Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of cancer treatment, often leading to cessation of therapy due to lack of adequate treatment options. In the peripheral nervous system the chemotherapeutic agent paclitaxel impairs mitochondrial function and induces vast changes in gene expression. However, changes at the protein level remain so far unexplored. Here we used an unbiased approach of quantitative proteome profiling in a clinically-relevant rat model of paclitaxel-induced peripheral neuropathy. We analysed two critical timepoints: (1) day 7, equivalent to 1 day after cessation of paclitaxel treatment, prior to neuropathy development; (2) approximately 4 weeks after paclitaxel initiation, when neuropathy has developed.
Project description:Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set. We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.
Project description:We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT) and conducted validation in an independent cohort of 114 MM patients. We identified one previously unreported gene locus associated with BiPN at 21q22.3 (rs2839629, PKNOX1; OR = 1.89, P= 6.47 x 10-7). PKNOX1 is known to regulate expression of MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium (LD, r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding an endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.
Project description:Peripheral sensory neuropathy is a common complication to cisplatin treatment in cancer patients. Multiple signaling pathways are likely to be implicated in the pathophysiology, there are no explicit treatments and little is known about predictive factors associated with the onset or progression of cisplatin induced peripheral neuropathy. The transcriptional profiles of differentially senesitive strains of dorsal root ganglion across two inbreed strain of mice will promote better understanding of progression and risk factors assocciated with cisplatin induced peripheral neuropathy. Peripheral neuropathy was induced with a bi-weekly treatment of 4mg/kg cisplatin. We used microarrays to detail the transciptional profile underlying cisplatin induced peirperal neuropathy in two differentailly sensitve inbreed strains of mice: A/J and C57BL/6J
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
