Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but eviden...Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.展开更多
目的研究程序性细胞死亡蛋白4(programmed cell death protein 4,PDCD4)在脓毒症诱导的急性肾损伤(acute kidney injury,AKI)中的作用机制,以及调控PDCD4表达通过丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAP2K3)和p38...目的研究程序性细胞死亡蛋白4(programmed cell death protein 4,PDCD4)在脓毒症诱导的急性肾损伤(acute kidney injury,AKI)中的作用机制,以及调控PDCD4表达通过丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAP2K3)和p38蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)对脓毒症AKI起到潜在治疗作用。方法用脂多糖(lipopolysaccharide,LPS)刺激人肾小管上皮细胞(HK-2)构建脓毒症AKI细胞模型。进一步用腺病毒介导siRNA和过表达载体抑制和上调AKI细胞模型中PDCD4的表达;CCK-8法检测细胞增殖;用DCFH-DA及激光共聚焦显微镜检测细胞中ROS水平,用总SOD活性检测试剂和MDA检测试剂盒检测细胞中SOD和MDA水平;免疫共沉淀验证PDCD4和MAP2K3之间的蛋白相互作用;TUNEL染色法检测细胞凋亡;RT-qPCR和Western blot检测PDCD4及相关基因的mRNA和蛋白表达水平;ELISA法检测患者血清中炎症相关因子水平。结果LPS诱导可以促进HK-2细胞中PDCD4表达,下调PDCD4可抑制LPS诱导的HK-2细胞的炎症、氧化应激及细胞凋亡。数据库预测及免疫共沉淀证实PDCD4可以与MAP2K3相互作用,且在LPS诱导的HK-2细胞中,MAP2K3表达水平显著增强。MAP2K3过表达和p38 MAPK激动剂可以减轻PDCD4下调对LPS诱导的细胞炎症和氧化应激的影响并抑制细胞凋亡。结论下调PDCD4可以通过抑制MAP2K3和p38 MAPK从而抑制LPS诱导的肾小管上皮细胞的炎症和凋亡。展开更多
Objective:To explore the diagnostic value of PDCD4 on the degree of arterial stenosis in"blood stasis"coronary heart disease.Methods:Select 80 patients with coronary heart disease in the Second Cardiovascula...Objective:To explore the diagnostic value of PDCD4 on the degree of arterial stenosis in"blood stasis"coronary heart disease.Methods:Select 80 patients with coronary heart disease in the Second Cardiovascular Zone of the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine in April 2020,and divide them into the"phlegm toxin"group(n=40)and the"phlegm stasis"group(n=40)based on the dialectics of traditional Chinese medicine.).Record the gender,age,smoking,and alcohol consumption of the subjects between the two groups,and detect their white blood cell count,neutrophil count,platelet count,platelet volume,platelet distribution width,blood creatinine,uric acid,cystatin,and fibrin The expression levels of original,high-sensitivity C-reactive protein,D-dimer,total cholesterol,triglycerides,high-density lipoprotein,low-density lipoprotein,apolipoprotein a,apolipoprotein b,and PDCD4.Multivariate logistic regression analysis was used to screen out the risk factors that affect coronary plaque formation,and the receiver operating characteristic(ROC)curve of each index was established to evaluate the severity of coronary stenosis in patients with stasis coronary heart disease by each index and combined index Diagnostic efficiency.Results:The two groups of patients were tested in terms of gender,age,smoking,drinking,triglycerides,cholesterol,high-density lipoprotein,low-density lipoprotein,apolipoprotein-a,apolipoprotein-b,white blood cell count,neutrophil The cell count,platelet count,platelet volume width and platelet distribution width were not statistically significant(P>0.05);the expression levels of hypersensitivity-C-reactive protein,serum creatinine,cystatin,uric acid and PDCD4 were statistically significant between the two groups Difference(P<0.05),and the corresponding hypersensitivity-C-reactive protein,creatinine,cystatin,uric acid and PDCD4 expression levels in the blood stasis group were higher than those in the phlegm blood stasis group.After multivariate logistic regression analysis,the level of PDCD4 in peripheral blood[OR=31.088,95%CI(2.498,3.869)]was an independent influencing factor of the"stagnation"type of coronary heart disease,and PDCD4 was diagnosed as the"stagnation"type of coronary heart disease The area under the ROC curve(AUC)is 88.6%,95%CI(1.894,2.532)(P=0.29);the level of PDCD4 in peripheral blood is positively correlated with the number and severity of coronary artery disease,the number of coronary artery disease and stenosis The greater the degree,the higher the detection value of PDCD4,(P<0.05).Conclusion:The expression level of PDCD4 in peripheral blood is closely related to the subtype of"stasis toxin"and the severity of coronary vascular stenosis.It can be used as a quantitative diagnostic index for the diagnosis of"stasis toxin"coronary heart disease and the severity of coronary vascular stenosis.展开更多
