目的 探究血清多聚嘧啶区结合蛋白1(polypyrimidine tract binding protein 1,PTBP1)、G蛋白信号调节因子2(regulator of G protein signaling 2,RGS2)、5-羟色胺(5-hydroxytryptamine, 5-HT)水平在慢性萎缩性胃炎(chronic atrophic gas...目的 探究血清多聚嘧啶区结合蛋白1(polypyrimidine tract binding protein 1,PTBP1)、G蛋白信号调节因子2(regulator of G protein signaling 2,RGS2)、5-羟色胺(5-hydroxytryptamine, 5-HT)水平在慢性萎缩性胃炎(chronic atrophic gastritis, CAG)诊断及病情严重程度评估中的价值。方法 选取2022年1月至2024年10月我院收治的143例CAG患者为研究组,根据胃固有腺体减少程度分为轻度组(n=26)、中度组(n=75)、重度组(n=42)。另纳入152名体检健康人群为对照组。采用酶联免疫吸附法(enzyme linked immunosorbent assay, ELISA)测定各组血清PTBP1、RGS2、5-HT的表达。Logistic回归分析CAG影响因素。ROC曲线分析血清PTBP1、RGS2、5-HT对CAG的诊断及病情严重程度评估价值。结果 与对照组相比,研究组血清PTBP1、RGS2、5-HT表达均升高(P<0.05)。重度组血清PTBP1、RGS2、5-HT高于轻度组、中度组(P<0.05),中度组血清PTBP1、5-HT高于轻度组(P<0.05)。PTBP1、RGS2、5-HT均为CAG发生的危险因素(P<0.05)。血清PTBP1、RGS2、5-HT联合诊断CAG的AUC为0.957,显著大于PTBP1(Z=6.160,P<0.001)、RGS2(Z=4.240,P<0.001)、5-HT(Z=3.248,P=0.001)单独诊断的AUC。PTBP1、RGS2、5-HT联合诊断重度CAG的AUC为0.973,显著大于PTBP1(Z=3.799,P<0.001)、RGS2(Z=5.018,P<0.001)单独诊断的AUC,与5-HT(Z=1.760,P=0.078)单独诊断的AUC,差异无统计学意义。结论 CAG患者血清PTBP1、RGS2、5-HT水平均升高,三者联合具有一定的CAG诊断及病情严重程度评估价值。展开更多
目的探讨X射线修复交叉互补蛋白1(X-ray repair cross-complementing protein 1,XRCC1)、三磷酸腺苷结合转运蛋白G超家族成员2(ATP-binding cassette superfamily G member 2,ABCG2)基因多态性与中晚期结直肠癌(colorectal cancer,CRC)...目的探讨X射线修复交叉互补蛋白1(X-ray repair cross-complementing protein 1,XRCC1)、三磷酸腺苷结合转运蛋白G超家族成员2(ATP-binding cassette superfamily G member 2,ABCG2)基因多态性与中晚期结直肠癌(colorectal cancer,CRC)患者铂类化疗敏感性的相关性。方法选择2021年1月至2022年8月温州医科大学附属平阳医院收治的75例中晚期CRC患者,均采用铂类药物化疗方案治疗24周。所有患者均于化疗前检测外周血XRCC1-Rs25487和ABCG2-Rs717620基因位点的多态性,探究其与患者2年总生存率的关系,采用比例风险(Cox)回归模型分析影响患者预后不良的因素。结果75例中晚期CRC患者的化疗总有效率为52.00%(39/75)。XRCC1-Rs25487基因型中,AA基因型携带者对铂类药物的化疗敏感性较GG+GA基因型携带者的化疗敏感性更低(P<0.05);ABCG2-Rs717620基因型中,TT基因型携带者对铂类药物的化疗敏感性较CC+CT基因型携带者的化疗敏感性更低(P<0.05)。Kaplan-Meier分析显示,XRCC1-Rs25487位点基因GA/GG型中位生存时间长于AA型;ABCG2-Rs717620位点基因CC/CT型中位生存时间长于TT型(P<0.05)。多因素Cox分析显示,铂类药物化疗效果和XRCC1-Rs25487位点基因AA型、ABCG2-Rs717620位点基因TT型均为中晚期CRC患者铂类药物化疗后2年总生存率的独立影响因素(P<0.05)。结论XRCC1、ABCG2基因多态性与中晚期CRC患者铂类药物化疗敏感性有关,XRCC1-Rs25487GG/GA基因型和ABCG2-Rs717620 CC/CT基因型可为中晚期CRC患者铂类化疗带来更好的药物敏感性和生存期。展开更多
Objectives:Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer(NSCLC).Glutamic acid-leucine-arginine positive(ELR+)CXC chemokines and thei...Objectives:Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer(NSCLC).Glutamic acid-leucine-arginine positive(ELR+)CXC chemokines and their receptors,CXC chemokine receptor 1 and 2(CXCR1 and CXCR2),mediate both inflammatory responses and tumor progression.This study evaluated the effects of CXCR1/2 antagonism by G31P,a CXC motif chemokine ligand 8(CXCL8)-mutated peptide,alone or in combination with gefitinib,on lung cancer growth and chemotherapyinduced pulmonary inflammation.Methods:Human NSCLC cell lines(A549 and H460)were treated with gefitinib and/or G31P.Cell proliferation,apoptosis,and signaling pathways,including protein kinase B(AKT)and extracellular signal-regulated kinase(ERK)phosphorylation,were evaluated by cell counting kit-8(CCK-8)assay,flow cytometry,and Western blotting.An orthotopic lung tumor xenograft model was established in BALB/c nude mice to evaluate tumor growth,metastasis,cytokine expression,and lung histopathology.A bleomycin-induced lung injury model was also used to assess the anti-inflammatory effects of G31P,with or without gefitinib,by quantitative reverse transcription polymerase chain reaction(qRT-PCR)and flowcytometry of inflammatorymarkers.Results:G31P andGefitinib,either alone or combined,inhibited proliferation and migration of