Study of tumor necrosis factor receptor in the inflammatory bowel disease

Ulcerative colitis(UC)and Crohn’s disease(CD)are part of Inflammatory Bowel Diseases(IBD)and have pathophysiological processes such as bowel necrosis and enteric neurons and enteric glial cells.In addition,the main inflammatory mediator is related to the tumor necrosis factor-alpha(TNF-α).TNF-αis a mediator of the intestinal inflammatory processes,thus being one of the main cytokines involved in the pathogenesis of IBD,however,its levels,when measured,are present in the serum of patients with IBD.In addition,TNF-αplays an important role in promoting inflammation,such as the production of interleukins(IL),for instance IL-1βand IL-6.There are two receptors for TNF as following:The tumor necrosis factor 1 receptor(TNFR1);and the tumor necrosis factor 2 receptor(TNFR2).They are involved in the pathogenesis of IBD and their receptors have been detected in IBD and their expression is correlated with disease activity.The soluble TNF form binds to the TNFR1 receptor with,and its activation results in a signaling cascade effects such as apoptosis,cell proliferation and cytokine secretion.In contrast,the transmembrane TNF form can bind both to TNFR1 and TNFR2.Recent studies have suggested that TNF-αis one of the main pro-inflammatory cytokines involved in the pathogenesis of IBD,since TNF levels are present in the serum of both patients with UC and CD.Intravenous and subcutaneous biologics targeting TNF-αhave revolutionized the treatment of IBD,thus becoming the best available agents to induce and maintain IBD remission.The application of antibodies aimed at neutralizing TNF-αin patients with IBD that induce a satisfactory clinical response in up to 60%of patients,and also induced long-term maintenance of disease remission in most patients.It has been suggested that anti-TNF-αagents inactivate the pro-inflammatory cytokine TNF-αby direct neutralization,i.e.,resulting in suppression of inflammation.However,anti-TNF-αantibodies perform more complex functions than a simple blockade.

Acute heart failure as an adverse event of tumor necrosis factor inhibitor therapy in inflammatory bowel disease:A review of the literature

Tumor necrosis factor inhibitors(anti-TNFs)are widely used therapies for the treatment of inflammatory bowel diseases(IBD);however,their administration is not risk-free.Heart failure(HF),although rare,is a potential adverse event related to administration of these medications.However,the exact mechanism of development of HF remains obscure.TNFαis found in both healthy and damaged hearts.Its effects are concentration-and receptor-dependent,promoting either cardio-protection or cardiomyocyte apoptosis.Experimental rat models with TNFαreceptor knockout showed increased survival rates,less reactive oxygen species formation,and improved diastolic left ventricle pressure.However,clinical trials employing anti-TNF therapy to treat HF had disappointing results,suggesting abolishment of the cardioprotective properties of TNFα,making cardiomyocytes susceptible to apoptosis and oxidation.Thus,patients with IBD who have risk factors should be screened for HF before initiating anti-TNF therapy.This review aims to discuss adverse events associated with the administration of anti-TNF therapy,with a focus on HF,and propose some approaches to avoid cardiac adverse events in patients with IBD.

Investigation of tumor necrosis factor receptor -p55expression in human colorectal cancer

Objective:To investigatetheclinicalsignificanceof tumornecrosisfactorreceptor-p55(TNFR-p55)expression anditsrelationshipwiththeclinicalpathologyandDukes’classificationof humancolorectalcancer.Methods:SABCimmuno-histochemistrymethodwasusedto examineTNFR-p55expressionin91specimensof colorectalcancer,81surroundingmu-cosasof thetumorsand13normaltissues.Results:TNFR-p55expressionincolorectalcancerwas significantlyhigher than thatinthesurroundingmucosaandnormaltissues,anditwassignificantlyhigherinthesurroundingmucosathaninnormal tissue.TNFR-p55was inverselycorrelatedto serousmembraneinvasionandlymphnodemetastasisof colorectalcancers.TNFR-p55expressioninDukes’A andB stageswassignificantlyhigherthanthatof C stage.Conclu sion:TNFR-p55expres-sionwasimportantto determinethedegreeof malignancyandassessinvasiondepth,lymphnodemetastasisandDukes’clas-sificationincolorectalcancer.

