Tumour necrosis factor alpha inhibitors: screening for tuberculosis infection in inflammatory bowel disease

Tumour necrosis factor (TNF) alpha inhibitors such as infliximab are becoming more widely used for the treatment of selected patients with Crohn's disease, rheumatoid arthritis, and other inflammatory disorders. TNFalpha inhibitors increase the risk of serious infections, including tuberculosis. Screening for and treatment of latent tuberculosis infection before infliximab therapy reduces the risk of developing active tuberculosis. New blood tests that measure interferon gamma production are an alternative to traditional tuberculin skin testing and offer some significant advantages over skin testing for screening of latent tuberculosis infection.     

肿瘤坏死因子抑制剂的研究进展

类风湿性关节炎（rheumatoid arthritis,RA）、节段性肠炎（Crohn′s disease,CD）等疾病具有类似的发病机制。肿瘤坏死因子（tumor necrosis factor,TNF）在这些疾病的发生发展中具有非常重要的作用。TNF分子在细胞因子免疫调节网络中位于中枢环节,是重要的炎症介质,过量的TNF导致炎症的发生。目前上市的TNF抑制剂种类繁多,治疗效果显著。然而随着TNF抑制剂广泛应用,这类药物的安全性逐渐受到重视。本文综述了TNF与疾病关系、上市的TNF蛋白抑制剂分子结构、临床应用等方面,重点关注药物潜在的不良反应,并对近期新型TNF抑制剂的研究开发进行总结。     

非异羟肟酸类肿瘤坏死因子转化酶抑制剂的研究进展

类风湿性关节炎属自身免疫性疾病，全球约有1%～2%的人群受该病困扰。肿瘤坏死因子转化酶(TACE)是治疗类风湿性关节炎的潜在的靶点，当前TACE抑制剂主要分为异羟肟酸类和非异羟肟酸类抑制剂两类。本文对近几年来出现的新型非异羟肟酸类TACE小分子抑制剂进行介绍，使读者对当前高活性、高选择性非异羟肟酸类TACE抑制剂的发展和设计研究现状有个总体的了解。     

我国类风湿关节炎患者应用肿瘤坏死因子抑制剂现况调查

目的:了解我国类风湿关节炎(rheumatoid arthritis,RA)患者应用肿瘤坏死因子(tumor necrosis factor,TNF)抑制剂的现状以及影响其应用的因素。方法:采用多中心现况调查问卷调查的方法,记录入选者的一般情况和应用TNF抑制剂的情况,计算患者应用TNF抑制剂的费用,分析我国TNF抑制剂的应用现状及影响其应用的相关因素。结果:2009年7月至2010年11月期间,共有全国范围内的21家大型医院风湿免疫科就诊的1 095位RA患者完成问卷,其中112位患者应用了TNF抑制剂(infliximab,商品名类克或etanercept,商品名益赛普)进行治疗,占总研究人群的10.2%(其中益赛普81例,占7.4%;类克26例,占2.4%;两种制剂都用过者5例,占0.5%)。应用类克疗程<3个月及3～6个月者均为38.1%,益赛普疗程<3个月及3～6个月者分别占38.5%和25.0%。应用类克疗程<3个月、3～6个月及6～9个月者的健康评估问卷(health assessment question-naire,HAQ)评分分别为1.1、0.5、0.1,益赛普的相应评分分别为1.3、1.0、0.3。应用类克疗程<3个月、3～6个月及6～9个月的费用分别为24 525.0、69 300.0、96 800.0元,益赛普的费用分别为7 394.8、9 158.6、54 910.9元。应用类克疗程<3个月、3～6个月及6～9个月的患者的间接经济损失分别为365.6、0、158.9元,益赛普分别为2 158.4、288.5、180.1元。出现过敏和感染的比例在应用益赛普者均为3.5%,在应用类克者均为6.5%。Logistic回归分析显示,受教育程度是影响TNF抑制剂应用的主要相关因素。结论:在我国大型医院就诊的RA患者中约有10%应用过TNF抑制剂,其病情随应用TNF抑制剂的疗程延长而减轻,治疗总费用随用药疗程延长而增加,但间接经济损失随疗程延长而减少,主要不良反应为过敏和感染,受教育程度是影响其应用的主要相关因素。     

Tumour necrotic factor (TNF) in the pathogenesis of liver necrosis in viral hepatitis and strategy for its prevention and treatment

We determined serum and peripheral blood mononuclear cell (PBM) TNF activity in 8 healthy donors and 47 patients with hepatitis by using 3H-thymidine release method of Maennel et al. The serum TNF levels were significantly increased in chronic active hepatitis and subacute hepatic failure (13.8 +/- 6.3, and 19.4 +/- 3.9). Patients with serum bilirubin more than 10 mg/ml showed a higher serum TNF level than those with lower serum bilirubin. A significant elevation of TNF level was also observed in patients with positive endotoxemia or concurrent bacterial or viral infections. Experimental liver injury in Wistar rats induced by galactosamine (GLN) and LPS produced marked increase of serum TNF level and submassive liver necrosis. It is noteworthy that normal serum TNF and markedly ameliorated liver injury were observed in rats that received combined treatment with GLN, LPS and hepatopoietin (HPN), a low molecular peptide extracted from suckling porcine liver. In vitro, HPN also significantly suppressed TNF activity when it was co-incubated with PBM and LPS. An encouraging result was observed in preliminary clinical trial of HPN for the treatment of subacute liver failure. It suggests that Serum TNF appears to play an important role in the pathogenesis of liver injury from viral hepatitis and HPN seems to be a protection in liver injury against TNF activity.     

