Project description:In this study, we identified a multi-kinase inhibitor MTX-216 to be efficacious in blocking NF1 loss-of-function melanoma cells. To identify the mechansisms of action of MTX-216, we treated NF1 loss-of-function melanoma cell lines with MTX-216, MTX-211 (the structural analogue of MTX-216 that has no effect on melanoma cells) as well as commericial kinase inhibitors, trametinib and pictilisib, and compared their gene expression profiles.
Project description:Siglec-9 has been of particular interest for their potential as immune checkpoints. Here, we employed docking-based virtual screening combined with bio-layer interferometry assays to identify a potential Siglec-9 inhibitor, MTX-3937. Analysis showed that MTX-3937-treatment significantly enhanced the production of IFN-γ, TNF-α, perforin and CD107a in human NK cells. Consistently, MTX-3937 largely promoted NK cells tumor killing activities both in vitro and in vivo. In mechanism, MTX-3937 inhibited the phosphorylation level of SHP-1/2 in NK92 cells.
Project description:Methotrexate (MTX) has been widely used for the treatment of a variety of tumors as well as for inflammatory diseases and rheumatoid arthritis (RA). MTX-induced toxicity has been a serious unpredictable side effect of the treatment and an important clinical problem. Possible causes include allergic, cytotoxic or immunologic reactions to this agent. We examined the consequences of the mechanism of MTX-induced pulmonary toxicity gene expression in BEAS-2B cells, huma bronchial cell line, by microarray. The expression of these genes are potential biomarker of methotrexate-induced pulmonary toxicity. Also, We provide a clue about mechanism of pulmonary toxic action by these clinical chemotherapeutic agents. Keywords: 48h treatment, 0.144uM (dose), MTX
Project description:MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomics analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments.
Project description:This microarray study was conducted along with SATORI study, the clinical trial evaluated 125 patients with active RA with an inadequate response to low dose of MTX. Patients were allocated to receive either Tocilizumab(TCZ) 8 mg/kg every 4 weeks (TCZ group) or MTX 8 mg/week (MTX/control group) for 24 weeks. Gene expression profiles (GEP) of 112 patients - 54 patients from TCZ group and 58 patients from MTX group - were obtained in this study.
Project description:Comparison of the transcriptome macrophages derived from CD14+ human monocyte-derived macrophages generated in the presence of M-CSF (M-Mphage) or GM-CSF (GM-Mphage) and MTX.
Project description:The role of innate immunity in modulating severity of chemotherapy-induced complications is so far unclear. The aim of this study was to determine how TLR2 may influence MTX-induced mucositis in the small intestine in mice. We used microarrays to assess gene expression profiles in proximal jejunum of WT vs. TLR2 KO mice after systemic treatment with MTX. Mucositis was induced by i.p. injection of MTX [40mg/kg BW/d] for 4 days in WT or TLR2 knockout (KO) mice. On day 7, mice were sacrificed and RNA was extracted from proximal jejunum (n=3 mice/group) and hybridized on Affymetrix microarrays.
Project description:The role of innate immunity in modulating severity of chemotherapy-induced complications is so far unclear. The aim of this study was to determine how TLR2 may influence MTX-induced mucositis in the small intestine in mice. We used microarrays to assess gene expression profiles in proximal jejunum of WT vs. TLR2 KO mice after systemic treatment with MTX.
