The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor

Tumors often are associated with a low extracellular pH, which induces a variety of cellular events. However, the mechanisms by which tumor cells recognize and react to the acidic environment have not been fully elucidated. T-cell death-associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor that is overexpressed in various tumors and tumor cell lines. In this report, we show that TDAG8 on the surface of tumor cells facilitates tumor development by sensing the acidic environment. Overexpression of TDAG8 in mouse Lewis lung carcinoma (LLC) cells enhanced tumor development in animal models and rendered LLC cells resistant to acidic culture conditions by increasing activation of protein kinase A and extracellular signal-regulated kinase in vitro. Moreover, shRNA-mediated knockdown of endogenous TDAG8 in NCI-H460 human non-small cell lung cancer cells reduced cell survival in an acidic environment in vitro as well as tumor development in vivo. Microarray analyses of tumor-containing lung tissues of mice injected with TDAG8-expressing LLC cells revealed up-regulation of genes related to cell growth and glycolysis. These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. TDAG8 may represent a therapeutic target for arresting tumor growth.     

人参瓜蒌莪术汤对小鼠lewis肺癌瘤组织微血管密度的影响

目的探讨人参瓜蒌莪术汤对lewis肺癌模型小鼠的治疗作用及机制。方法建立小鼠Lewis肺癌移植瘤模型,分为模型对照组,环磷酰胺对照组,人参瓜蒌莪术汤高、中、低剂量组。在计算抑瘤率的基础上,运用免疫组化法检测瘤组织微血管密度（MVD）。结果人参瓜蒌莪术汤对小鼠Lewis肺癌表现出明显的抑制作用,中剂量组效果最为明显,抑瘤率可达47．88％;人参瓜蒌莪术汤低、中、高剂量组均能明显降低瘤组织微血管密度,与空白对照组相比差异非常显著（P〈0．01）。中剂量组降低瘤组织微血管密度的作用显著强于环磷酰胺阳性对照组（P〈0．01）。结论人参瓜蒌莪术汤具有抑制小鼠Lewis肺癌生长的作用,其作用机制可能与抑制瘤组织中微血管的形成有关。     

康莱特注射液对Lewis肺癌小鼠免疫功能的影响

目的 观察康莱特注射液（KLT）对Lewis肺癌小鼠模型免疫功能的影响。方法 将40只C57BL/6小鼠制成Lewis肺癌模型,随机分为模型组和KLT高、中、低剂量组,每组10只。建模第2天起,KLT高、中、低剂量组每天分别给予腹腔注射KLT 25、12.5、6.25 mL/kg,连续14 d;模型组不予任何处理。第16天,处死小鼠,称取体质量、肿瘤和脾脏质量,计算肿瘤抑制率和脾脏指数;MTT法检测脾脏中T细胞增殖活力;ELISA检测脾细胞中IL-2的表达;Western blot检测脾脏组织中NF-κB和IκBα蛋白的表达。结果 KLT高、中、低剂量组的肿瘤抑制率逐渐降低;KLT高、中剂量组的脾脏指数高于模型组（P<0.05或P<0.01）。与模型组比较,KLT高、中、低剂量组脾脏中T细胞增殖活力明显升高,KLT高、中剂量组脾细胞中IL-2的表达水平明显升高（P<0.05或P<0.01）。与模型组比较,KLT高、中、低剂量组胞核中NF-κB蛋白表达随给药剂量增加而升高;胞质中NF-κB和IκBα蛋白表达随给药剂量增加而下降。结论 KLT在抗肿瘤的同时能通过提高T细胞增殖活力,调节IL-2、NF-κB、IκBα等因子的表达,达到增强机体免疫功能的目的。     

川陈皮素对肺癌的增殖抑制作用及其机制

目的 观察川陈皮素对肺癌的体内外抑瘤作用并初步探讨其机制.方法 应用MTT法检测不同浓度川陈皮素作用对人肺腺癌细胞A549增殖的抑制作用.Western blot检测川陈皮素处理后A549细胞Bcl-2和Bax蛋白的表达情况.彗星电泳检测川陈皮素作用后A549细胞DNA损伤情况.通过C57BL/6小鼠Lewis肺癌模型进行体内抗瘤实验,TUNEL法观察药物作用后的肿瘤细胞凋亡情况,并用免疫组化法检测瘤组织中Bax、Bcl-2和Caspase-9蛋白表达情况.结果 体外实验显示,川陈皮素作用对A549细胞有明显的增殖抑制作用,并且抑制效应随浓度增加而增强;川陈皮素作用A549细胞24 h后,随着作用剂量的加大,Bcl-2蛋白表达下调,而Bax蛋白则表达上调;对细胞DNA具有损伤作用,当达到一定作用剂量和作用时间时可以使A549细胞发生凋亡.体内抑瘤实验表明,川陈皮素高(300 mg/kg)、中(200 mg/kg)、低(100 mg/kg)浓度组对小鼠Lewis肺癌的抑瘤率分别为43.70%、27.59%和20.14%,与对照组相比,差异具有统计学意义(P<0.01);川陈皮素能使Lewis肺癌细胞发生凋亡;使Lewis肺癌组织内Bax和Caspase-9表达上调,Bcl-2表达下调.结论 川陈皮素在体内外均有明显的抑制肿瘤细胞增殖的作用,其作用机制可能与改变Bcl-2/Bax的比值,启动Caspase级联反应相关.     

