMZ-resistant cell line and TMZ-sensitive cell line using miRNA gene expression microarrays.
Project description:Expression profiling of 559T(proneural subtype of glioblastoma), 592T(mesenchymal subtype of glioblastoma) and normal human astrocyte (NHA) Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with poor survival rate and temozolomide (TMZ) has been used as the standard chemotherapy for GBM treatment. However, a large number of patients either respond poorly to TMZ and/or develop resistance after long-term use, urging the need for the development of potent drugs with novel mechanisms of action. Here, using high-throughput compound screening (HTS), we found azathioprine, an immunosuppressive medication, to be a promising therapeutic agent for TMZ-resistant GBM treatment. Through integrative genome-wide analysis and global proteomic analysis, we identified the elevated lipid metabolism due to hyperactive EGFR/AKT/SREBP-1 signaling pathway being inhibited by azathioprine. In addition, azathioprine causes ER stress-induced apoptosis. Orthotopic xenograft models injected with patient-derived GBM cells exhibits reduced tumor volumes and increased apoptosis by azathioprine. These overall data indicate that azathioprine could be a powerful therapeutic option for TMZ-resistant GBM patients.
Project description:We report the application of RNA-based sequencing technology for high-throughput profiling of T cell enriched peripheral blood mononuclear cells. By sequencing in total of 12 pairs GBM patient samples, we extracted TCRαβ V(D)J sequences from the deep RNA-seq of T cells isolated from the 24 PBMCs to determine if TTFields treatment affected TCR diversity, using the Simpson’s diversity index (DI), which is the average proportional abundance of TCR clones based on the weighted arithmetic mean. Of the 12 patients, 9 exhibited negative log fold change (logFC) of TCR DI after TTFields, indicating clonal expansion. Notably, in all but 1 patient, the top 200 most abundant clones post TTFields, which accounted for 38.1% to 100% (median 67%) of detectable clones, showed substantial expansion compared to pre-TTFields T cells, and inversely correlated with the DI. Thus, TTFields treatment is associated with adaptive immune activation as evidenced by clonal expansion of peripheral T cells.
Project description:Glioblastoma multiforme (GBM) is the most common and lethal malignant primary brain tumor. Temozolomide (TMZ) is a promising chemo-therapeutic agent to treat GBM. However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells’ resistance to TMZ are not fully understood. Long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and are highly involved in their pathogenesis including drug-resistence. In order to systematically study the role of lncRNAs in GBM cells' resistence to TMZ , we built gene expression profiles of TMZ-resistant cell line and TMZ-sensitive cell line using lncRNA and mRNA gene expression microarrays.
