Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significant...Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.展开更多
[Objective]To explore the protective effect of selenomethionine(Se-Met)on oxidative stress and intestinal barrier damage in mice infected with porcine deltacoronavirus(PDCoV)and the potential regulatory mechanism.[Met...[Objective]To explore the protective effect of selenomethionine(Se-Met)on oxidative stress and intestinal barrier damage in mice infected with porcine deltacoronavirus(PDCoV)and the potential regulatory mechanism.[Methods]Forty female C57 mice were randomly grouped as follows:control,Se-Met(0.3 mg/kg Se),PDCoV,and Se-Met+PDCoV(0.3 mg/kg Se).After being fed with or without Se-Met for 23 days,the mice in the PDCoV group and the Se-Met+PDCoV group were administrated with 300μL suspension of PDCoV HNZK-02-P5 strain(1×10^(6)TCID50)by gavage,while those in the other two groups were administered with the same volume of Dulbecco’s Modified Eagle Medium(DMEM).All the mice were observed daily for clinical signs,food intake,and body weight changes until day 28.At five days post-inoculation(dpi),intestinal tissues were collected and PDCoV titers were determined.Hematoxylin staining and eosin staining were used to monitor pathological changes in intestinal tissues.Oxidative stress-related indicators such as malondialdehyde(MDA),superoxide dismutase(SOD),and glutathione peroxidase(GSH-PX)were investigated.The level of ROS in the jejunum tissue was measured via a 2′,7′-dichlorofluorescein diacetate(DCFH-DA)probe.Immunofluorescence was used to analyze the changes of small intestinal tight junction proteins(ZO-1 and Occludin).The mRNA levels of inflammatory cytokines(TNF-α,IL-1β,IL-6,and IL-10),intestinal tight junction proteins(ZO-1 and Occludin),and the Nrf2 signaling pathway-associated factors(Nrf2,HO-1,and NQO1)were determined by RT-qPCR.Western blotting was employed to assess the protein levels of factors related to the Nrf2 signaling pathway.[Results]The results of body weight,food intake,pathological examination,and viral RNA titers in different intestinal tissues revealed that Se-Met might increase the body weight,decrease viral titers in intestinal tissues,and attenuate PDCoV-induced structural damage of intestinal villi in PDCoV-infected mice.Se-Met attenuated PDCoV-induced inflammation by lowering the mRNA levels of major inflammatory cytokines,such as IL-1β,IL-6,and TNFαin the jejunum.Se-Met ameliorated PDCoV-induced intestinal mucosal barrier damage by up-regulating the mRNA levels of ZO-1 and Occludin in the jejunum.Se-Met ameliorated PDCoV-induced oxidative stress by decreasing the levels of ROS and MDA and increasing the levels of GSH-PX and SOD in the jejunum.Se-Met inhibited PDCoV-induced oxidative stress by activating the Nrf2 signaling pathway.[Conclusion]Se-Met may attenuate the intestinal injury in mice infected with PDCoV by activating the Nrf2 signaling pathway,which provides a theoretical basis for the prevention and treatment of PDCoV infection.展开更多
Growing evidences showed that heavy metals exposure may be associated with metabolic diseases.Nevertheless,themechanism underlying arsenic(As)exposure and metabolic syndrome(MetS)risk has not been fully elucidated.So ...Growing evidences showed that heavy metals exposure may be associated with metabolic diseases.Nevertheless,themechanism underlying arsenic(As)exposure and metabolic syndrome(MetS)risk has not been fully elucidated.So we aimed to prospectively investigate the role of serum uric acid(SUA)on the association between blood As exposure and incident MetS.A sample of 1045 older participants in a community in China was analyzed.We determined As at baseline and SUA concentration at follow-up in the Yiwu Elderly Cohort.MetS events were defined according to the criteria of the International Diabetes Federation(IDF).Generalized linear model with log-binominal regression model was applied to estimate the association of As with incident MetS.To investigate the role of SUA in the association between As andMetS,amediation analysiswas conducted.In the fully adjusted log-binominal model,per interquartile range increment of As,the risk of MetS increased 1.25-fold.Compared with the lowest quartile of As,the adjusted relative risk(RR)of MetS in the highest quartile was 1.42(95%confidence interval,CI:1.03,2.00).Additionally,blood As was positively associated with SUA,while SUA had significant association with MetS risk.Further mediation analysis demonstrated that the association of As and MetS risk was mediated by SUA,with the proportion of 15.7%.Our study found higher As was remarkably associated with the elevated risk of MetS in the Chinese older adults population.Mediation analysis indicated that SUA might be a mediator in the association between As exposure and MetS.展开更多
Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molec...Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.展开更多
文摘Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.