Circulating KL-6/MUC1 mucin carrying sialyl Lewisa oligosaccharide is an independent prognostic factor in patients with lung adenocarcinoma

MUC1 mucin is frequently observed in adenocarcinomas, and its association with metastasis has been postulated through the interaction between sialyl Lewis oligosaccharides present on this glycoprotein and selectins. Levels of soluble MUC1 recognized by anti-KL-6 monoclonal antibody were also frequently elevated in the sera of lung adenocarcinoma patients. The aim of this study was to demonstrate the presence of KL-6/MUC1 carrying sialyl Lewis(a) oligosaccharide, designated as SLAK, and subsequently evaluate the clinical significance of circulating SLAK in patients with lung adenocarcinoma. We developed a sandwich ELISA system using anti-sialyl Lewis(a) and anti-KL-6 antibodies to detect SLAK, and also measured circulating SLAK levels in 97 healthy controls and 103 patients with lung adenocarcinoma. Circulating SLAK levels were measured in the sera taken before treatment and then were evaluated to clarify whether such levels were related to the clinical outcomes. Levels of circulating SLAK were significantly higher in lung adenocarcinoma patients than in healthy subjects, and a higher serum SLAK level was correlated with the presence of distant metastasis. The overall survival rate for patients with high serum SLAK levels was significantly poorer than that of patients with low serum SLAK levels. The survival analysis restricted to the patients with distant metastasis also showed the same trend. In a multivariate survival analysis in lung adenocarcinoma patients, a high serum SLAK level was indicated as an independent prognostic factor. In conclusion, the circulating SLAK level at diagnosis is useful for predicting a poor prognosis in patients with lung adenocarcinoma.     

Acute superior vena cava obstruction following Ivor–Lewis oesophagectomy

A 53 year old man developed upper body swelling, hypotension, anuria and a metabolic acidosis within 24 h following an Ivor–Lewis oesophagectomy. His co-morbidities included hypertension, hypercholesterolaemia, ischaemic heart disease and he was a smoker. He did not have radiotherapy but had received neo-adjuvant chemotherapy through an in-dwelling right subclavian central venous catheter. Azygous vein ligation during oesophagectomy resulted in acute upper body venous hypertension and signs of hypovolaemic shock which were attributed to undiagnosed thrombotic occlusion of the superior vena cava. The patient was anticoagulated and made a full recovery after a period of stay in intensive care.     

蒲黄水提物对小鼠Lewis肺癌的抑制作用

目的探讨蒲黄水提物对Lewis肺癌荷瘤小鼠的抑瘤作用。方法建立Lewis肺癌小鼠模型，随机分为阴性对照组，氟尿嘧啶注射液组，蒲黄水提物50、100、200rag·kg^-1·d^-1 3个剂量组，每组8只，连续治疗14d后，剥取胸腺、脾脏、肿瘤，称取重量，计算免疫器官指数及抑瘤率，并用流式细胞仪检测肿瘤细胞凋亡率及细胞周期。结果连续灌服给药14d后蒲黄水提物3个剂量，对Lewis肺癌移植瘤的生长具有明显的抑制作用，其中100、200mg·kg^-1·d^-1剂量组有显著性差异（P〈0．05）；流式细胞仪检测各剂量组均出现不同程度的细胞周期阻滞，诱导肿瘤细胞凋亡率分别为：5．73％、20．76％、4．55％。结论蒲黄水提物对Lewis肺癌小鼠移植瘤的生长有一定的抑制作用，在肿瘤的预防及综合治疗中具有一定的应用价值。     

New minimum length requirement for a T cell epitope for experimental allergic neuritis

The bovine P2 protein induces experimental allergic neuritis (EAN) in Lewis rats. Using synthetic peptides representing regions of the P2 protein sequence and P2-specific neuritogenic T cell lines, we have demonstrated that the minimum peptide length requirement for the T cell epitope for EAN is residues 61-70 of the P2 protein having the sequence EISFKLGQEF. Adding a threonine at the NH2 terminus of this peptide reproduces residues 60-70 of the P2 protein sequence and significantly enhances the neuritogenic capability of this peptide.