Association between genetic variations in tumor necrosis factor receptor genes and survival of patients with T-cell lymphoma

The prognosis of T-cell lymphoma (TCL) has been shown to be associated with the clinical characteristics of patients. However, there is little knowledge of whether genetic variations also affect the prognosis of TCL. This study investigated the associations between single nucleotide polymorphisms(SNPs) in tumor necrosis factor receptor superfamily(TNFRSF) genes and the survival of patients with TCL. A total of 38 tag SNPs in 18 TNFRSF genes were genotyped using Sequenom platform in 150 patients with TCL. Kaplan-Meier survival estimates were plotted and significance was assessed using log-rank tests. Cox proportional hazard models were used to analyze each of these 38 SNPs with adjustment for covariates that might influence patient survival, including sex and international prognostic Index score. Hazard ratios (HRs) and their 95% confidence intervals(CIs) were calculated. Among the 38 SNPs tested, 3 were significantly associated with the survival of patients with TCL. These SNPs were located at LTβR (rs3759333C>T) and TNFRSF17(rs2017662C>T and rs2071336C>T). The 5-year survival rates were significantly different among patients carrying different genotypes and the HRs for death between the different genotypes ranged from 0.45 to 2.46. These findings suggest that the SNPs in TNFRSF genes might be important determinants for the survival of TCL patients.

Increased tumor necrosis factor receptor 1 expression in human colorectal adenomas

AIM: To determine the expression statuses of tumor necrosis factor (TNF)-α, its receptors (TNF-R) and downstream effector molecules in human colorectal adenomas. METHODS: We measured the serum concentrations of TNF-α and its receptors in 62 colorectal adenoma patients and 34 healthy controls. The protein expression of TNF-α, TNF-R1, TNF-R2 and downstream signals of the TNF receptors, such as c-Jun N-terminal kinase (JNK), nuclear factor-κ B and caspase-3, were also investigated in human colorectal adenomas and in normal colorectal mucosal tissues by immunohistochemistry. Immunofluorescence confocal microscopy was used to investigate the consistency of expression of TNF-R1 and phospho-JNK (p-JNK). RESULTS: The serum levels of soluble TNF-R1 (sTNF-R1) in adenoma patients were significantly higher than in the control group (3.67 ± 0.86 ng/mL vs 1.57 ± 0.72 ng/mL, P < 0.001). Receiver operating characteristic analysis revealed the high diagnostic sensitivity of TNF-R1 measurements (AUC was 0.928) for the diagnosis of adenoma, and the best cut-off level of TNF-R1 was 2.08 ng/mL, with a sensitivity of 93.4% and a specificity of 82.4%. There were no significant differences in the serum levels of TNF-α or sTNF-R2 between the two groups. Immunohistochemistry showed high levels of TNF-R1 and p-JNK expression in the epithelial cells of adenomas. Furthermore, a high incidence of co-localization of TNF-R1 and p-JNK was identified in adenoma tissue. CONCLUSION: TNF-R1 may be a promising biomarker of colorectal adenoma, and it may also play an important role in the very early stages of colorectal carcinogenesis.

Choroid plexus tumor necrosis factor receptor 1:a new neuroinflammatory piece of the complex Alzheimer's disease puzzle

Due to the aging of the population and despite the enormous scientific effort,Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine.Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease.Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2,but that also regulates several brain functions in health and disease.However,clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results,partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1,but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials.We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer's disease patients,signaling via tumor necrosis factor receptor 1.In agreement with this,choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models.Interestingly,both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation,choroidal morphology and cognitive functioning.Here,we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in(early) Alzheimer's disease,and the consequences this might have on the disease progression.As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade,the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline.

