BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the p...BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent mechanisms.展开更多
电离层F2层的临界频率(f_(o)F_(2))的平方与峰值电子密度(N_(m)F2)成正比,是影响GNSS性能的关键参数之一,提升电离层f_(o)F_(2)的预测精度对于优化GNSS广播电离层模型性能并提升GNSS的定位精度具有重要意义.本文基于中国及周边区域的18...电离层F2层的临界频率(f_(o)F_(2))的平方与峰值电子密度(N_(m)F2)成正比,是影响GNSS性能的关键参数之一,提升电离层f_(o)F_(2)的预测精度对于优化GNSS广播电离层模型性能并提升GNSS的定位精度具有重要意义.本文基于中国及周边区域的18个测高仪台站和COSMIC(constellation observing system for meteorology,ionosphere,and climate)掩星观测数据,综合考虑世界时、年积日、地理位置、太阳和地磁活动等多维特征,利用随机森林(random forest,RF)算法构建了电离层f_(o)F_(2)预测模型.通过与国际参考电离层(international reference ionosphere,IRI)-2020模型对比分析,验证了该模型的预测精度.研究结果表明,与IRI国际无线电咨询委员会(International Radio Consultative Committee,CCIR)和IRI国际无线电科学联盟(International Union of Radio Science,URSI)模型相比,RF模型的平均绝对误差(mean absolute error,MAE)分别降低了14.81%和17.11%,均方根误差(root mean squared error,RMSE)分别降低了11.21%和13.14%.此外,该模型在不同纬度、地方时、太阳活动和地磁活动条件下,均展现出优于IRI-2020的预测精度.本研究不仅有效提升了中国及周边区域电离层f_(o)F_(2)的预测精度,还为提高GNSS的准确性和可靠性奠定了重要基础.展开更多
基金the S and T Program of Hebei,No.22377704DMedical Science Research Project of Hebei Province,No.20190510Postgraduate’s Innovation Fund Project of Hebei Province,No.CXZZBS2021077.
文摘BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent mechanisms.
文摘电离层F2层的临界频率(f_(o)F_(2))的平方与峰值电子密度(N_(m)F2)成正比,是影响GNSS性能的关键参数之一,提升电离层f_(o)F_(2)的预测精度对于优化GNSS广播电离层模型性能并提升GNSS的定位精度具有重要意义.本文基于中国及周边区域的18个测高仪台站和COSMIC(constellation observing system for meteorology,ionosphere,and climate)掩星观测数据,综合考虑世界时、年积日、地理位置、太阳和地磁活动等多维特征,利用随机森林(random forest,RF)算法构建了电离层f_(o)F_(2)预测模型.通过与国际参考电离层(international reference ionosphere,IRI)-2020模型对比分析,验证了该模型的预测精度.研究结果表明,与IRI国际无线电咨询委员会(International Radio Consultative Committee,CCIR)和IRI国际无线电科学联盟(International Union of Radio Science,URSI)模型相比,RF模型的平均绝对误差(mean absolute error,MAE)分别降低了14.81%和17.11%,均方根误差(root mean squared error,RMSE)分别降低了11.21%和13.14%.此外,该模型在不同纬度、地方时、太阳活动和地磁活动条件下,均展现出优于IRI-2020的预测精度.本研究不仅有效提升了中国及周边区域电离层f_(o)F_(2)的预测精度,还为提高GNSS的准确性和可靠性奠定了重要基础.