A549 and H460 cells in vitro.Combination treatment effectively reducedAKT and ERKphosphorylation in both cell lines.In vivo,G31Pwith gefitinib significantly suppressed tumor growth,metastasis,and increased apoptosis.G31P decreased CXCL1 and CXCL2,and tumor necrosis factoralpha(TNF-α)mRNA levels,lung hydroxyproline content,and myeloperoxidase(MPO)activity in the lungs of mice.In the bleomycin-induced lung injury model,G31P similarly reduced inflammatory responses.Conclusion:CXCR1/2 antagonismby G31P attenuates chemotherapy-induced pulmonary inflammation and enhances the anti-tumor efficacy of gefitinib in NSCLC.These findings support the therapeutic potential of G31P as an adjuvant to epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)to improve clinical outcomes by limiting inflammation.展开更多
Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises...Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises from tumor protein p53(p53)alterations and loss of cell cycle control.However,the role of p53 status in GIST therapeutic potential has rarely been studied,so this study aimed to employ both wild-type andmutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.Methods:The efficacy of the mouse double minute 2 homolog(MDM2)inhibitor(HDM201)and the Wee1 G2 checkpoint kinase(Wee1)inhibitor(adavosertib)was confirmed in both p53 wild-type(p53 WT)and p53 mutant(p53 MT)GIST cells.The anti-proliferative effects were assessed using the Cell Counting Kit-8(CCK-8)assay.Flow cytometry(FACS)and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy.These findings were further validated in a xenograft model.Results:HDM201 selectively inhibited growth and triggered apoptosis in p53WT GIST cells,while adavosertib was effective mainly in p53 MT cells.Western blot analysis revealed thatHDM201 increased p53 and p21 levels in p53WT cells,and adavosertib affectedWee1 and phospho-cdc2 expression in both p53WT and p53 MT cells.In a xenograft mouse model,HDM201 significantly reduced the tumor volume and weight in p53WTGIST cells,whereas p53MT tumors showed only a moderate size reduction with adavosertib,without significant changes.Conclusions:Our results highlight the importance of p53 status in guiding GIST treatment.p53 WT tumors respond toMDM2 inhibitors,while p53 MTtumors show greater sensitivity toWee1 inhibitors,supporting p53 pathway targeting as a promising strategy for GIST patients.展开更多
文摘目的探讨X射线修复交叉互补蛋白1(X-ray repair cross-complementing protein 1,XRCC1)、三磷酸腺苷结合转运蛋白G超家族成员2(ATP-binding cassette superfamily G member 2,ABCG2)基因多态性与中晚期结直肠癌(colorectal cancer,CRC)患者铂类化疗敏感性的相关性。方法选择2021年1月至2022年8月温州医科大学附属平阳医院收治的75例中晚期CRC患者,均采用铂类药物化疗方案治疗24周。所有患者均于化疗前检测外周血XRCC1-Rs25487和ABCG2-Rs717620基因位点的多态性,探究其与患者2年总生存率的关系,采用比例风险(Cox)回归模型分析影响患者预后不良的因素。结果75例中晚期CRC患者的化疗总有效率为52.00%(39/75)。XRCC1-Rs25487基因型中,AA基因型携带者对铂类药物的化疗敏感性较GG+GA基因型携带者的化疗敏感性更低(P<0.05);ABCG2-Rs717620基因型中,TT基因型携带者对铂类药物的化疗敏感性较CC+CT基因型携带者的化疗敏感性更低(P<0.05)。Kaplan-Meier分析显示,XRCC1-Rs25487位点基因GA/GG型中位生存时间长于AA型;ABCG2-Rs717620位点基因CC/CT型中位生存时间长于TT型(P<0.05)。多因素Cox分析显示,铂类药物化疗效果和XRCC1-Rs25487位点基因AA型、ABCG2-Rs717620位点基因TT型均为中晚期CRC患者铂类药物化疗后2年总生存率的独立影响因素(P<0.05)。结论XRCC1、ABCG2基因多态性与中晚期CRC患者铂类药物化疗敏感性有关,XRCC1-Rs25487GG/GA基因型和ABCG2-Rs717620 CC/CT基因型可为中晚期CRC患者铂类化疗带来更好的药物敏感性和生存期。
基金supported by grants from the National Natural Science Foundation of China,No.U1604174Health Commission of Henan Province-Province and Ministry Co-Construction Project,Nos.20170123,SBGJ202002004Health Commission of Henan Province-Research Innovative Talents Project(51282).