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia

AIM：To examine the association of genetic polymorphisms（-308）G/A TNFα,（＋250）A/G Ltα,（＋36）A/G TNFR1,（＋1663）A/G TNFR2 with the development of primary open angle glaucoma（POAG）among people in Central Russia.METHODS：The study sample included 443 individuals,of which 252 patients with POAG and 191 individuals in the control group.Genotyping of（-308）G/A TNFα,（＋250）A/G Ltα,（＋36）A/G TNFR1,（＋1663）A/G TNFR2 was performed using polymerase chain reaction.The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables andχ2with the Yates’s correction for continuity and odds ratios（OR）with95%confidence intervals（CI）.RESULTS：Allele（-308）G TNFα（Р=0.01,OR=1.78,95%CI1.12-2.85）was identified as a risk factor for POAG.Homozygotes（-308）AA TNFαare at a lowest risk for development of the disease（Р=0.01,OR=0.0005）.The following combination of genetic variants of cytokines were associated with a reduced risk of POAG：（＋1663）A TNFR2 and（＋250）G Ltα（OR=0.34）CONCLUSION：Genetic polymorphisms（-308）G/A TNFα,（＋250）A/G Ltα,（＋1663）A/G TNFR2 associated with the development of POAG in the population of Central Russia.

Correlation of tumor necrosis factor receptor superfamily 13B variation with sporadic intracranial aneurysm and clinical characteristics in Han Chinese populations

BACKGROUND： Inflammatory reaction correlates with sporadic intracranial aneurysm （IA）. Variation of tumor necrosis factor receptor superfamily 13B （TNFRSF13B）, an inflammatory mediator receptor, may associate with IA. OBJECTIVE： To explore the relationship between TNFRSF13B gene and sporadic IA, as well as the clinical characteristics of sporadic IA. DESIGN, TIME AND SETTING： Case-control study of genetic association was performed at the Experimental Technology Center of China Medical University from November 2006 to January 2008. PARTICIPANTS： A total of 367 patients with IA, confirmed by three-dimensional computed tomography angiography, magnetic resonance angiography, digital subtraction angiography, and neuro surgery, were admitted to the Department of Neurosurgery, First Affiliated Hospital of China Medical University from 2006 to 2007, and were selected as the case group. All patients were Han, with no family history of IA. In addition, a total of 396 non-lA patients were selected as control subjects. METHODS： Peripheral vein blood was harvested to extract whole blood genomic DNA. Genotyping and TNFRSF13B single nucleotide polymorphism （SNP） rs11078355 G〉A allele polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationship of TNFRSF13B SNP rs11078355 G〉A polymorphisms to IA and IA clinical characteristics were analyzed using the chi-square and two-sided test. MAIN OUTCOME MEASURES： TNFRSF13B SNP rs11078355 G〉A genotype distribution. RESULTS： In the IA patients, TNFRSF13B SNP rs11078355 G〉A genotype frequency was significantly increased （X2 = 16.306, odds ratio = 1.881,95% confidence interval = 1.382 2.560, P 〈 0.001）. In IA patients aged 〉 65 years, the frequency of TNFRSF13B SNP rs11078355 GA ＋ AA genotype was significantly greater than the GG genotype （X2 = 26.604, odds ratio = 5.248, 95% confidence interval = 2.662 10.345, P 〈 0.001）. CONCLUSION： The TNFRSF13B gene may associate with sporadic IA in Han Chinese populations In elderly patients, allele A may be an independent risk factor for IA, in addition to senile diseases, such as hypertension and diabetes mellitus.

Increase of tumor necrosis factor receptor 1 expression in women with unexplained early spontaneous abortion