血清TNF—α变化在小儿全身炎症反应综合征中的作用

目的 探讨肿瘤坏死因子（TNF－α）在全身炎症反应综合征（SIRS）中的作用。方法 用酶联免疫吸附法（ELISA）检测46例感染性疾病患儿（其中SIRS 26例、非SIRS20例）及20例健康体检儿的血清TNF－α含量。结果 SIRS组患儿血清TNF－α含量明显高于非SIRS组与正常对照组（P＜0．01），且血清TNF－α含量随符合SIRS诊断标准数目的增多而增高。结论 TNF－α是SIRS中的主要炎性介质，它对脏器的损害起关键作用。     

肿瘤坏死因子α与妊娠高血压综合征发病关系的研究

探讨肿瘤坏死因子α在妊娠高血压综合征发病中的作用。方法对４１例妊高征患者（妊高征组）和１７例正常妊娠妇女（正常妊娠组）进行了下列研究：（１）测定血浆中ＴＮＦα水平,观察胎盘血管内皮细胞的形态学变化;（２）利用其血清对离体培养的脐血管内皮细胞作用,观察其损情表现;（３）利用４００Ｕ／ｍｌ的人重组ＴＮＦα对离体培养的脐血管内皮细胞作用,比较ＴＮＦα和妊娠高征孕妇血清对内皮细胞的损伤作用。结果（１）妊娠     

TNF对小鼠急性肝坏死的双重作用

研究肿瘤坏死因子致小鼠坏死作用的规律，探讨ＴＮＦ对肝脏保护的的诱导作用及机理。应用重组从ＴＮＦα对经Ｄ－氨基半乳糖增敏的雄性ＢＡＬＢ／ｃ小鼠行腹腔注射，诱发急性肝坏死模型。另一实验中，先单独用ｒｈＴＮＦ－α预处理小鼠，然后在不同时间再予ＧａｌＮ＋ｒｈＴＮＦ－α，观察小鼠损害发生情况。     

肿瘤坏死因子与充血性心力衰竭

肿瘤坏死因子（TNF）是一类促炎症细胞因子，现已证明TNF可由成熟的心肌细胞分泌产生，参与充血性心力衰竭（CHF）的病理生理过程，在抑制心肌收缩性，促进心肌重构，增加内皮、心肌细胞凋亡中起重要作用，针对CHF的抗TNF治疗研究尚处于尝试阶段，有待进一步评价。     

肿瘤坏死因子与子宫内膜异位症相关性研究

目的:探讨肿瘤坏死因子TNF-α、TNF-β与子宫内膜异位症的相关性。方法:选取子宫内膜异位症患者87例作为研究组,将同期体检结果健康的女性92例作为对照组。分别检测两组血清肿瘤坏死因子(TNF-α、TNF-β)水平,并进行相关性分析。结果:研究组TNF-α、TNF-β水平与对照组比较明显增高,差异有统计学意义(P<0.05);研究组Ⅲ~Ⅳ期TNF-α、TNF-β水平明显高于Ⅰ~Ⅱ期,P<0.05;两组分泌期、增生期分别比较,P<0.05;分泌期与增生期组内比较,差异无统计学意义(P>0.05);实验组患者术后与术前比较,TNF-α、TNF-β水平均明显降低(P<0.05);Ⅲ~Ⅳ期患者术后与术前比较,TNF-α、TNF-β水平下降更明显(P<0.001);EMT患者血清TNF-α、TNF-β与AFS-r评分呈直线相关(r值分别为0.88、0.76,P均<0.05)。结论:子宫内膜异位症患者血清肿瘤坏死因子水平明显增高,术后血清肿瘤坏死因子水平明显降低,其血清水平与病变程度有一定相关性。     

Tumor necrosis factor alpha affect hydrocortisone expression in mice adrenal cortex cells mainly through tumor necrosis factor alpha-receptor 1

Background  Tumor necrosis factor alpha (TNF-α) is important in promoting relative adrenal insufficiency (RAI) due to systemic inflammatory response syndrome (SIRS). We identified the TNF-α receptor involved in the inhibition of adrenal corticotrophin (ACTH)-stimulated hydrocortisone release by studying the expression of TNF-α receptors in adrenal cortex Y1 cells and the effect of downregulating TNF receptors on ACTH-stimulated hydrocortisone release.

