β-elemene has been observed to exert inhibitory effects on a multitude of tumors,primarily through multiple pathways such as the inhibition of cancer cell proliferation and the induction of apoptosis.The present stud...β-elemene has been observed to exert inhibitory effects on a multitude of tumors,primarily through multiple pathways such as the inhibition of cancer cell proliferation and the induction of apoptosis.The present study is designed to elucidate the role and underlying mechanisms ofβ-elemene in the therapeutic intervention of non-small cell lung cancer(NSCLC).Both in vitro and in vivo experimental models corroborate the inhibitory potency ofβ-elemene on NSCLCs.Our findings indicate thatβ-elemene facilitates the maturation of miR-127-3p by inhibiting CBX8.Functioning as an upstream regulator of MAPK4,miR-127-3p deactivates the Akt/mTOR/p70S6K pathway by targeting MAPK4,thereby inducing autophagy in NSCLCs.Additionally,β-elemene augments the packaging of miR-127-3p into exosomes via SYNCRIP.Exosomal miR-127-3p further stimulates M1 polarization of macrophages by suppressing ZC3H4.Taken together,the detailed understanding of the mechanisms through whichβ-elemene induces autophagy in NSCLCs and facilitates M1 polarization of macrophages provides compelling scientific evidence supporting its potential utility in NSCLC treatment.展开更多
目的评估肺间质异常(ILA)合并非小细胞肺癌(NSCLC)患者接受免疫检查点抑制剂(ICIs)治疗而发生免疫检查点抑制剂相关性肺炎(CIP)的风险因素。方法回顾性收集2019年1月至2023年12月在西安交通大学第一附属医院初次进行ICIs治疗的ILA合并NS...目的评估肺间质异常(ILA)合并非小细胞肺癌(NSCLC)患者接受免疫检查点抑制剂(ICIs)治疗而发生免疫检查点抑制剂相关性肺炎(CIP)的风险因素。方法回顾性收集2019年1月至2023年12月在西安交通大学第一附属医院初次进行ICIs治疗的ILA合并NSCLC患者(共149例)的基线期临床资料及CT图像,将患者分为CIP(+)组(n=49)及CIP(-)组(n=100);采用影像分析工具uAI Research Portal对两组患者胸部CT图像基线期ILA体积进行定量分析,对比ILA体积在肺内的总占比、各肺叶内的占比及各类征象体积的占比;进一步对比CIP(+)轻至中度组(1~2级,n=32)与重度组(3~4级,n=17)基线期ILA体积在肺内的总占比、各肺叶内的占比及各类征象体积的占比。结果CIP(+)组及CIP(-)组的基线期全肺ILA体积总占比、左肺下叶和右肺中叶基线期ILA体积占比中位数差异均有统计学意义(2.69%vs.1.31%,P=0.001;7.22%vs.1.83%,P=0.001;0.51%vs.0.28%,P=0.028);两组的磨玻璃密度影体积占比中位数差异有统计学意义(1.23%vs.0.47%,P=0.012)。轻至中度CIP组及重度CIP组间的全肺基线期ILA体积占比中位数差异有统计学意义(2.26%vs.3.91%,P=0.048),磨玻璃密度影体积占比中位数差异有统计学意义(0.63%vs.2.36%,P=0.02)。结论基于CT定量分析ILA合并NSCLC患者基线期ILA体积占比与CIP发生相关,其中磨玻璃密度影体积占比是重度CIP发生的重要预测因素。展开更多
Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 tr...Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 trial)showed no additional advantage.The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment(TME)to aid in optimizing sequencing of combination therapies.Methods:The PD-RAD trial(ClinicalTrials.gov identifier:NCT03258788)aimed to enroll thirty NSCLC patients receiving radical-intent RT.Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry(mIHC)and high-dimensional mass cytometry(CyTOF),respectively.Results:Paired biopsies were collected from only three patients(Pts 1,3&4)and blood from four patients(Pts 1-4)before the study was closed early during the COVID-19 pandemic.Programmed Death-Ligand 1(PD-L1)expression in the TME was raised in Patient 1,who responded well to treatment,and unaltered in two patients with progressive disease.CyTOF analysis revealed elevated circulating classical monocytes,highest in the patient with a good response.Conclusions:This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint.The hypothesis-generating findings highlight PD-L1+macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response,but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.展开更多