Objective: To investigate membrane tumor necrosis factor receptor 1 protein expression level in decidua and concentration of soluble tumor necrosis factor receptor 1 in serum in women with unexplained early spontaneous abortion, threatened abortion, and compare the levels with healthy pregnant women. Methods: Thirty-seven women with unexplained early spontaneous abortion, 27 women with threatened abortion, and 34 healthy pregnant women undergoing artificial abortion of pregnancy at 6 - 10 weeks of gestation were selected. Decidual samples were collected when women were undergoing artificial abortion, and blood samples were collected at the same time. The level of membrane tumor necrosis factor receptor 1 in decidua was detected by flow cytometer, and the concentration of soluble tumor necrosis factor receptor 1 in sera was measured with an enzyme-linked immunosorbent assay. Results: The percentages of membrane tumor necrosis factor receptor 1 positive decidual cells were 16.42 ± 7.10 Mean ± SD for women with unexplained early spontaneous abortion and 13. 14 ± 6.30 for healthy pregnant women ( P < 0.05). Serum concentration of soluble tumor necrosis factor receptor 1 was significantly higher in women with unexplained early spontaneous abortion than in healthy pregnant women and in women with threatened abortion, and no difference was found between healthy pregnant women and women with threatened abortion. Conclusion: Women with unexplained early spontaneous abortion present significantly higher expression of tumor necrosis factor receptor 1 than healthy pregnant women, suggesting that over-expression of tumor necrosis factor receptor 1 may contribute to the development of early spontaneous abortion.

Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice

BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies.The inflammatory cytokine tumor necrosis factor alpha(TNF-α)is important for the progression of liver disease.TNF signaling via TNF receptor 1(TNFR1)has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.AIM To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH.METHODS NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes(TNFR1ΔHEP)and their wild-type littermates(TNFR1fl/fl).Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding.After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight,liver steatosis,liver fibrosis and markers of liver inflammation.RESULTS Obesity,liver injury,inflammation,steatosis and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice.However,Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance.CONCLUSION Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH.However,improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.

The interleukin-1 receptor antagonist (IL-1-Ra) and soluble tumor necrosis factor receptor I (sTNF RI) in periodontal disease

The course and severity of periodontitis can be significantly affected by bacterial virulence as well as host immunity dysfunction. Periodontal tissue destruction has been proved to result from cascade of cytokines synthesized by reactive cells upon stimulation by pathogenic bacteria and lipopolysaccharides within their cell membranes. The clinical use of genetically programmed cells, producing substances blocking IL-1, based on recombinant IL-1 antagonist, as well as cytokines activating fibroblasts and osteoblasts to regenerate the destroyed periodontal tissue could prove alternative to the conventional treatment. Another cytokine of interest in respect to periodontitis ethiopathogenesis is soluble tumor necrosis factor receptor I (sTNF RI). Observation of soluble TNF receptors as physiologic inhibitors of TNF led to its administration in therapeutic process as well as in therapy selected cases of aggressive periodontitis.

Effects of liraglutide on soluble tumor necrosis factor receptor in patients with diabetic nephropathy

Objective:To observe the effects of Liraglutide combined with sequential dialysis on soluble tumor necrosis factor receptor in patients with diabetic nephropathy.Methods: A total of 110 patients with early diabetic nephropathy who had been seeking treatment in the hospital between December 2016 and December 2017 were selected and according to the random number table method, these patients were randomly divided into two groups, with 55 cases in each group. Patients in the control group were given conventional symptomatic treatment such as hypoglycemic therapy, whereas the observation group was treated with Liraglutide based on the conventional symptomatic treatment given to the control group. The renal function, blood glucose metabolism level, serum indexes, vascular endothelial function and adverse drug reactions were compared between the two groups.Results: After treatment, the levels of 24 hUpor, UAER and Scr in the two groups were both shown to be lower than those before treatment, and the levels in the observation group were shown to be lower than those in the control group, with the differences being statistically significant. After treatment, the levels of PBG, FPG, HOMA-IR , HbA1c and FIns in the two groups were both significantly lower than before treatment, and the levels of PBG, FPG, HOMA-IR , HbA1c and FIns in the observation group were shown to be lower than those in the control group, where the differences were statistically significant. After treatment, the levels of TNF-α, sTNFR1 and hs-CRP in the two groups were significantly reduced than before treatment, and the levels in the observation group were shown to be significantly lower than the control group, with statistically significant differences. After treatment, the NO levels in both groups were significantly increased and ET-1 level significantly reduced than before treatment, and the NO level in the observation group was shown to be higher and the ET-1 level lower than the control group, where the difference was statistically significant.Conclusion: Liraglutide is with higher safety for patients with diabetic nephropathy, which can effectively improve their renal function and blood glucose, enhance insulin sensitivity, reduce the levels of inflammatory factors, and improve the endothelial function.

