A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

Magnesium lithospermate B acts against dextran sodiumsulfate-induced ulcerative colitis by inhibiting activation of the NRLP3/ASC/Caspase-1 pathway

This study aimed to observe the therapeutic effects of magnesium lithospermate B on acute and chronic colitis induced by dextran sodiumsulfate (DSS) and the role of inflammasome complex (NOD-like receptor protein, NLRP; apoptosis-associated speck-like protein containing, ASC; caspase-1). Establishment of acute and chronic colitis models were by using 5% DSS oral administration in BALB/C male mice. Magnesium lithospermate B (240 mg/kg body weight) was given by subcutaneous injection. Samples were collected for biomarker assay, histological examination, immunohistochemical evaluation and western blot. There was obvious increase in TNF-α level and NLPR3, ASC, and caspase-1 expressions in acute and chronic colitis groups compared with the normal control. Significant decrease of the tumor necrosis factor-α level and the expressions of NLPR3, ASC, and caspase-1 were observed after treatment with magnesium lithospermate B. This study showed that magnesium lithospermate B could be used to treat acute and chronic colitis by inhibiting the activation of the NLRP3/ASC/Caspase-1 pathway.     

miR-451a suppresses the development of breast cancer via targeted inhibition of CCND2

Extensive research has indicated that miRNAs are crucial for the occurrence and progression of cancers. miR-451a, involved in breast cancer (BC), is one of the miRNAs. This study focused on the mechanism by which miR-451a regulates BC. The levels of miR-451a in BC tissues and cell lines were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan‒Meier analysis showed that this was intimately related to the patient's overall survival rate. Functional experiments revealed the negative effects of miR-451a on the abilities of BC cells to multiply (tested by Cell Counting Kit-8), migrate (tested by wound healing assay), and invade (tested by Transwell assay) and its positive effects on apoptosis (tested by flow cytometry). Western blotting indicated that the expression of tumor-related proteins was affected by miR-451a. Moreover, in vivo experiments suggested that tumor growth was clearly restrained by an miR-451a agonist in a xenograft tumor model. Bioinformatic analysis indicated that miR-451a directly targeted Cyclin D2 (CCND2), as demonstrated by the luciferase reporter assay. An opposite change in the level of CCND2 and miR-451a in BC was indicated by qRT-PCR, western blotting, and immunohistochemistry. Subsequently, functional experiments and western blotting analysis confirmed that CCND2 accelerated BC progression, which was regulated by miR-451a. Cumulatively, research on miR-451a may be valuable for BC treatment.     

热疗对肿瘤免疫微环境中免疫细胞及免疫相关细胞因子的影响

随着对肿瘤热疗和肿瘤免疫微环境(TIME)的深入研究,近年来热疗对TIME的作用越来越受到学者们的重视。本文就目前国内外研究进展,对热疗与TIME中几类主要免疫细胞和免疫相关细胞因子的影响及作用机制作一综述。全面而透彻的了解热疗对TIME的调控作用,有助于为肿瘤治疗提供新的思路和方法。     

Evaluation of mutagenic,recombinogenic and carcinogenic potential of (+)-usnic acid in somatic cells of Drosophila melanogaster

The main of this study was to evaluate the mutagenic and carcinogenic potential of (+) – usnic acid (UA), using Somatic Mutation and Recombination Test (SMART) and the test for detecting epithelial tumor clones (wts) in Drosophila melanogaster. Larvae from 72 ± 4 h from Drosophila were fed with UA (5.0, 10.0 or 20.0 mM); urethane (10.0 mM) (positive control); and solvent (Milli-Q water, 1% Tween-80 and 3% ethanol) (negative control). ST cross produced increase in total mutant spots in the individuals treated with 5.0, 10.0 or 20.0 mM of UA. HB cross produced spot frequencies in the concentration of 5.0 mM that were higher than the frequency for the same concentration in the ST cross. In the highest concentrations the result was negative, which means that the difference observed can be attributed, in part, to the high levels of P450, suggesting that increasing the metabolic capacity maximized the toxic effect of these doses. In the evaluation of carcinogenesis using the wts test, the results obtained for the same concentrations of UA show a positive result for the presence of tumors when compared to the negative control. We conclude that UA has recombinogenic, mutagenic and carcinogenic effects on somatic cells in D. melanogaster.     