Objectives:Acquired resistance to paclitaxel represents a critical barrier to the effective chemotherapy of non-small cell lung cancer(NSCLC).The present study aimed to elucidate the molecular and pharmacological mech...Objectives:Acquired resistance to paclitaxel represents a critical barrier to the effective chemotherapy of non-small cell lung cancer(NSCLC).The present study aimed to elucidate the molecular and pharmacological mechanisms promoting paclitaxel resistance in NSCLC and to explore potential strategies for overcoming this resistance.Methods:Here,we report an integrated pharmacological and analytical approach to quantify paclitaxel disposition and overcome resistance in a A549/TAX cell model(paclitaxel-resistant A549 cells).Results:Cell counting kit-8(CCK-8)assay,colony formation,and apoptosis assays confirmed that A549/TAX cells exhibited marked resistance to paclitaxel relative to parental A549 cells.Based on transcriptome profiling by RNA sequencing analysis and validation by western blotting assay,we found that the expression of the ATP-binding cassette subfamily B member 1(ABCB1)(the encoded protein is termed P-glycoprotein)was significantly upregulated in resistant cells.By using ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS),we demonstrated that ABCB1 overexpression promotes enhanced efflux of intracellular paclitaxel,thereby lowering its cytotoxic accumulation.Genetic silencing of ABCB1 or pharmacological inhibition with the specific P-glycoprotein modulator elacridar or tariquidar restored intracellular paclitaxel levels,as determined by UPLC-MS/MS,and synergistically decreased cell viability as observed in CCK-8 assay.Conclusion:These findings reveal that the ABCB1-mediated drug efflux is a crucial mechanism underlying paclitaxel resistance in NSCLC cells,with UPLC-MS/MS serving as a sensitive analytical method to detect paclitaxel concentration.Inhibition of ABCB1 is a promising therapeutic strategy to resensitize resistant tumor cells to paclitaxel.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:81973525)Traditional Chinese Medicine Development Project of Jiangsu Province(Grant No.:ZT202112).
文摘β-elemene has been observed to exert inhibitory effects on a multitude of tumors,primarily through multiple pathways such as the inhibition of cancer cell proliferation and the induction of apoptosis.The present study is designed to elucidate the role and underlying mechanisms ofβ-elemene in the therapeutic intervention of non-small cell lung cancer(NSCLC).Both in vitro and in vivo experimental models corroborate the inhibitory potency ofβ-elemene on NSCLCs.Our findings indicate thatβ-elemene facilitates the maturation of miR-127-3p by inhibiting CBX8.Functioning as an upstream regulator of MAPK4,miR-127-3p deactivates the Akt/mTOR/p70S6K pathway by targeting MAPK4,thereby inducing autophagy in NSCLCs.Additionally,β-elemene augments the packaging of miR-127-3p into exosomes via SYNCRIP.Exosomal miR-127-3p further stimulates M1 polarization of macrophages by suppressing ZC3H4.Taken together,the detailed understanding of the mechanisms through whichβ-elemene induces autophagy in NSCLCs and facilitates M1 polarization of macrophages provides compelling scientific evidence supporting its potential utility in NSCLC treatment.
