T-cells' gene expression after high-dose melphalan
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148770 | GEO | 2020/11/23
REPOSITORIES: GEO
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Project description:T-cells' gene expression after high-dose melphalan
| PRJNA625689 | ENA
Project description:Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the U.S. Treatment for eligible patients includes three stages: induction, consolidation with stem cell rescue, and maintenance. High dose therapy with the DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem cell transplant. As a result, melphalan resistance remains a clinical challenge. Here, we use proteometabolomics to examine mechanisms of melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP), acute treatment metabolomics, and immunoblotting analyses have allowed us to further elucidate metabolic processes contributing to melphalan resistance. Proteometabolomics data indicate that both drug resistant cells have higher levels of pentose phosphate pathway metabolites than their naïve counterparts. Interestingly, we also observed cell line specific changes in purine, pyrimidine and glutathione metabolism that are linked to the differences in steady state metabolism of naïve cells and highlight the heterogeneity of melphalan resistance in these models. Because of the diversity of metabolic changes, our data suggest that omics approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the delivery of this therapy.
2020-07-17 | PXD019725 | Pride
Project description:Background Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Methods and Findings Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Conclusions Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity
2016-12-19 | GSE81979 | GEO
Project description:Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an organ-specific drug-delivery strategy to treat retinoblastoma, the most common primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. To explore the reason for the unexpected vascular toxicities, we have developed in vitro studies with human retinal endothelial cells to test the effects of the chemotherapeutics and a non-human primate model to monitor the SSIOAC treatment in real-time and post-treatment. Melphalan and carboplatin (another chemotherapeutic used to treat retinoblastoma via SSIOAC) triggered migration, proliferation, and apoptosis when used to treat human retinal endothelial cells. Melphalan was associated with increased adhesion of leukocytes to human retinal endothelial cells, and tended to increase with increased cell expression of adhesion proteins (ICAM-1) and soluble chemotactic factors (IL-8). Histopathology post-SSIOAC indicated vessel wall sloughing, leukostasis, and vessel occlusion. We have established an in vitro human cell culture model and a non-human primate model to evaluate strategies designed to obviate vascular side effects, and optimize the efficacy of SSIAOC and the drug preparations used in SSIOAC. 4 non-treated (MNT) vs. 4 melphalan-treated primary human retinal endothelial cells (RECs).
2011-12-13 | E-GEOD-34381 | biostudies-arrayexpress
Project description:Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling. Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells. To investigate large scale alterations in gene expression accompanying melphalan resistance, we used the multiple myeloma cell line RPMI8226 and its melphalan-resistant derivative LR5. The stable isotope labeling by amino acids in cell culture (SILAC) approach.
2015-05-26 | PXD001276 | Pride
Project description:To identify patterns of change in gene expression that correlated with drug treatment (saline control, ADH-1 alone, melphalan alone and ADH-1 plus melphalan) in our animal model of regional therapy for extremity melanoma we evaluated gene expression using microarray genechips and a Pearson correlation analysis. Genes were ranked according to the degree to which expression correlated with systemic ADH-1 treatment alone or in combination with regional melphalan. Tissue samples were harvested at 4, 24 and 48 hours after treatment with melphalan. Specific cellular pathways associated with drug treatment were identified using gene set enrichment analysis (GSEA). Keywords: time course; chemotherapy; melanoma; melphalan; N-cadherin; ADH-1
2008-10-30 | GSE8615 | GEO
Project description:Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an organ-specific drug-delivery strategy to treat retinoblastoma, the most common primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. To explore the reason for the unexpected vascular toxicities, we have developed in vitro studies with human retinal endothelial cells to test the effects of the chemotherapeutics and a non-human primate model to monitor the SSIOAC treatment in real-time and post-treatment. Melphalan and carboplatin (another chemotherapeutic used to treat retinoblastoma via SSIOAC) triggered migration, proliferation, and apoptosis when used to treat human retinal endothelial cells. Melphalan was associated with increased adhesion of leukocytes to human retinal endothelial cells, and tended to increase with increased cell expression of adhesion proteins (ICAM-1) and soluble chemotactic factors (IL-8). Histopathology post-SSIOAC indicated vessel wall sloughing, leukostasis, and vessel occlusion. We have established an in vitro human cell culture model and a non-human primate model to evaluate strategies designed to obviate vascular side effects, and optimize the efficacy of SSIAOC and the drug preparations used in SSIOAC.