六西格玛在肿瘤标志物质量目标选择上的应用

目的应用6σ理论对肿瘤标志物项目的分析性能进行评价，并初步确定各项目的质量目标。 方法收集本实验室2018年1至12月室内质控数据和国家卫生健康委临床检验中心室间质量评价结果，以生物学变异导出的质量规范和国家室间质量评价标准作为允许总误差(TEa)计算6项肿瘤标志物的σ水平，并依据质量目标选择流程图和肿瘤标志物分析性能验证图评价肿瘤标志物的分析性能，进而为肿瘤标志物选择合适的质量目标。 结果应用不同层级的生物学变异导出的质量规范和国家室间质量评价标准，肿瘤标志物项目的σ水平存在显著差异；依据质量目标选择流程图：选择生物学变异导出的"适当的"质量规范作为CA125项目的质量目标，选择生物学变异导出的"最低的"质量规范作为t-PSA、CEA、AFP、CA199和CA153项目的质量目标。 结论6σ能够客观评价肿瘤标志物的分析性能，并为实验室质量目标的选择提供重要的参考价值。     

放射性心脏损伤动物模型相关实验研究进展

当利用放射线对胸部恶性肿瘤进行治疗时，位于纵隔的心脏会不可幸免受到照射，从而诱发放射性心脏损伤（radiation-induced heart disease, RIHD）。随着手术以及放化疗技术的提升，肿瘤患者生存时间得到延长，使得RIHD这一放疗远期并发症被越来越多的报道。因此，学者们对于RIHD的研究逐渐升温。目前国内外学者关于该疾病尚未形成统一的认识，临床上缺乏有效阻止其发生的方法。动物模型研究可为临床该疾病治疗及预防提供可靠证据，为此本文回顾分析近年来放射性心脏损伤动物模型实验研究情况，旨在为后续实验开展及临床应用提供参考。     

程序性细胞死亡蛋白配体1在结直肠癌免疫治疗中的研究进展

近年来,抗程序性细胞死亡蛋白1(PD-1)药物在转移性结直肠癌患者错配修复缺陷治疗中的成功使得该疾病的免疫治疗得以重视。然而,失配修复缺陷的结直肠癌患者仅占结肠癌患者的一部分。目前的研究重点是将免疫治疗应用到疾病的早期阶段,包括辅助一线治疗,以及检测免疫检查点抑制剂治疗的敏感性。然而,哪些患者能够从该免疫治疗中获益仍是值得商榷的问题,因为这类药物具有自身免疫毒性。PD-1的配体之一程序性细胞死亡蛋白配体1(PD-L1)作为一种检测生物标记物,其检测可以通过免疫组化来实现。但其免疫组化的检测存在一些混杂因素,包括应用不同的检测抗体、不同的免疫组化临界值、肿瘤组织的采集准备方式不同、处理过程的不同、原发与继发的活检标本、肿瘤源性或诱导的PD-L1表达,以及肿瘤与免疫细胞的染色等。目前的结果表明,免疫组化检测肿瘤过表达PD-L1的患者在接受抗PD-L1治疗时临床效果更理想,而有些低表达的肿瘤也对该治疗有所缓解,这使PD-L1的分析中存在复杂性。阐明宿主免疫系统与肿瘤微环境的机制则能够更好地解释针对PD-L1药物是否让患者受益。     

胃癌侵袭性对患者血清E-钙粘附素浓度的影响

探讨E-钙粘附素(E-Cd)对人胃癌侵袭性的作用。方法:应用酶联免疫吸附方法测定29例胃癌患者血清可溶性E-Cd浓度。结果:胃癌组明显高于对照组(P<0.01),浸润组或有淋巴结转移组明显高于膨胀组或无淋巴结转移组(P<0.01～0.05),切除瘤体后上述各组的血清E-Cd浓度均明显下降(P<0.01～0.05)。结论:血清可溶性E-Cd浓度可能与人胃癌的生长方式和淋巴结转移密切相关。