Effects of hemoperfusion combined with sequential dialysis on soluble tumor necrosis factor receptor in patients with diabetic kidney disease

Objective: To observe the effects of hemoperfusion combined with sequential dialysis on soluble tumor necrosis factor receptor in patients with diabetic kidney disease. Methods:A total of 100 patients with diabetic kidney disease who had been seeking treatment in the hospital between May 2015 and July 2017 were selected, and then according to the random number table method, these patients were divided into a control group and an observation group, with 50 cases in each group. The control group was treated with hemodialysis only, whereas the observation group was given hemoperfusion combined with sequential dialysis for treatment. The changes of soluble tumor necrosis factor receptor, oxidant factor and metabolic indexes after 12 weeks of treatment were compared between the two groups. Results: After treatment, the metabolic indexes in the observation group were shown to be lower than the control group, the levels of soluble tumor necrosis factor receptor related indexes in the former group were lower than the control group, and the level of oxidative stress indicators in the former group was shown to be better than the control group, where the differences were statistically significant. Conclusion: For patients with diabetic kidney disease, hemoperfusion combined with sequential dialysis is with significant clinical curative effects, which can effectively relieve their oxidative stress, better control the blood glucose level, significantly improve their renal function and significantly reduce the level of soluble tumor necrosis factor receptor.

Effects of Irbesartan and Metformin on tumor necrosis factor receptor and monocyte chemotactic protein 1 in patients with early diabetic nephropathy

Objective: To explore the effect of Irbesartan and Metformin on tumor necrosis factor receptor 1 and monocyte chemoattractant protein-1 in patients with early diabetic nephropathy. Methods: A total of 162 patients with early diabetic nephropathy who had been admitted to the Hospital between February 2017 and February 2018 were randomly assigned into a Metformin group, an Irbesartan group, and a combination therapy group. The Metformin group were treated with oral Metformin, those in the Irbesartan group were given oral Irbesartan for treatment, and the combination therapy group was treated with Metformin combined with Irbesartan. After 3 months of continuous treatment, the levels of sTNFR1, high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, glucose metabolism index, proteinuria, and serum creatinine levels in the two groups were compared. Results:After treatment, the levels of sTNFR1, sICAM-1, hs-CRP, and MCP-1 in the three groups decreased compared with those before treatment, and the levels in the combination therapy group were all shown to be lower than those of the Metformin group and the Irbesartan group, with statistically significant differences (P<0.05). The levels of glycosylated hemoglobin and fasting blood glucose in the three groups were significantly lower than before treatment, and those in the combination therapy group were lower than the Metformin group and Irbesartan group, where the difference was statistically significant (P<0.05). The 24-hour urinary protein quantification, urinary albumin excretion rate, and serum creatinine in the combination therapy group were lower than those in the Metformin group and in the Irbesartan group, where the differences were statistically significant (P<0.05). Conclusion: The effects of metformin combined with irbesartan on early diabetic nephropathy patients were significant, which can effectively reduce the levels of serum sTNFR1 and MCP-1, relieve inflammation and improve glucose metabolism and proteinuria level.

Effect of Llinagliptin on tumor necrosis factor receptor and monocyte chemoattractant protein-1 in patients with diabetic nephropathy

Objective:To explore the effect of Linagliptin on tumor necrosis factor receptor and monocyte chemoattractant protein-1 in patients with diabetic nephropathy.Methods: A total of 98 patients with diabetic nephropathy admitted to the Hospital from January 2017 to September 2018 were enrolled. The patients were divided into two groups according to the random double-blind method, with 49 cases in each group. The control group was treated with Metformin, whereas the experimental group was treated with Linagliptin plus Metformin. After 3 months of continuous treatment, the renal function [urinary albumin excretion rate, 24 h urine protein quantitation and serum creatinine], glycolipids metabolic levels [glycated hemoglobin, fasting blood glucose, total cholesterol and triglycerides], monocyte chemoattractant protein-1, tumor necrosis factor receptor, high-sensitivity C-reactive protein, and adverse reactions were compared between the two groups.Results:After 3 months of treatment, the levels of UAER, 24 h Upor and Scr in the experimental group were shown to be lower than those in the control group, and the difference was statistically significant. After 3 months of treatment, the levels of HbA1c, FPG, TC and TG in the experimental group were shown to be lower than the control group, and the difference was statistically significant. After 3 months of treatment, the levels of MCP-1, sTNFR1 and hs-CRP in the experimental group were lower than those in the control group, and the difference was statistically significant. There was no significant difference in incidence of adverse reactions between the two groups.Conclusion: For patients with diabetic nephropathy, Linagliptin is with higher safety, which can help improve their glycolipids metabolic levels and renal function, reduce the inflammatory response and the levels of MCP-1 and sTNFR1, and yet incur fewer adverse reactions.

