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Background: Vascular smooth muscle cell (VSMC) proliferation plays an important role in the failure of autologous vein grafts. The c-myc gene activation is highly involved in the VSMC proliferation. In this study, we made an attempt to determine whether VSMC proliferation and vein graft restenosis could be attenuated by silencing the c-myc gene with small interference RNA (siRNA). Methods: The effects of c-myc siRNA on VSMCs in vitro were examined both in cell proliferation and c-myc expression. Thirty-two Sprague-Dawley rats underwent autologous jugular vein to carotid artery reverse interposition grafting and were randomly divided in to four groups. Vein grafts were treated with pluronic gel or gel containing a scrambled siRNA or c-myc siRNA and the control group received no treatment. Intimal thickness of the vein grafts was evaluated at 3 wk after the surgery. Results: In vitro, c-myc siRNA inhibited cell proliferation by 40%, reduced c-myc mRNA level by 70%, and c-myc protein level by 50% compared with the controls. In vivo, the c-myc siRNA treatment reduced intimal hyperplasia by 75%. Conclusions: Our data suggested that c-myc siRNA, when given immediately after the surgery, is an effective approach for the prevention of vein graft restenosis. [Copyright &y& Elsevier]

For locally advanced colorectal cancer (CRC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision or complete mesocolic excision is the standard therapeutic strategy, which is key to patient survival. Involvement of the tumor immune microenvironment is a factor that regulates tumor progression and sensitivity to nCRT in CRC. In this study, we aimed to identify the effect of heat-shock protein 70 (HSP70)/toll-like receptor-2 (TLR-2) on mFOLFOX sensitization for CRC. A total of 22 patients with advanced CRC who had received neoadjuvant mFOLFOX were enrolled and classified into the mFOLFOX-insensitive or -sensitive group, according to the tumor regression grade. The abundance of immune infiltrates was significantly higher in the post-operative pathological specimens of the mFOLFOX-insensitive group, as compared to those of the mFOLFOX-sensitive group. After transcriptome sequencing, differentially expressed genes between the two groups were annotated to inflammatory and immune responses using Gene Ontology (GO) analysis, and the TLR signaling pathway was analyzed using Kyoto Encyclopedia of Genes and Genomes pathway analysis. Significantly higher expression levels of HSP60, HSP70, HSP90, and TLR-2 in the mFOLFOX-insensitive group were detected using immunofluorescence assays. TIMER2.0 platform was introduced to further narrow the scope of HSP70 (HSPA6 or HSPA7) and TLR-2, which exhibited positive correlations with dendritic cells, Tregs, or CD4+ T cells and negative correlations with CD3+ or CD8+ T cells, implying that HSP70/TLR-2 activation mediates immunosuppressive cells to counteract CD8+ T cells, which may be a novel target of CRC treatment. A promising synergistic effect of mFOLFOX combined with a TLR-2 inhibitor was observed in vivo in mouse allograft models, which could be partly rescued by recombinant HSP70 protein. Immunohistochemical staining of allografts and immunofluorescence assays of clinical specimens corroborated the regulatory effects of the immune microenvironment. In summary, HSP70/TLR-2 activation can regulate the tumor immune microenvironment of CRC and further remodel its sensitivity to mFOLFOX. However, the specific mechanisms remain unclear and require further investigation. This study is expected to provide a new direction for the clinical treatment of CRC. [ABSTRACT FROM AUTHOR]