BACKGROUND Programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating t...BACKGROUND Programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating tumor immunity.AIM To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC.METHODS Gene expression data from the Gene Expression Omnibus database(GEO;n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine(FAHZUSM;n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot.RESULTS In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121(32%), 43(11%), 91(24%), and 51(13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment(P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells.CONCLUSION RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.展开更多
Nantai town is located at the south of Liaoning Province, North is Anshan, Haichengis on the south, Shenda expressway, Hada highway and railway crisscross the town fromnorth to south. Nantai town covers an areas of 95...Nantai town is located at the south of Liaoning Province, North is Anshan, Haichengis on the south, Shenda expressway, Hada highway and railway crisscross the town fromnorth to south. Nantai town covers an areas of 95 square Kgs with 23 administrativevillages, 4 sub-district offices, 1 economic development zone and there are 15 thousandfamilies and 54 thousand populations. Nantai town is a trial place for overall structuralreform in Liaoning Province and a center on larger-scale production, processing anddistributing of boxes and bags nationwide.展开更多
针对典型感潮河网地区水环境污染日趋严重与洪涝灾害频发的问题,为优化河网水动力和降低河道漫溢风险,基于Info Works ICM(integrated catchment management)模型建立福州市仓山区龙津阳岐片区城市水文模型与一维河网水动力耦合模型,以2...针对典型感潮河网地区水环境污染日趋严重与洪涝灾害频发的问题,为优化河网水动力和降低河道漫溢风险,基于Info Works ICM(integrated catchment management)模型建立福州市仓山区龙津阳岐片区城市水文模型与一维河网水动力耦合模型,以2022年6月14日实测降雨及河道水位数据对模型参数进行校准,平均纳什效率系数为0.78,平均洪峰误差为1.5%。设计并模拟3种晴天工况和3种“卢碧”台风雨天工况,结果表明:晴天从无调控到工况3,随着引水量的增加,河网平均流速逐步增加,总体增加66.4%,河道水动力提升显著;雨天从原有调控工况到工况3,随着河道预降水位值增大,关键断面平均超警历时逐步减少,总体下降73%,河道漫溢风险明显降低。构建河网水文水动力耦合模型和工况优选,可为仓山区进一步提升河网水动力与城市汛期洪涝灾害防治能力的方案制定提供决策依据,也可为其他同类研究提供借鉴。展开更多
基金the National Natural Science Foundation of China,No. 81872883 (to Yao HP)Zhejiang Major Medical Health&Sciences Technology s,No. WKJ-ZJ-13 (to Yao HP)Zhejiang Provincial Natural Science Foundation of China,NoLY18H160014(to Xu XM)。
文摘BACKGROUND Programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating tumor immunity.AIM To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC.METHODS Gene expression data from the Gene Expression Omnibus database(GEO;n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine(FAHZUSM;n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot.RESULTS In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121(32%), 43(11%), 91(24%), and 51(13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment(P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells.CONCLUSION RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.
文摘Nantai town is located at the south of Liaoning Province, North is Anshan, Haichengis on the south, Shenda expressway, Hada highway and railway crisscross the town fromnorth to south. Nantai town covers an areas of 95 square Kgs with 23 administrativevillages, 4 sub-district offices, 1 economic development zone and there are 15 thousandfamilies and 54 thousand populations. Nantai town is a trial place for overall structuralreform in Liaoning Province and a center on larger-scale production, processing anddistributing of boxes and bags nationwide.
文摘针对典型感潮河网地区水环境污染日趋严重与洪涝灾害频发的问题,为优化河网水动力和降低河道漫溢风险,基于Info Works ICM(integrated catchment management)模型建立福州市仓山区龙津阳岐片区城市水文模型与一维河网水动力耦合模型,以2022年6月14日实测降雨及河道水位数据对模型参数进行校准,平均纳什效率系数为0.78,平均洪峰误差为1.5%。设计并模拟3种晴天工况和3种“卢碧”台风雨天工况,结果表明:晴天从无调控到工况3,随着引水量的增加,河网平均流速逐步增加,总体增加66.4%,河道水动力提升显著;雨天从原有调控工况到工况3,随着河道预降水位值增大,关键断面平均超警历时逐步减少,总体下降73%,河道漫溢风险明显降低。构建河网水文水动力耦合模型和工况优选,可为仓山区进一步提升河网水动力与城市汛期洪涝灾害防治能力的方案制定提供决策依据,也可为其他同类研究提供借鉴。