AIM:To investigate the expression of programmed cell death 4(Pdcd4)tumor suppressor gene in tissue specimen of renal cell carcinoma(RCC),testicular germ cell cancer and penile cancer.METHODS:Pdcd4 expression was studi...AIM:To investigate the expression of programmed cell death 4(Pdcd4)tumor suppressor gene in tissue specimen of renal cell carcinoma(RCC),testicular germ cell cancer and penile cancer.METHODS:Pdcd4 expression was studied using immunohistochemistry in 188 cases of RCC and 28 controls(including 9 oncocytoma);in 74 cases of penile carcinoma(including 17 metastatic tissue samples)and26 controls;in 11 cases of seminoma,in 14 cases of non-seminoma and 5 controls.RESULTS:Control tissues exhibited strong core and cytoplasmatic Pdcd4 staining.In contrast,core and cy-toplasmatic Pdcd4 levels were significantly decreased in cancer tissues.CONCLUSION:Our data support a role for Pdcd4(down-)regulation in urologic tumors.Interestingly,Pdcd4 expression seem to be a potential diagnostic marker for renal or penile tumors.展开更多
目的检测妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)孕妇血清程序性细胞死亡因子4(programmed cell death factor 4,PDCD4)和葡萄糖转运蛋白1(glucose transporter 1,GLUT1)的表达水平,分析二者与孕妇妊娠结局...目的检测妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)孕妇血清程序性细胞死亡因子4(programmed cell death factor 4,PDCD4)和葡萄糖转运蛋白1(glucose transporter 1,GLUT1)的表达水平,分析二者与孕妇妊娠结局的相关性。方法收集巴中市巴州区妇幼保健院产科2018年7月~2020年7月收治的ICP孕妇126例作为研究组,其中轻度ICP组46例,重度ICP组80例,选择同期该院120例健康产检孕妇作为对照组。采用实时荧光定量PCR(qRT-PCR)法测定ICP孕妇血清PDCD4和GLUT1水平,多因素Logistic回归分析影响ICP孕妇妊娠结局的因素,Pearson相关性分析ICP孕妇血清PDCD4和GLUT1水平的相关性。结果与对照组比较,研究组PDCD4(1.36±0.23 vs 1.02±0.21),GLUT1(1.40±0.22 vs 0.99±0.18)水平升高,差异具有统计学意义(t=15.935,12.090,均P=0.000)。重度ICP组PDCD4(1.41±0.25),GLUT1(1.45±0.22)水平显著高于轻度ICP组(1.27±0.20,1.31±0.21),差异具有统计学意义(t=3.246,3.496,均P<0.05)。研究组羊水胎粪污染(20.63%)、自发性早产(7.14%)、产后出血(8.73%)、宫内窘迫(11.90%)等不良妊娠结局的发生率均高于对照组(0.00%,0.83%,0.83%,1.67%),差异均具有统计学意义(χ^(2)=1.049~29.159,均P<0.05);妊娠结局良好组和妊娠结局不良组患者的发病程度(OR=1.109,95%CI=1.035~1.188)、PDCD4(OR=1.428,95%CI=1.013~2.012)以及GLUT1(OR=1.453,95%CI=1.066~1.980)水平差异具有统计学意义(均P<0.05);多因素Logistic回归分析显示,发病程度、PDCD4,GLUT1为ICP孕妇妊娠结局不良的影响因素(Waldχ^(2)==8.738,1.428,1.453;P=0.003,0.041,0.018);Pearson相关性分析显示,ICP孕妇血清PDCD4与GLUT1水平呈正相关(r=0.460,P<0.05)。结论PDCD4,GLUT1在ICP孕妇血清中表达均上调,二者呈正相关,是ICP孕妇妊娠结局不良的影响因素。展开更多
BACKGROUND SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting(SWI/SNF)complexes and plays an essential role in oncogenesis.SMARCA4-deficient malignancies arising from the gastrointestinal t...BACKGROUND SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting(SWI/SNF)complexes and plays an essential role in oncogenesis.SMARCA4-deficient malignancies arising from the gastrointestinal tract are rare and have a poor prognosis.There is no standard treatment for advanced and undifferentiated SMARCA4-deficient duodenal malignancies.Programmed death 1(PD-1)antibodies,known as immune checkpoint inhibitor antibodies,potentially play a role in treating gastrointestinal tract malignancies.CASE SUMMARY We present two patients with SMARCA4 deficiency and TP53 gene mutation in advanced undifferentiated carcinomas of the duodenum.For both patients,SMARCA4 deficiency was confirmed by immunohistochemical staining for the BRG1 protein,while TP53 gene