2011-12-13 | GSE34381 | GEO
Project description:To determine which genes are affected by NG25 and melphalan, we performed an RNA-seq on INA-6 cells treated with NG25, melphalan or a combination of the two. GSEA focusing on the hallmark pathways showed that melphalan-treatment upregulated genes involved in UV-response, DNA-repair, p53-pathway and TNF-signaling via NF-kB. NG25 induced expression of genes involved in cholesterol homeostasis and mTORC1-signaling and down-regulated MYC- and E2F-targets. MYC is a central driver of MM pathology, and regulate survival as well as cell cycle control through E2F. NG25 reversed the melphalan-induced UV-response.
2021-06-17 | GSE178292 | GEO
Project description:Autologous peripheral hematopoietic stem cell transplantation (autoHSCT) is one front-line therapy with high-dose melphalan for multiple myeloma (MM). Patients with MM who receive conditioning regimen with melphalan usually suffer from severe gastrointestinal symptoms, as one of nonhematological toxicities. Aim: It is an urgent demand to develop an effective methods to repair the intestinal injuries in patients with MM receiving conditioning regimen with high-dose melphalan for autoHSCT. Therefore, the protective effects of Human umbilical cord derived-mesenchymal stem cells (hucMSCs) is investigated after infusion into mouse model with melphalan-induce gastrointestinal injuries.
2024-04-01 | GSE225899 | GEO
Project description:Purpose: Evaluate the molecular changes associated with melphalan-induced cardiotoxicity and rescue by N-acetyl-L-cysteine (NAC) supplementation. Methods: RNA-Seq analysis was performed to analyze global transcriptome profiles of hiPSC-CMs treated with DMSO (Control group), 20 µM melphalan (Mel group), and 20 µM melphalan with 1 mM NAC (Mel+NAC group), respectively. The Illumina TruSeq technology was used to prepare RNA-Seq libraries, and next-generation sequencing was done via an Illumina HWI-ST1276. RNA sequence reads were aligned to the human reference genome (GRCh38) using STAR v2.5. HTSeq v0.6.1 was used to count the read numbers mapped of each gene, and then Fragments Per Kilobase Million (FPKM) was calculated to estimate gene abundance. Differential expression analysis was performed using the DESeq2 R package (2_1.6.3). The resulting P-values were adjusted using the Benjamini and Hochberg's approach. Results: As detected by RNA-Seq, more genes were down-regulated than up-regulated by the treatment of melphalan, whereas NAC supplementation resulted in more genes being up-regulated than down-regulated. Among the top 10 up-regulated genes by melphalan treatment, 4 were direct p53 effectors (CDKN1A, EDXR, TNFRSF10C, and GDF15). And among the top 10 down-regulated genes by melphalan treatment, 5 were correlated to cell adhesion (CDH13, CNTN1, SDK1, CTNND2, and PARD3B). In addition, the up- and down-regulation of genes involved in oxidative stress (e.g., DUOX2 and NOX4) following melphalan treatment (Mel vs. control) was attenuated with NAC supplementation (Mel+NAC vs. Control). Similarly, the up- and down-regulation of genes involved in cardiac muscle contraction (e.g., Ca2+ handling proteins CACNA1C, RYR2 and CASQ2 and cardiac contractile proteins TNNC1, ACTC1, TNNC1) and cardiac conduction (e.g., ATP2B2 and ABCC9) following melphalan treatment (Mel vs. Control) was attenuated with NAC supplementation (Mel+NAC vs. Control). Conclusion: NAC ameliorates melphalan-induced alteration of hiPSC-CM transcriptomic profiles.
2020-10-07 | GSE150055 | GEO