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Down-regulation of atherosclerosis signaling in patients treated with on-line haemodiafiltration may contribute to lower cardiovascular risk in hemodialysis

ABSTRACT: Recent studies suggest that on-line hemodiafiltration (OL-HDF) may reduce the progression of dialysis-related cardiovascular diseases, but the molecular mechanisms underlying this effect are unclear. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in peripheral blood mononuclear cells (PBMCs) associated with OL-HDF and bicarbonate dialysis (BHD). The transcriptomic profile was investigated in PBMCs isolated from 8 patients on OL-HDF and 8 patients on BHD by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by qPCR in an independent cohort of patients (OL-HDF N=20, BHD n=20, testing group). Eight-hundred and sixty-eight genes were differentially expressed in the comparison between OL-HDF and BHD. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by OL-HDF. Among the genes modulated by OL-HDF in this pathway there were PDGF A chain (FC=-2.13), Clusterin (FC=-2.14), Monoamine Oxidase A (MAO-A, FC=-2.43), IL-6 (FC=-1.56), VEGF C (FC=-1.83) and Apolipoprotein E (Apo-E) (FC=+1.69). qPCR, performed in the testing-group, confirmed the microarray data. In the same set of patients PDGF AA, IL-6 and VEGF C serum levels were significantly lower in the OL-HDF group. Finally, 10 BHD patients were switched to OL-HDF and PBMC were harvested after 6 months. The qPCR results from this perspective group further confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis. In conclusion, OL-HDF might contribute to cardiovascular risk reduction through the modulation of specific proteins involved in atherosclerotic disease

ORGANISM(S): Homo sapiens

PROVIDER: GSE129247 | GEO | 2021/12/01

REPOSITORIES: GEO

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Project description:Delayed graft function (DGF) is associated with a reduced long-term graft survival. Ischemia-reperfusion damage and donors' features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the role of recipients' characteristics in the development of DGF to discover early genomics biomarkers in peripheral blood mononuclear cells (PBMC) in order to identify patients at risk. We prospectively enrolled 932 kidney graft recipients from 466 donors for both kidneys. A total of 226 recipients experienced DGF. Among the 466 donors, 290 couples of recipients both patients presented with early graft function (EGF, group A), 50 couples experienced DGF (group B) and 126 couples of recipients were discordant as one presented DGF and the other promptly recovered graft function (group C). In group C we randomly selected 10 couples of DGF/EGF recipients. Peripheral blood mononuclear cells (PBMC) were harvested before transplantation; their transcriptomic profile was investigated by a microarray approach and microarray results were validated by qPCR in an independent group (DGF n=25; EGF n=25). In the whole study group, DGF was independently associated with both donors’ and recipient’s features. Moreover, group A, B and C presented significant differences in both donors’ and recipients’ characteristics. In group C of patients, DGF was significantly associated with body mass index, dialysis modality and number of mismatches. Two-hundred and seventy-three genes were differentially expressed before transplantation in discordant EGF/DGF patients of group C. Their main biological functions were immune dysfunction and inflammation. Among the differentially expressed genes, we observed a significant increase in the expression of CCR2, the MCP-1 receptor, in DGF patients. CCR-2 and MCP-1 up-regulation was confirmed in an independent cohort of patients. Our results suggest that recipients' clinical and immunological features, potentially modulated by dialysis modality, are associated with the development of DGF independently of donors' features.

Project description:Abstract Introduction Understanding a tumor's immune context is paramount in the fight against cancer. Oral melanoma in dogs serves as an excellent translational model for human immunotherapy. However, additional study is necessary to comprehend the immune landscape of dog oral melanomas, including their similarity to human melanomas in this context. Methods This retrospective study utilizes formalin-fixed paraffin-embedded (FFPE) tissue samples to analyze RNA sequences associated with oral melanoma in dogs. Nanostring Technologies was used for conducting RNA sequencing. The focus is on understanding the differences between melanoma tumors restricted to the oral cavity (OL) and the same primary oral tumors with a history of metastasis to the lymph nodes or other organs (OM). Normal buccal mucosa samples are also included as a normal tissue reference. Results In the OM patient group, gene signatures exhibit significant changes relative to the OL patient group, including significantly decreased expression of S100, BRAF, CEACAM1, BCL2, ANXA1, and tumor suppressor genes (TP63). Relative to the OL tumors, the OM tumors had significantly increased expression of hypoxia-related genes (VEGFA expression), cell mobility genes (MCAM), and PTGS2 (COX2). The analysis of the immune landscape in the OM group indicates a shift from a possible "hot" tumor suppressed by immune checkpoints (PDL1) to significantly heightened expression not only of those checkpoints but also the inclusion of other immune blockades such as PD1 and IDO2. In addition, the OM group had significantly reduced expression of Toll-like receptors (TLR4) and IL-18 relative to the OL group, contributing to the tumor's immune escape. Additionally, signs of immune cell exhaustion are evident in both the OM and OL groups through significantly increased expression of TIGIT relative to normal tissue. Both the OM and OL groups had significantly increased expression of the immune cell marker CD4 expression relative to normal tissue. Further, CD4 expression significantly decreased in OM relative to OL; however, this study cannot determine the specific cell types expressing CD4 in OM and OL tumors. Discussion This preliminary study reports significant changes in gene expression for oral melanoma between canine patients with localized disease relative to those with metastatic disease. In the future, a more in-depth investigation involving immunohistochemistry analysis and single-cell RNA expression is necessary to confirm our findings.

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Down-regulation of atherosclerosis signaling in patients treated with on-line haemodiafiltration may contribute to lower cardiovascular risk in hemodialysis

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