mutations were observed via next-generation sequencing.Both patients were administered chemotherapy in combination with an anti-PD-1 antibody.The two patients exhibited completely different responses to treatment and had different prognoses.Case 1 experienced rapid progression after PD-1 infusion and chemotherapy,case 2 experienced a remarkable response after treatment,and the progression-free survival was more than 6 months.CONCLUSION This study described our clinical and pathological observations of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum.PD-1 combined with chemotherapy showed a certain efficacy in select patients,providing options for treating these highly malignant tumors.Patients with liver metastases had a worse prognosis than did those with only lymph node metastasis.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity...BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies.However,ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma(HCC)patients due to the complex pathological mechanisms of HCC.AIM To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model,aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.METHODS The levels of PD-1 and TIM-3 on CD4+and CD8+T cells from tumor tissues,ascites,and matched adjacent tissues from HCC patients were determined with flow cytometry.An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody(mAb)and/or anti-PD-1 mAb.Tumor growth in each group was measured.Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors.The percentage of CD4+and CD8+T cells in tissue samples from mice was tested with flow cytometry.The percentages of PD-1+CD8+,TIM-3+CD8+,and PD-1+TIM-3+CD8+T cells was accessed by flow cytometry.The levels of the cytokines including tumor necrosis factor alpha(TNF-α),interferon-γ(IFN-γ),interleukin(IL)-6,and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.RESULTS We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+and CD8+T cells isolated from tumor tissues and ascites of HCC patients.TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight,while combined blockade had more substantial anti-tumor effects than individual treatment.Then we showed that combined therapy increased T cell infiltration into tumor tissues,and downregulated PD-1 and TIM-3 expression on CD8+T cells in tumor tissues.Moreover,combined treatment facilitated the production of T cell effector cytokines TNF-α and IFN-γ,and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues.Thus,we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.CONCLUSION Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+T cell-mediated antitumor immune responses.展开更多
文摘Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.
文摘目的研究程序性细胞死亡蛋白4(programmed cell death protein 4,PDCD4)在脓毒症诱导的急性肾损伤(acute kidney injury,AKI)中的作用机制,以及调控PDCD4表达通过丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAP2K3)和p38蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)对脓毒症AKI起到潜在治疗作用。方法用脂多糖(lipopolysaccharide,LPS)刺激人肾小管上皮细胞(HK-2)构建脓毒症AKI细胞模型。进一步用腺病毒介导siRNA和过表达载体抑制和上调AKI细胞模型中PDCD4的表达;CCK-8法检测细胞增殖;用DCFH-DA及激光共聚焦显微镜检测细胞中ROS水平,用总SOD活性检测试剂和MDA检测试剂盒检测细胞中SOD和MDA水平;免疫共沉淀验证PDCD4和MAP2K3之间的蛋白相互作用;TUNEL染色法检测细胞凋亡;RT-qPCR和Western blot检测PDCD4及相关基因的mRNA和蛋白表达水平;ELISA法检测患者血清中炎症相关因子水平。结果LPS诱导可以促进HK-2细胞中PDCD4表达,下调PDCD4可抑制LPS诱导的HK-2细胞的炎症、氧化应激及细胞凋亡。数据库预测及免疫共沉淀证实PDCD4可以与MAP2K3相互作用,且在LPS诱导的HK-2细胞中,MAP2K3表达水平显著增强。MAP2K3过表达和p38 MAPK激动剂可以减轻PDCD4下调对LPS诱导的细胞炎症和氧化应激的影响并抑制细胞凋亡。结论下调PDCD4可以通过抑制MAP2K3和p38 MAPK从而抑制LPS诱导的肾小管上皮细胞的炎症和凋亡。
基金Regional Fund Project of National Natural Science Foundation of China(No.8196086181460712)+1 种基金Guangxi Science Key Research and Development Program(No.AB19110006)Guangxi Support Project for Graduate Education Innovation(No.YCXJ2021052)。