基金supported by the National Natural Science Foundation of China(No.81472656)Anhui Provincial Natural Science Foundation(No.2022AH040224)+2 种基金Anhui Provincial Natural Science Foundation(No.2023AH051991)Key Research Project at the School Level of Bengbu Medical College(No.Byycx23084)Bengbu Medical College National College Students'Innovation and Entrepreneurship Training Program Project(No.202310367011).
文摘[Objective]To explore the protective effect of selenomethionine(Se-Met)on oxidative stress and intestinal barrier damage in mice infected with porcine deltacoronavirus(PDCoV)and the potential regulatory mechanism.[Methods]Forty female C57 mice were randomly grouped as follows:control,Se-Met(0.3 mg/kg Se),PDCoV,and Se-Met+PDCoV(0.3 mg/kg Se).After being fed with or without Se-Met for 23 days,the mice in the PDCoV group and the Se-Met+PDCoV group were administrated with 300μL suspension of PDCoV HNZK-02-P5 strain(1×10^(6)TCID50)by gavage,while those in the other two groups were administered with the same volume of Dulbecco’s Modified Eagle Medium(DMEM).All the mice were observed daily for clinical signs,food intake,and body weight changes until day 28.At five days post-inoculation(dpi),intestinal tissues were collected and PDCoV titers were determined.Hematoxylin staining and eosin staining were used to monitor pathological changes in intestinal tissues.Oxidative stress-related indicators such as malondialdehyde(MDA),superoxide dismutase(SOD),and glutathione peroxidase(GSH-PX)were investigated.The level of ROS in the jejunum tissue was measured via a 2′,7′-dichlorofluorescein diacetate(DCFH-DA)probe.Immunofluorescence was used to analyze the changes of small intestinal tight junction proteins(ZO-1 and Occludin).The mRNA levels of inflammatory cytokines(TNF-α,IL-1β,IL-6,and IL-10),intestinal tight junction proteins(ZO-1 and Occludin),and the Nrf2 signaling pathway-associated factors(Nrf2,HO-1,and NQO1)were determined by RT-qPCR.Western blotting was employed to assess the protein levels of factors related to the Nrf2 signaling pathway.[Results]The results of body weight,food intake,pathological examination,and viral RNA titers in different intestinal tissues revealed that Se-Met might increase the body weight,decrease viral titers in intestinal tissues,and attenuate PDCoV-induced structural damage of intestinal villi in PDCoV-infected mice.Se-Met attenuated PDCoV-induced inflammation by lowering the mRNA levels of major inflammatory cytokines,such as IL-1β,IL-6,and TNFαin the jejunum.Se-Met ameliorated PDCoV-induced intestinal mucosal barrier damage by up-regulating the mRNA levels of ZO-1 and Occludin in the jejunum.Se-Met ameliorated PDCoV-induced oxidative stress by decreasing the levels of ROS and MDA and increasing the levels of GSH-PX and SOD in the jejunum.Se-Met inhibited PDCoV-induced oxidative stress by activating the Nrf2 signaling pathway.[Conclusion]Se-Met may attenuate the intestinal injury in mice infected with PDCoV by activating the Nrf2 signaling pathway,which provides a theoretical basis for the prevention and treatment of PDCoV infection.
基金supported by the Fundamental Research Funds for the Central Universities(Nos.2021FZZX001-39 and 2020QNA7018)the Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province(No.20220204)the Medical Science and Technology Project of Zhejiang Province(No.2023RC037).
文摘Growing evidences showed that heavy metals exposure may be associated with metabolic diseases.Nevertheless,themechanism underlying arsenic(As)exposure and metabolic syndrome(MetS)risk has not been fully elucidated.So we aimed to prospectively investigate the role of serum uric acid(SUA)on the association between blood As exposure and incident MetS.A sample of 1045 older participants in a community in China was analyzed.We determined As at baseline and SUA concentration at follow-up in the Yiwu Elderly Cohort.MetS events were defined according to the criteria of the International Diabetes Federation(IDF).Generalized linear model with log-binominal regression model was applied to estimate the association of As with incident MetS.To investigate the role of SUA in the association between As andMetS,amediation analysiswas conducted.In the fully adjusted log-binominal model,per interquartile range increment of As,the risk of MetS increased 1.25-fold.Compared with the lowest quartile of As,the adjusted relative risk(RR)of MetS in the highest quartile was 1.42(95%confidence interval,CI:1.03,2.00).Additionally,blood As was positively associated with SUA,while SUA had significant association with MetS risk.Further mediation analysis demonstrated that the association of As and MetS risk was mediated by SUA,with the proportion of 15.7%.Our study found higher As was remarkably associated with the elevated risk of MetS in the Chinese older adults population.Mediation analysis indicated that SUA might be a mediator in the association between As exposure and MetS.
基金supported by the National Natural Science Foundation of China(Grant No.81602057)the Beijing Natural Science Foundation(Grant No.Z210015)。
文摘Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.