文摘Objectives:Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer(NSCLC).Glutamic acid-leucine-arginine positive(ELR+)CXC chemokines and their receptors,CXC chemokine receptor 1 and 2(CXCR1 and CXCR2),mediate both inflammatory responses and tumor progression.This study evaluated the effects of CXCR1/2 antagonism by G31P,a CXC motif chemokine ligand 8(CXCL8)-mutated peptide,alone or in combination with gefitinib,on lung cancer growth and chemotherapyinduced pulmonary inflammation.Methods:Human NSCLC cell lines(A549 and H460)were treated with gefitinib and/or G31P.Cell proliferation,apoptosis,and signaling pathways,including protein kinase B(AKT)and extracellular signal-regulated kinase(ERK)phosphorylation,were evaluated by cell counting kit-8(CCK-8)assay,flow cytometry,and Western blotting.An orthotopic lung tumor xenograft model was established in BALB/c nude mice to evaluate tumor growth,metastasis,cytokine expression,and lung histopathology.A bleomycin-induced lung injury model was also used to assess the anti-inflammatory effects of G31P,with or without gefitinib,by quantitative reverse transcription polymerase chain reaction(qRT-PCR)and flowcytometry of inflammatorymarkers.Results:G31P andGefitinib,either alone or combined,inhibited proliferation and migration of A549 and H460 cells in vitro.Combination treatment effectively reducedAKT and ERKphosphorylation in both cell lines.In vivo,G31Pwith gefitinib significantly suppressed tumor growth,metastasis,and increased apoptosis.G31P decreased CXCL1 and CXCL2,and tumor necrosis factoralpha(TNF-α)mRNA levels,lung hydroxyproline content,and myeloperoxidase(MPO)activity in the lungs of mice.In the bleomycin-induced lung injury model,G31P similarly reduced inflammatory responses.Conclusion:CXCR1/2 antagonismby G31P attenuates chemotherapy-induced pulmonary inflammation and enhances the anti-tumor efficacy of gefitinib in NSCLC.These findings support the therapeutic potential of G31P as an adjuvant to epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)to improve clinical outcomes by limiting inflammation.
基金financially supported by grants from the Chang-Gung Memorial Hospital(CMRPG3J0971~3,CMRPVVP0111,and CMRPVVQ0041 to CEWCMRPG3P0101 to HJS)the National Science and Technology Council(113-2628-B-182-001-MY3 and 113-2811-B-182-024 to CEW).
文摘Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises from tumor protein p53(p53)alterations and loss of cell cycle control.However,the role of p53 status in GIST therapeutic potential has rarely been studied,so this study aimed to employ both wild-type andmutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.Methods:The efficacy of the mouse double minute 2 homolog(MDM2)inhibitor(HDM201)and the Wee1 G2 checkpoint kinase(Wee1)inhibitor(adavosertib)was confirmed in both p53 wild-type(p53 WT)and p53 mutant(p53 MT)GIST cells.The anti-proliferative effects were assessed using the Cell Counting Kit-8(CCK-8)assay.Flow cytometry(FACS)and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy.These findings were further validated in a xenograft model.Results:HDM201 selectively inhibited growth and triggered apoptosis in p53WT GIST cells,while adavosertib was effective mainly in p53 MT cells.Western blot analysis revealed thatHDM201 increased p53 and p21 levels in p53WT cells,and adavosertib affectedWee1 and phospho-cdc2 expression in both p53WT and p53 MT cells.In a xenograft mouse model,HDM201 significantly reduced the tumor volume and weight in p53WTGIST cells,whereas p53MT tumors showed only a moderate size reduction with adavosertib,without significant changes.Conclusions:Our results highlight the importance of p53 status in guiding GIST treatment.p53 WT tumors respond toMDM2 inhibitors,while p53 MTtumors show greater sensitivity toWee1 inhibitors,supporting p53 pathway targeting as a promising strategy for GIST patients.