文摘Objective:To explore the diagnostic value of PDCD4 on the degree of arterial stenosis in"blood stasis"coronary heart disease.Methods:Select 80 patients with coronary heart disease in the Second Cardiovascular Zone of the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine in April 2020,and divide them into the"phlegm toxin"group(n=40)and the"phlegm stasis"group(n=40)based on the dialectics of traditional Chinese medicine.).Record the gender,age,smoking,and alcohol consumption of the subjects between the two groups,and detect their white blood cell count,neutrophil count,platelet count,platelet volume,platelet distribution width,blood creatinine,uric acid,cystatin,and fibrin The expression levels of original,high-sensitivity C-reactive protein,D-dimer,total cholesterol,triglycerides,high-density lipoprotein,low-density lipoprotein,apolipoprotein a,apolipoprotein b,and PDCD4.Multivariate logistic regression analysis was used to screen out the risk factors that affect coronary plaque formation,and the receiver operating characteristic(ROC)curve of each index was established to evaluate the severity of coronary stenosis in patients with stasis coronary heart disease by each index and combined index Diagnostic efficiency.Results:The two groups of patients were tested in terms of gender,age,smoking,drinking,triglycerides,cholesterol,high-density lipoprotein,low-density lipoprotein,apolipoprotein-a,apolipoprotein-b,white blood cell count,neutrophil The cell count,platelet count,platelet volume width and platelet distribution width were not statistically significant(P>0.05);the expression levels of hypersensitivity-C-reactive protein,serum creatinine,cystatin,uric acid and PDCD4 were statistically significant between the two groups Difference(P<0.05),and the corresponding hypersensitivity-C-reactive protein,creatinine,cystatin,uric acid and PDCD4 expression levels in the blood stasis group were higher than those in the phlegm blood stasis group.After multivariate logistic regression analysis,the level of PDCD4 in peripheral blood[OR=31.088,95%CI(2.498,3.869)]was an independent influencing factor of the"stagnation"type of coronary heart disease,and PDCD4 was diagnosed as the"stagnation"type of coronary heart disease The area under the ROC curve(AUC)is 88.6%,95%CI(1.894,2.532)(P=0.29);the level of PDCD4 in peripheral blood is positively correlated with the number and severity of coronary artery disease,the number of coronary artery disease and stenosis The greater the degree,the higher the detection value of PDCD4,(P<0.05).Conclusion:The expression level of PDCD4 in peripheral blood is closely related to the subtype of"stasis toxin"and the severity of coronary vascular stenosis.It can be used as a quantitative diagnostic index for the diagnosis of"stasis toxin"coronary heart disease and the severity of coronary vascular stenosis.
文摘AIM:To investigate the expression of programmed cell death 4(Pdcd4)tumor suppressor gene in tissue specimen of renal cell carcinoma(RCC),testicular germ cell cancer and penile cancer.METHODS:Pdcd4 expression was studied using immunohistochemistry in 188 cases of RCC and 28 controls(including 9 oncocytoma);in 74 cases of penile carcinoma(including 17 metastatic tissue samples)and26 controls;in 11 cases of seminoma,in 14 cases of non-seminoma and 5 controls.RESULTS:Control tissues exhibited strong core and cytoplasmatic Pdcd4 staining.In contrast,core and cy-toplasmatic Pdcd4 levels were significantly decreased in cancer tissues.CONCLUSION:Our data support a role for Pdcd4(down-)regulation in urologic tumors.Interestingly,Pdcd4 expression seem to be a potential diagnostic marker for renal or penile tumors.
