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.     

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.     

A trip through the signaling pathways of melanoma

Many cellular signaling pathways are involved in the development of cancer. Depending on the tumor entity, the nature as well as the mode of activation can differ. Some signaling pathways frequently show changes as all tumor cells have to fulfill some basic requirements such as independence from growth factors or insensitivity against apoptosis. In this review, the possibilities of a tumor to manipulate signaling pathways to reach these goals are exemplified based on an archetypical melanoma cell. In addition, new therapeutic options based on the knowledge of signaling pathways will be discussed.     

38例非小细胞癌脑转移的综合治疗分析

目的探讨非小细胞肺癌脑转移的有效治疗方案.方法对38例非小细胞肺癌脑转移患者进行头部、胸部放疗并结合全身化疗的综合治疗.结果近期疗效的有效率为76.3%(29/38).神经精神症状缓解率73.7%(28/38),肺部症状缓解率60.5%(23/38).1年生存率31.5%(12/38),2 a生存率10.5%(4/38).结论合理采用综合治疗可有效提高非小细胞肺癌脑转移患者的生存率.     

绝经前后T1期乳腺癌患者临床特征的分析

目的:分析T1期(肿瘤直径<2cm)原发性乳腺癌女性患者绝经前后在肿瘤大小、病理分类、淋巴结转移率和数目。方法:常规病理检验以及应用免疫组化、HE法分别测定绝经前乳腺癌患者和绝经后乳腺癌患者者的ER、PR。结果:两组患者在肿瘤大小上无明显差异,但绝经前乳腺癌患者浸润导管癌的百分比为 84. 7%,绝经后乳腺癌患者的浸润导管癌百分比为 62. 2%,经χ2 检验,P<0. 01。两组淋巴结转移率分别为 39. 3%和 25. 5%,经χ2 检验,P<0. 01。两组ER和PR阳性伴淋巴结转移的比例经χ2 检验,P<0. 05。结论:绝经前乳腺癌患者和绝经后乳腺癌患者在病理分类、淋巴结转移率及数目、ER、PR阳性伴淋巴结转移上有显著性差异。对于T1原发性乳腺癌患者不论有无淋巴结转移,均应行癌肿切除伴Ⅰ、Ⅱ级淋巴结清扫。     

旋转铰链型与单纯铰链型膝关节肿瘤假体置换的临床比较研究

目的 研究膝关节肿瘤保肢手术两种假体置换的术后效果及其比较.方法 随访我院1999年6月2006年3月治疗的72例膝关节肿瘤患者，失访9例，余63例中40例采用单纯铰链型假体置换(A组)，23例采用旋转铰链型假体置换（B组）63例随访时间9月~8年平均3年9个月，按MSTS膝关节评分标准、ambulation scores、关节屈伸度及感染、复发、手术时间进行评估。结果：A组：手术时间2.6625±0.3362h，复发5例，转移死亡3例，感染2例； B组：手术时间2.5722±0.2878h，复发3例，转移死亡2例，感染2例 。B组1例术后发生旋转轴聚乙烯轴套断裂关节脱位，再次手术更换轴套后未再出现并发症，两组无假体松动病例。两组手术时间无统计学意义；去除复发及转移死亡病例后,剩50例, A组32例， MSTS评分平均23.0/30分。 B组18例，MSTS评分平均23.7/30分。两组MSTS评分p>0.05，无统计学意义；ambulation scores各分项总分均p<0.05，有统计学意义．两组关节伸直时为0°或接近0°,屈曲度A组119.3750±17.49°，B组125.0000±15.34°，无统计学意义（p>0.05）。结论： 1. 按ambulation scores标准，在步行舒适度和快速步行方面，旋转型铰链假体置换组与单纯铰链型假体置换比较有统计学意义；2.而MSTS标准则未能体现出两组术后功能方面的统计学意义，因此ambulation scores较MSTS评分更灵敏，更适合对膝关节保肢术后功能评价；3.两组在手术时间、术后临床屈伸功能及并发症方面，如复发、感染，未见显著差别，单纯铰链型不会出现脱位，而可旋转铰链型假体有脱位的可能。     

hTERT启动子调控hNIS基因介导肺癌细胞碘摄取和131I治疗的实验研究

目的 构建含人端粒酶反转录酶(hTERT)核心启动子调控的人钠/碘同向转运体(hNIS)基因重组腺病毒,并靶向转染至肺癌A549细胞中特异性表达.探讨hTERT启动子调控的hNIS基因介导放射性碘治疗肿瘤的可能性.方法 应用AdEasy系统构建重组腺病毒Ad-hTERT-hNIS,同时构建巨细胞病毒(CMV)启动子调控的hNIS重组腺病毒Ad-CMV.hNIS作为阳性对照,不含hNIS的重组腺病毒Ad-CMV作为阴性对照.应用反转录.聚合酶链反应(RT-PCR)方法验证hTERT在转染肿瘤细胞中的转录活性,摄碘实验检测表达的hNIS蛋白功能,细胞克隆形成实验评价131I对转染肿瘤细胞的毒性作用.结果 成功构建重组腺病毒Ad-hTERT-hNIS、Ad-CMV-hNIS及Ad-CMV,并经PCR验证正确.RT-PCR证实hNIS cDNA能从Ad-hTERT-hNIS转染的细胞中扩增出来.Ad-hTERT-hNIS和Ad-CMV-hNIS转染的肺癌A549细胞摄碘能力比阴性对照组Ad-CMV转染的细胞分别提高了23和31倍,且摄碘能力可以被NaClO4抑制.Ad-hTERT-hNIS和Ad-CMV-hNIS转染的肺癌A549细胞均可被131I杀死,2组细胞成活率分别为(31.2±1.45)%和(23.6±4.08)%,而阴性对照组和未转染病毒组分别为(89.0 ±2.99)%和(91.2 ±4.63)%.结论 hTERT启动子调控的hNIS重组腺病毒转染肿瘤细胞后,应用131I治疗有望成为一种新的基因靶向治疗手段.