No abstract

Attenuated Salmonella typhimurium possess the ability to stimulate innate immune responses and preferentially allocate within the solid tumor. These two main characteristics make attenuated Salmonella one of the most attractive vehicles for development of vaccine and also targeted cancer therapies. However, location of Salmonella prevents the process of antigen presentation. Salmonella Type III secretion system can be utilized to circumvent this problem because this system secretes the protein it encoded outside the cells. Heat shock protein 70 (Hsp70) is referred to as an "immunochaperone" for its capacity to elicit tumor-specific adaptive immune responses in the form of Hsp70-TAA (tumor associated antigen) complex. Hsp70 facilitates the cross-presentation of exogenous antigens through its receptor on antigen-presenting cells and therefore activates an antigen-specific cytotoxic T lymphocyte (CTL) response, which can directly contribute to potent anti-tumor immunity. Here, we designed a novel therapeutic vaccine utilizing the type III secretion system and Hsp70 to deliver and present the tumor-specific antigen. This live recombinant bacteria vaccine, when administrated orally, successfully broke the immune tolerance, induced a specific CTL response against tumor cells, and therefore revealed protective and therapeutic effects against generation and growth of B16F10 melanoma in C57BL/6J mice.

Background: Stanford type A aortic dissection (AAD) is a catastrophic disease. An immune infiltrate has been found within the aortic wall of dissected aortic specimens. The recall and activation of macrophages are key events in the early phases of AAD. Herein, the immune filtration profile of AAD was uncovered.Methods: Gene expression data from the GSE52093, GSE98770 and GSE153434 datasets were downloaded from the Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) of each dataset were calculated and then integrated. A protein-protein interaction (PPI) network was established with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the hub genes were identified in Cytoscape. Furthermore, gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of hub genes were performed. Finally, we set GSE52093 and GSE98770 as the training set and GSE153434 as the validation set to assess immune infiltration in AAD using CIBERSORTx and analyzed the correlations between immune cells and hub genes in both the training and validation sets.Results: Sixty-one integrated DEGs were identified. The top 10 hub genes were selected from the PPI network, and 140 biological process (BP) terms and 12 pathways were enriched among the top 10 hub genes. The proportions of monocytes and macrophages were significantly higher in AAD tissues than in normal tissues. Notably, this result was consistent in the training set and the validation set. In addition, we found that among the hub genes, CA9, CXCL5, GDF15, VEGFA, CCL20, HMOX1, and SPP1 were positively correlated with CD14, a cell marker of monocytes, while CA9, CXCL5, GDF15, and VEGFA were positively correlated with CD68, a cell marker of macrophages in the training set. Finally, according to the results of the GO and KEGG analysis of hub genes, we found that the monocyte/macrophage-related genes were involved in immune-inflammatory responses through degradation of the extracellular matrix, endothelial cell apoptosis, hypoxia and the interaction of cytokines and chemokines.Conclusion: The monocyte-macrophage system plays a major role in immune-inflammatory responses in the development of AAD. Several hub genes are involved in this process via diverse mechanisms.

Attenuated salmonella have been reported to be capable of both selectively growing in tumors and expressing exogenous genes for tumor-targeted therapy. As 6-methoxypurine 2′ ′ ′ ′-deoxyriboside (MoPdR) is similar to 6-methylpurine 2′ ′ ′ ′-deoxyriboside in structure, we aimed to evaluate the antitumoral effect of the Escherichia coli purine nucleoside phosphorylase (ePNP) gene, using an attenuated salmonella-mediated delivery system, in combination with MoPdR. A novel mutant serovar Typhimurium (SC36) was used to carry the pEGFP-C1-ePNP vector that contains an enhanced green fluorescent protein and an ePNP gene under the control of the cytomegalovirus promoter. The function of the ePNP expression vector was confirmed in vitro using the enzymic conversion of MoPdR into methoxypurine. We also observed a high bystander effect induced by the ePNP/MoPdR system with a very low proportion ( (1) To resolve these problems, Salmonella enterica serovar typhimurium (S. typhimurium) strains, which are facultative anaerobes, have been considered intriguing candidates because of their selective growth in tumors and essential ability to deliver exogenous genes encoding therapeutic proteins.(2,3) To increase their applicability for treatments, the S. typhimurium strains were first attenuated by purine and other auxotrophic mutations to improve tumor-specific targeting as well as to reduce toxicity.(2-7) Then genetic modification of the salmonella lipid A was carried out to reduce septic shock and the lipid A-attenuated S. typhimurium has been evaluated in a phase I clinical trial. (4,8) Recently, Zhao et al. (9)(10)(11) developed S. typhimurium strains A1 and A1-R and detected real-time imaging of S. typhimurium A1-R-induced exogenous gene expression in vitro using fluorescence microscopy. Experience from clinical trials of cancer gene therapy indicates that no single therapeutic strategy can effectively eradicate a fairly large tumor, whereas combined gene therapy represents a more reliable approach to combat tumor growth. (12,13)

Purpose: Total aortic arch replacement (TAR) with frozen elephant trunk (FET) is the standard operation for treating aortic dissection (AD) patients involving aortic arch with high operative risk due to long circulatory arrest (CA). We used aortic balloon occlusion technique that safely reduced the CA time to 5 min in average and investigated whether it can improve the clinical endpoints. Methods: All patients diagnosed with AD and underwent TAR with FET operation (123 with aortic balloon occlusion and 221 with conventional method) in Fuwai Hospital during August 2017 and February 2019 was reviewed in this retrospective observational study. Results: After propensity score matching, the 30-day mortality of aortic balloon occlusion group and conventional group was 4.88% and 11.38% (P = 0.062), respectively. In multivariate analysis, aortic balloon occlusion is one of the factors that reduced the risk for renal and hepatic injury, shortened postoperative conscious revival time, and reduced red blood cell (RBC) transfusion during operation. Conclusions: The aortic balloon occlusion technique, as a perfusion strategy during operation, could alleviate postoperative complication. This method deserves further attention in future clinical practice for its value in treating patients with higher operative risks.