文摘目的评估肺间质异常(ILA)合并非小细胞肺癌(NSCLC)患者接受免疫检查点抑制剂(ICIs)治疗而发生免疫检查点抑制剂相关性肺炎(CIP)的风险因素。方法回顾性收集2019年1月至2023年12月在西安交通大学第一附属医院初次进行ICIs治疗的ILA合并NSCLC患者(共149例)的基线期临床资料及CT图像,将患者分为CIP(+)组(n=49)及CIP(-)组(n=100);采用影像分析工具uAI Research Portal对两组患者胸部CT图像基线期ILA体积进行定量分析,对比ILA体积在肺内的总占比、各肺叶内的占比及各类征象体积的占比;进一步对比CIP(+)轻至中度组(1~2级,n=32)与重度组(3~4级,n=17)基线期ILA体积在肺内的总占比、各肺叶内的占比及各类征象体积的占比。结果CIP(+)组及CIP(-)组的基线期全肺ILA体积总占比、左肺下叶和右肺中叶基线期ILA体积占比中位数差异均有统计学意义(2.69%vs.1.31%,P=0.001;7.22%vs.1.83%,P=0.001;0.51%vs.0.28%,P=0.028);两组的磨玻璃密度影体积占比中位数差异有统计学意义(1.23%vs.0.47%,P=0.012)。轻至中度CIP组及重度CIP组间的全肺基线期ILA体积占比中位数差异有统计学意义(2.26%vs.3.91%,P=0.048),磨玻璃密度影体积占比中位数差异有统计学意义(0.63%vs.2.36%,P=0.02)。结论基于CT定量分析ILA合并NSCLC患者基线期ILA体积占比与CIP发生相关,其中磨玻璃密度影体积占比是重度CIP发生的重要预测因素。
基金the National Institute for Health and Care Research(NHR)Manchester Biomedical Research Centre(BRC)(NIHR203308,NIHR-BRC-1215-20007)Astra-Zeneca(ESR-14-10711)+2 种基金CRUK RadNet(C19941/A27801)TMI and CFF are the recipient of an NIHR Senior Investigator Award(NIHR205054 and NIHR205061)CTH is supported by the NIHR University College London Hospitals NHS Foundation Trust BRC,the City of London CRUK RadNet and the CRUK Lung Cancer Centre of Excellence.
文摘Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 trial)showed no additional advantage.The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment(TME)to aid in optimizing sequencing of combination therapies.Methods:The PD-RAD trial(ClinicalTrials.gov identifier:NCT03258788)aimed to enroll thirty NSCLC patients receiving radical-intent RT.Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry(mIHC)and high-dimensional mass cytometry(CyTOF),respectively.Results:Paired biopsies were collected from only three patients(Pts 1,3&4)and blood from four patients(Pts 1-4)before the study was closed early during the COVID-19 pandemic.Programmed Death-Ligand 1(PD-L1)expression in the TME was raised in Patient 1,who responded well to treatment,and unaltered in two patients with progressive disease.CyTOF analysis revealed elevated circulating classical monocytes,highest in the patient with a good response.Conclusions:This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint.The hypothesis-generating findings highlight PD-L1+macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response,but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82172840)Gusu Health Talents Project of Suzhou Municipal Health Commission(Grant Nos.GSWS2023007 and GSWS2022062)+2 种基金Suzhou Science and Technology Development Plan Project(Grant No.SYW2024005)Chinese Pharmaceutical Association Hospital Pharmacy Department(Grant No.CPA-Z05-ZC-2024002)Jiangsu Research Hospital Association for Precision Medication(Grant No.JY202202).
文摘Objectives:Acquired resistance to paclitaxel represents a critical barrier to the effective chemotherapy of non-small cell lung cancer(NSCLC).The present study aimed to elucidate the molecular and pharmacological mechanisms promoting paclitaxel resistance in NSCLC and to explore potential strategies for overcoming this resistance.Methods:Here,we report an integrated pharmacological and analytical approach to quantify paclitaxel disposition and overcome resistance in a A549/TAX cell model(paclitaxel-resistant A549 cells).Results:Cell counting kit-8(CCK-8)assay,colony formation,and apoptosis assays confirmed that A549/TAX cells exhibited marked resistance to paclitaxel relative to parental A549 cells.Based on transcriptome profiling by RNA sequencing analysis and validation by western blotting assay,we found that the expression of the ATP-binding cassette subfamily B member 1(ABCB1)(the encoded protein is termed P-glycoprotein)was significantly upregulated in resistant cells.By using ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS),we demonstrated that ABCB1 overexpression promotes enhanced efflux of intracellular paclitaxel,thereby lowering its cytotoxic accumulation.Genetic silencing of ABCB1 or pharmacological inhibition with the specific P-glycoprotein modulator elacridar or tariquidar restored intracellular paclitaxel levels,as determined by UPLC-MS/MS,and synergistically decreased cell viability as observed in CCK-8 assay.Conclusion:These findings reveal that the ABCB1-mediated drug efflux is a crucial mechanism underlying paclitaxel resistance in NSCLC cells,with UPLC-MS/MS serving as a sensitive analytical method to detect paclitaxel concentration.Inhibition of ABCB1 is a promising therapeutic strategy to resensitize resistant tumor cells to paclitaxel.
