BACKGROUND The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis.SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer.AIM To determine the prognostic value...BACKGROUND The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis.SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer.AIM To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer.METHODS This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years(median age 65)between July 2006 and April 2007.Patients were followed up until death or the study ended(median follow-up duration of 28.5 mo).The samples were used to generate tissue microarrays(TMAs)for immunohistochemical(IHC)staining.The expressions of TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 in gastric cancer(GC)tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients.Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015.The relationship between TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient.The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test.A survival curve was generated using the Kaplan-Meier survival analysis.RESULTS TGFβ-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent noncancerous tissue.The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site[pSMAD3C(S423/425):51.0%and pSMAD3L(S204):31.6%].High expression of pSMAD-3L(S204)was significantly correlated with larger tumors(P=0.038)and later N stages(P=0.035).Additionally,high expression of VEGFR-1 was closely correlated with tumor size(P=0.015)and pathological grading(P=0.013).High expression of both pSMAD3L(S204)and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival(OS).Multivariate analysis indicated that high expression of pSMAD3L(S204)and VEGFR-1 were independent risk factors for prognosis in GC patients.VEGFR-1 protein expression was correlated with TGF-β1(r=0.220,P=0.029),pSMAD3C(S423/425)(r=0.302,P=0.002),and pSMAD3L(S204)(r=0.201,P=0.047),respectively.Simultaneous overexpression of pSMAD3L(S204)and VEGFR-1 was associated with poor OS in gastric cancer patients.CONCLUSION Co-upregulation of pSMAD3L(S204)and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis,and pSMAD3L(204)may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.展开更多
Accurate preoperative prediction of lymph node metastasis(LNM)in esophageal cancer(EC)patients is of crucial clinical significance for treatment planning and prognosis.AIM To develop a clinical radiomics nomogram that...Accurate preoperative prediction of lymph node metastasis(LNM)in esophageal cancer(EC)patients is of crucial clinical significance for treatment planning and prognosis.AIM To develop a clinical radiomics nomogram that can predict the preoperative lymph node(LN)status in EC patients.METHODS A total of 32 EC patients confirmed by clinical pathology(who underwent surgical treatment)were included.Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy,and its correlation with LNM was analyzed.Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python.Feature extraction,data dimensionality reduction,and feature selection were performed using XGBoost model and leave-one-out cross-validation.Multivariable logistic regression analysis was used to establish the prediction model,which included radiomics features,LN status from computed tomography(CT)reports,and B7-H3 mRNA expression,represented by a radiomics nomogram.Receiver operating characteristic area under the curve(AUC)and decision curve analysis(DCA)were used to evaluate the predictive performance and clinical application value of the model.RESULTS The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis,and the difference was statistically significant(P<0.05).The AUC value in the receiver operating characteristic(ROC)curve was 0.718(95%CI:0.528-0.907),with a sensitivity of 0.733 and specificity of 0.706,indicating good diagnostic performance.The individualized clinical prediction nomogram included radiomics features,LN status from CT reports,and B7-H3 mRNA expression.The ROC curve demonstrated good diagnostic value,with an AUC value of 0.765(95%CI:0.598-0.931),sensitivity of 0.800,and specificity of 0.706.DCA indicated the practical value of the radiomics nomogram in clinical practice.CONCLUSION This study developed a radiomics nomogram that includes radiomics features,LN status from CT reports,and B7-H3 mRNA expression,enabling convenient preoperative individualized prediction of LNM in EC patients.展开更多
Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although c...Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.展开更多
基金Supported by National Nature Science Foundation of China,No.82060450,No.82360517,No.81460374,and No.31460304Nature Science Foundation of Jiangxi Province of China,No.20232BAB206086,No.20192BAB205072,No.20203BBGL73206,No.2017BCB23086,No.2017BAB205062,and No.20181BAB205050.
文摘BACKGROUND The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis.SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer.AIM To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer.METHODS This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years(median age 65)between July 2006 and April 2007.Patients were followed up until death or the study ended(median follow-up duration of 28.5 mo).The samples were used to generate tissue microarrays(TMAs)for immunohistochemical(IHC)staining.The expressions of TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 in gastric cancer(GC)tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients.Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015.The relationship between TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient.The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test.A survival curve was generated using the Kaplan-Meier survival analysis.RESULTS TGFβ-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent noncancerous tissue.The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site[pSMAD3C(S423/425):51.0%and pSMAD3L(S204):31.6%].High expression of pSMAD-3L(S204)was significantly correlated with larger tumors(P=0.038)and later N stages(P=0.035).Additionally,high expression of VEGFR-1 was closely correlated with tumor size(P=0.015)and pathological grading(P=0.013).High expression of both pSMAD3L(S204)and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival(OS).Multivariate analysis indicated that high expression of pSMAD3L(S204)and VEGFR-1 were independent risk factors for prognosis in GC patients.VEGFR-1 protein expression was correlated with TGF-β1(r=0.220,P=0.029),pSMAD3C(S423/425)(r=0.302,P=0.002),and pSMAD3L(S204)(r=0.201,P=0.047),respectively.Simultaneous overexpression of pSMAD3L(S204)and VEGFR-1 was associated with poor OS in gastric cancer patients.CONCLUSION Co-upregulation of pSMAD3L(S204)and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis,and pSMAD3L(204)may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.
基金The Yancheng Key Research and Development Program(Social Development),No.YCBE202324。
文摘Accurate preoperative prediction of lymph node metastasis(LNM)in esophageal cancer(EC)patients is of crucial clinical significance for treatment planning and prognosis.AIM To develop a clinical radiomics nomogram that can predict the preoperative lymph node(LN)status in EC patients.METHODS A total of 32 EC patients confirmed by clinical pathology(who underwent surgical treatment)were included.Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy,and its correlation with LNM was analyzed.Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python.Feature extraction,data dimensionality reduction,and feature selection were performed using XGBoost model and leave-one-out cross-validation.Multivariable logistic regression analysis was used to establish the prediction model,which included radiomics features,LN status from computed tomography(CT)reports,and B7-H3 mRNA expression,represented by a radiomics nomogram.Receiver operating characteristic area under the curve(AUC)and decision curve analysis(DCA)were used to evaluate the predictive performance and clinical application value of the model.RESULTS The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis,and the difference was statistically significant(P<0.05).The AUC value in the receiver operating characteristic(ROC)curve was 0.718(95%CI:0.528-0.907),with a sensitivity of 0.733 and specificity of 0.706,indicating good diagnostic performance.The individualized clinical prediction nomogram included radiomics features,LN status from CT reports,and B7-H3 mRNA expression.The ROC curve demonstrated good diagnostic value,with an AUC value of 0.765(95%CI:0.598-0.931),sensitivity of 0.800,and specificity of 0.706.DCA indicated the practical value of the radiomics nomogram in clinical practice.CONCLUSION This study developed a radiomics nomogram that includes radiomics features,LN status from CT reports,and B7-H3 mRNA expression,enabling convenient preoperative individualized prediction of LNM in EC patients.
基金supported by St.Vincent’s Hospital,the Research Institute of Medical Science(Grant Number:SVHR-2021-03).
文摘Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.