肺癌组织中ERO1L、TNFRSF4的表达与患者免疫功能、炎症反应因子及预后的关系

目的探究肺癌组织中内质网氧化物蛋白(ERO1L)、肿瘤坏死因子受体4(TNFRSF4)的表达与肺癌患者免疫功能、炎症反应因子及其预后的关系。方法选取2018年7月~2020年7月于本院进行手术治疗的108例肺癌患者,收集术中留取的癌组织和癌旁组织标本。采用qRT-PCR检测ERO1L和TNFRSF4的mRNA相对表达量;使用免疫组织化学法检测ERO1L和TNFRSF4蛋白表达情况,分析二者表达水平与患者临床病理特征的关系,采用Kaplan-Meier法分析ERO1L、TNFRSF4蛋白表达水平与患者预后的关系。肺癌患者预后生存率的影响因素采用Cox多因素分析。结果肺癌患者癌组织中ERO1L mRNA表达水平显著高于癌旁组织,TNFRSF4 mRNA表达水平显著低于癌旁组织(P<0.05);肺癌组织中ERO1L蛋白高表达率显著高于癌旁组织,TNFRSF4蛋白高表达率显著低于癌旁组织(P<0.05)。ERO1L蛋白高表达组患者CD3^(+)、CD4^(+)显著低于低表达组(P<0.05),IL-1β、IL-6、TNF-α显著高于低表达组(P<0.05);TNFRSF4蛋白高表达组患者CD3^(+)、CD4^(+)显著高于低表达组,IL-1β、IL-6、TNF-α显著低于低表达组(P<0.05)。ERO1L高表达组患者3年累积生存率显著低于低表达组(Log rankχ^(2)=6.100,P=0.014),TNFRSF4高表达组患者3年累积生存率显著高于低表达组(Log rankχ^(2)=11.296,P=0.001)。肺癌组织的低分化、淋巴结转移、TNM分期为Ⅲ-Ⅳ期、ERO1L高表达、TNFRSF4低表达是影响患者生存率的危险因素。结论肺癌组织中ERO1L、TNFRSF4表达与患者免疫功能、炎症因子以及预后具有一定关系。

Increased serum and ascitic fluid levels of soluble tumor necrosis factor-p55 in hepatocellular carcinoma patients

Objective: To explore the levels of serum and ascitic fluid soluble tumor necrosis factor receptor-p55 (sTNFR-p55) and understand their clinical implication in primary hepatocellular carcinoma (HCC) patients. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to examine the levels of sTNFR-p55 in the serum and ascitic fluid in 25 HCC patients and 25 patients with liver cirrhosis (LC). The test was also performed on the serum of 30 healthy subjects who served as control group. To assess the clinical effects of increased serum concentrations of sTNFR-p55, four parameters were analyzed by logistic regression. Results: Serum and ascitic fluid levels of sTNFR-p55 in HCC patients were significantly higher than those in LC patients and controls (P=0. 001). No significant difference was found between serum sTNFR-p55 levels in the latter 2 groups (P = 0. 19), and positive correlation between serum levels of sTNFR-p55 and that in ascitic fluid was noted in the 2 patient groups (r=1. 000, P<0. 001). Levels of the sTNFR-p55 positively correlated with TBIL and AFP in the peripheral blood of HCC patients (r=0. 524, P = 0. 01 and r=0. 234, P = 0. 03, respectively). Conclusion: Increased levels of sTNFRs-p55 in the serum and ascitic fluid could reflect the abnormal immune status of the HCC patients and may help predict the development of the tumor.