Methods  We used real-time PCR and immunocytochemistry to evaluate the expression of TNF receptors on Y1 cells. TNF-receptor 1 (TNF-R1) DNA fragments corresponding to the short hairpin RNA (shRNA)-sequences were synthesized and cloned into pcDNA^TM 6.2-GW/EmGFP expression vector. Knockdown efficiency of TNF-R1 expression was evaluated in miRNA transfected and mock-miRNA transfected Y1 cells by quantitative real-time PCR (Q-PCR). Hydro- cortisone expression levels were determined in TNF-R1-knockdown and control Y1 cells treated with TNF-α and ACTH.

Results  Mouse adrenal cortex Y1 cells were positive for type I TNF-R1, but not type II TNF-receptor (TNF-R2). Blocking TNF-R1 expression resulted in loss of TNF-α-mediated inhibition of ACTH-stimulated hydrocortisone expression, suggesting a role for the TNF-R1 related signaling pathway in ACTH-stimulated hydrocortisone synthesis.

Conclusion  The inhibitory effect of TNF-α on ACTH-stimulated hydrocortisone synthesis was mediated via TNF-R1 in adrenal cortex.

     

Tumour length is an independent prognostic factor of esophageal squamous cell carcinomas

 

Background  The latest version of the American Joint Committee on Cancer (AJCC) TNM staging system has not comprehensively evaluated the impact of tumour length on survival in patients with esophageal squamous cell carcinoma. Our study explored the relationship between tumour length and clinicopathological characteristics as well as long-term survival.

Methods  All 202 cases of esophageal resections done from January 1, 2004 to December 31, 2008 in Huashan Hospital, Fudan University were reviewed and followed up.

Results  Patients with tumour length ≥3 cm were related to more advanced tumour stage (χ²=55.9, P <0.001), more metastatic lymph nodes (χ²=14.6, P <0.001), increased metastatic lymph node ratio (χ²=16.1, P <0.001) and worse overall TNM stage (χ²=48.1, P <0.001). Univariate and multivariate analyses indicated that tumour length was a significant prognostic risk factor (95% CI 0.235–0.947, P=0.035).  Subgroup analyses disclosed that tumour length was a valuable prognostic predictor in patients with lower T stage, absence of metastatic lymph nodes and lower TNM stage.

Conclusions  Esophageal tumour length is a predictive factor for long-term survival especially for lower tumour stage, absence of metastatic lymph nodes and lower TNM stage patients. Tumour length should be incorporated in the staging system as an important grouping factor for better prognostic evaluation.

     

肿瘤坏死因子α主要通过其受体1作用于鼠肾上腺皮质Y1细胞皮质醇的表达

背景和目的：全身炎症反应综合征时肿瘤坏死因子α（TNF-α）在导致肾上腺相对不足中起着重要的作用。为探讨TNF-α是通过其哪个受体来抑制皮质醇释放,我们研究肾上腺皮质Y1细胞TNF-α受体表达情况及其受体阻断与皮质醇释放间的关系。 方法: 应用RT-PCR和免疫细胞化学方法来评估Y1细胞中的TNF受体的表达。 合成与TNF受体1（TNF-R1）DNA片段相对应的shRNA序列,并克隆于表达载体pcDNA™6.2-GW/EmGFP中,然后转染Y1细胞。采用实时定量PCR（Q-PCR）检测转染shRNA或 mock-shRNA Y1细胞TNF-R1表达的阻断率,同时对转染的Y1细胞加入TNF-α 和 ACTH,检测Y1细胞皮质醇的表达水平。 结果： RT-PCR和免疫细胞化学方法,在肾上腺皮质Y1细胞检测到TNF-R1的表达,而检测不到TNF-R2的表达。shRNA 转染的Y1细胞中TNF-R1 mRNA表达明显低于mock shRNA转染的Y1细胞（P<0.05）。通过shRNA阻断TNF-R1表达,TNF-α就不能抑制ACTH促皮质醇的合成,shRNA 转染Y1细胞的皮质醇表达水平明显高于mock-shRNA Y1细胞(P<0.05)。 结论：我们的结果显示,在肾上腺皮质中,TNF-α抑制ACTH促皮质醇的合成是通过TNF-R1受体。     

肿瘤坏死因子的基因多态性和脓毒症易感性

位于人类主要组织相容性复合体Ⅲ类基因区内的TNF基因有多态性，这些多态性与个体对脓毒症的易感性、发展、预后密切相关。本文综述TNF基因多态性与脓毒症的关系，发现可以寻找判断预后的基因标志，还可以为脓毒症的免疫基因治疗奠定基础.     

凝血因子Ⅹa抑制剂专利技术分析

抗凝血药物被广泛用于血栓栓塞性疾病的预防和治疗。近年来,凝血因子Ⅹa抑制剂成为新型抗凝血药物的研发热点,但目前上市的抗凝药物仍存在长期使用会增加出血风险等不良反应。本文通过文献检索,对凝血因子Ⅹa抑制剂相关专利申请状况进行了分析,以百时美施贵宝公司和广东东阳光药业有限公司作为该领域重点企业代表,对其专利申请发展路线进行梳理,总结凝血因子Ⅹa抑制剂化合物的改造位点和研发方向,以期能够为国内研发机构和相关企业对凝血因子Ⅹa的新药研发、专利保护以及知识产权布局提供有益的参考和建议。