文摘目的检测妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)孕妇血清程序性细胞死亡因子4(programmed cell death factor 4,PDCD4)和葡萄糖转运蛋白1(glucose transporter 1,GLUT1)的表达水平,分析二者与孕妇妊娠结局的相关性。方法收集巴中市巴州区妇幼保健院产科2018年7月~2020年7月收治的ICP孕妇126例作为研究组,其中轻度ICP组46例,重度ICP组80例,选择同期该院120例健康产检孕妇作为对照组。采用实时荧光定量PCR(qRT-PCR)法测定ICP孕妇血清PDCD4和GLUT1水平,多因素Logistic回归分析影响ICP孕妇妊娠结局的因素,Pearson相关性分析ICP孕妇血清PDCD4和GLUT1水平的相关性。结果与对照组比较,研究组PDCD4(1.36±0.23 vs 1.02±0.21),GLUT1(1.40±0.22 vs 0.99±0.18)水平升高,差异具有统计学意义(t=15.935,12.090,均P=0.000)。重度ICP组PDCD4(1.41±0.25),GLUT1(1.45±0.22)水平显著高于轻度ICP组(1.27±0.20,1.31±0.21),差异具有统计学意义(t=3.246,3.496,均P<0.05)。研究组羊水胎粪污染(20.63%)、自发性早产(7.14%)、产后出血(8.73%)、宫内窘迫(11.90%)等不良妊娠结局的发生率均高于对照组(0.00%,0.83%,0.83%,1.67%),差异均具有统计学意义(χ^(2)=1.049~29.159,均P<0.05);妊娠结局良好组和妊娠结局不良组患者的发病程度(OR=1.109,95%CI=1.035~1.188)、PDCD4(OR=1.428,95%CI=1.013~2.012)以及GLUT1(OR=1.453,95%CI=1.066~1.980)水平差异具有统计学意义(均P<0.05);多因素Logistic回归分析显示,发病程度、PDCD4,GLUT1为ICP孕妇妊娠结局不良的影响因素(Waldχ^(2)==8.738,1.428,1.453;P=0.003,0.041,0.018);Pearson相关性分析显示,ICP孕妇血清PDCD4与GLUT1水平呈正相关(r=0.460,P<0.05)。结论PDCD4,GLUT1在ICP孕妇血清中表达均上调,二者呈正相关,是ICP孕妇妊娠结局不良的影响因素。
文摘BACKGROUND SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting(SWI/SNF)complexes and plays an essential role in oncogenesis.SMARCA4-deficient malignancies arising from the gastrointestinal tract are rare and have a poor prognosis.There is no standard treatment for advanced and undifferentiated SMARCA4-deficient duodenal malignancies.Programmed death 1(PD-1)antibodies,known as immune checkpoint inhibitor antibodies,potentially play a role in treating gastrointestinal tract malignancies.CASE SUMMARY We present two patients with SMARCA4 deficiency and TP53 gene mutation in advanced undifferentiated carcinomas of the duodenum.For both patients,SMARCA4 deficiency was confirmed by immunohistochemical staining for the BRG1 protein,while TP53 gene mutations were observed via next-generation sequencing.Both patients were administered chemotherapy in combination with an anti-PD-1 antibody.The two patients exhibited completely different responses to treatment and had different prognoses.Case 1 experienced rapid progression after PD-1 infusion and chemotherapy,case 2 experienced a remarkable response after treatment,and the progression-free survival was more than 6 months.CONCLUSION This study described our clinical and pathological observations of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum.PD-1 combined with chemotherapy showed a certain efficacy in select patients,providing options for treating these highly malignant tumors.Patients with liver metastases had a worse prognosis than did those with only lymph node metastasis.
基金Supported by the First-Class Discipline Construction Founded Project of Ningxia Medical University and the School of Clinical Medicine,No.2020008.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies.However,ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma(HCC)patients due to the complex pathological mechanisms of HCC.AIM To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model,aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.METHODS The levels of PD-1 and TIM-3 on CD4+and CD8+T cells from tumor tissues,ascites,and matched adjacent tissues from HCC patients were determined with flow cytometry.An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody(mAb)and/or anti-PD-1 mAb.Tumor growth in each group was measured.Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors.The percentage of CD4+and CD8+T cells in tissue samples from mice was tested with flow cytometry.The percentages of PD-1+CD8+,TIM-3+CD8+,and PD-1+TIM-3+CD8+T cells was accessed by flow cytometry.The levels of the cytokines including tumor necrosis factor alpha(TNF-α),interferon-γ(IFN-γ),interleukin(IL)-6,and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.RESULTS We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+and CD8+T cells isolated from tumor tissues and ascites of HCC patients.TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight,while combined blockade had more substantial anti-tumor effects than individual treatment.Then we showed that combined therapy increased T cell infiltration into tumor tissues,and downregulated PD-1 and TIM-3 expression on CD8+T cells in tumor tissues.Moreover,combined treatment facilitated the production of T cell effector cytokines TNF-α and IFN-γ,and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues.Thus,we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.CONCLUSION Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+T cell-mediated antitumor immune responses.