Effect of tumor necrosis factor-α on ventricular arrhythmias in rats with acute myocardial infarction in vivo

Acute myocardial infarction （AMI） is an acute cardiovascular emergency. This study was undertaken to assess the effect of tumor necrosis factor-a （TNF-a） on ventricular arrhythmias induced byAMI in rats in vivo. Two hundred and forty male Wistar rats were randomized into a sham- operation group, an AMI group, and a recombinant human tumor necrosis factor receptor：Fc fusion protein（rhTNFR：Fc） group. Acute anterior wall myocardial infarction was produced in the AMI group by ligating the left anterior descending coronary artery （LAD）, and there was no ligation but operation in the sham-operation group. The rhTNFR：Fc group was treated with rhTNFR：Fc（10 mg/kg）, a TNF-a antagonist, 24 hours before LAD ligation. The spontaneous and induced programmed electrical stimulation ventricular arrhythmias were recorded at baseline and 10 minutes, 20 minutes, 30 minutes, 60 minutes, 3 hours, 6 hours and 12 hours after ligation. At the same time the protein and mRNA expression levels of TNF-a among different groups were detected by histochemistry and real-time fluorescent quantitative PCR. Expression of TNF-a increased markedly from 10 minutes after infarction, peaked at 20-30 minutes, and returned to baseline gradually in the AMI group and rhTNFR：Fc group. The time- windows of spontaneous and induced ventricular arrhythmias were similar. Compared with the AMI group, the rhTNFR：Fc group showed a lesser expression of TNF-a protein and a lower incidence of ventricular arrhythmias （P〈0.05）. There was no obvious change in the sham-operation group. The expression of TNF-a induced by AMI could contribute to the onset of ventricular arrhythmias.

血清PKN1、TNFRSF4、DDIT4预测子宫内膜癌患者淋巴结转移及预后的临床价值

目的探讨血清蛋白激酶N1(PKN1)、肿瘤坏死因子受体超家族成员4(TNFRSF4)、DNA损伤诱导转录因子4(DDIT4)预测子宫内膜癌患者淋巴结转移和预后的临床价值。方法选取2019年10月至2021年10月于唐山市妇幼保健院治疗的180例子宫内膜癌患者为子宫内膜癌组。另选取同期在该院治疗的子宫良性疾病患者180例作为良性疾病组,以及在该院体检的180例健康者作为健康组。子宫内膜癌组根据是否发生淋巴结转移分为淋巴结转移组42例和无淋巴结转移组138例,按照随访结果将患者分为预后不良组和预后良好组。比较各组血清PKN1、TNFRSF4、DDIT4水平,Logistic模型分析患者预后的影响因素,以及绘制受试者工作特征曲线分析血清PKN1、TNFRSF4、DDIT4对患者预后的预测价值。结果与健康组比较,子宫内膜癌组、良性疾病组血清PKN1、DDIT4水平升高,血清TNFRSF4水平降低,差异有统计学意义(P<0.05)。淋巴结转移组血清PKN1、DDIT4水平高于无淋巴结转移组,TNFRSF4水平低于无淋巴结转移组,差异有统计学意义(P<0.05)。预后不良组低分化程度、淋巴脉管间隙浸润阳性、肌层浸润≥1/2的占比高于预后良好组,差异有统计学意义(P<0.05)。预后不良组血清PKN1、DDIT4水平高于预后良好组,TNFRSF4水平低于预后良好组,差异有统计学意义(P<0.05)。血清PKN1、DDIT4、LVSI、肌层浸润是子宫内膜癌预后的危险因素,血清TNFRSF4为子宫内膜癌预后的保护因素(P<0.05)。血清PKN1、TNFRSF4、DDIT4联合对子宫内膜癌患者预后状况的预测效能高于各血清指标单独预测(P<0.05)。结论血清PKN1、TNFRSF4、DDIT4与子宫内膜癌患者淋巴结转移及预后有关,且对患者预后的预测效能较高。