Alternative splicing(AS)is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs(mRNAs),extremely improving the richness of transcriptome and proteome.Both mamm...Alternative splicing(AS)is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs(mRNAs),extremely improving the richness of transcriptome and proteome.Both mammal hosts and pathogens require AS to maintain their life activities,and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS.Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA(named cis-splicing).Parasites also use spliceosomes to splice,but this splicing can occur among different mRNAs(named trans-splicing).Bacteria and viruses directly hijack the host’s splicing machinery to accomplish this process.Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators(abundance,modification,distribution,movement speed,and conformation),which further radiate to alterations in the global splicing profiles.Genes with splicing changes are enriched in immune-,growth-,or metabolism-related pathways,highlighting approaches through which hosts crosstalk with pathogens.Based on these infection-specific regulators or AS events,several targeted agents have been developed to fight against pathogens.Here,we summarized recent findings in the field of infection-related splicing,including splicing mechanisms of pathogens and hosts,splicing regulation and aberrant AS events,as well as emerging targeted drugs.We aimed to systemically decode host–pathogen interactions from a perspective of splicing.We further discussed the current strategies of drug development,detection methods,analysis algorithms,and database construction,facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.展开更多
Background:There is limited information about thymosinα1(Tα1)as adjuvant immunomodulatory therapy,either used alone or combined with other treatments,in patients with non-small cell lung cancer(NSCLC).This study aim...Background:There is limited information about thymosinα1(Tα1)as adjuvant immunomodulatory therapy,either used alone or combined with other treatments,in patients with non-small cell lung cancer(NSCLC).This study aimed to evaluate the effect of adjuvant Tα1 treatment on long-term survival in margin-free(R0)-resected stage IA–IIIA NSCLC patients.Methods:A total of 5746 patients with pathologic stage IA-IIIA NSCLC who underwent R0 resection were included.The patients were divided into the Tα1 group and the control group according to whether they received Tα1 or not.A propensity score matching(PSM)analysis was performed to reduce bias,resulting in 1027 pairs of patients.Results:After PSM,the baseline clinicopathological characteristics were similar between the two groups.The 5-year disease-free survival(DFS)and overall survival(OS)rates were significantly higher in the Tα1 group compared with the control group.The multivariable analysis showed that Tα1 treatment was independently associated with an improved prognosis.A longer duration of Tα1 treatment was associated with improved OS and DFS.The subgroup analyses showed that Tα1 therapy could improve the DFS and/or OS in all subgroups of age,sex,Charlson Comorbidity Index(CCI),smoking status,and pathological tumor-node-metastasis(TNM)stage,especially for patients with non-squamous cell NSCLC and without targeted therapy.Conclusion:Tα1 as adjuvant immunomodulatory therapy can significantly improve DFS and OS in patients with NSCLC after R0 resection,except for patients with squamous cell carcinoma and those receiving targeted therapy.The duration of Tα1 treatment is recommended to be>24 months.展开更多
Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a c...Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.展开更多
Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKl)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiti...Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKl)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiting clinical efficacy.We found that TET2 was poly-ubiquitinated by E3 ligase CUL7^(FBXW11) and degraded in EGFR-TKI resistant NSCLC ells.Genetic perturbationof TET2 rendered parental cells more tolerant to TKI treatment.TET2 was stabilized by MEK1 phosphorylation at Ser 1107,while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7^(FBXW11),Loss of TET2 resulted in the upregulation of TNF/NF-kB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-kB attenuate the TKI resistance both in vitro and in vivo.Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2,and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency.Therefore,combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.展开更多
基金National Natural Science Foundation of China(No.82272416)
文摘Alternative splicing(AS)is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs(mRNAs),extremely improving the richness of transcriptome and proteome.Both mammal hosts and pathogens require AS to maintain their life activities,and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS.Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA(named cis-splicing).Parasites also use spliceosomes to splice,but this splicing can occur among different mRNAs(named trans-splicing).Bacteria and viruses directly hijack the host’s splicing machinery to accomplish this process.Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators(abundance,modification,distribution,movement speed,and conformation),which further radiate to alterations in the global splicing profiles.Genes with splicing changes are enriched in immune-,growth-,or metabolism-related pathways,highlighting approaches through which hosts crosstalk with pathogens.Based on these infection-specific regulators or AS events,several targeted agents have been developed to fight against pathogens.Here,we summarized recent findings in the field of infection-related splicing,including splicing mechanisms of pathogens and hosts,splicing regulation and aberrant AS events,as well as emerging targeted drugs.We aimed to systemically decode host–pathogen interactions from a perspective of splicing.We further discussed the current strategies of drug development,detection methods,analysis algorithms,and database construction,facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.
基金1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(Nos.ZYGD18021 and ZYJC18009).
文摘Background:There is limited information about thymosinα1(Tα1)as adjuvant immunomodulatory therapy,either used alone or combined with other treatments,in patients with non-small cell lung cancer(NSCLC).This study aimed to evaluate the effect of adjuvant Tα1 treatment on long-term survival in margin-free(R0)-resected stage IA–IIIA NSCLC patients.Methods:A total of 5746 patients with pathologic stage IA-IIIA NSCLC who underwent R0 resection were included.The patients were divided into the Tα1 group and the control group according to whether they received Tα1 or not.A propensity score matching(PSM)analysis was performed to reduce bias,resulting in 1027 pairs of patients.Results:After PSM,the baseline clinicopathological characteristics were similar between the two groups.The 5-year disease-free survival(DFS)and overall survival(OS)rates were significantly higher in the Tα1 group compared with the control group.The multivariable analysis showed that Tα1 treatment was independently associated with an improved prognosis.A longer duration of Tα1 treatment was associated with improved OS and DFS.The subgroup analyses showed that Tα1 therapy could improve the DFS and/or OS in all subgroups of age,sex,Charlson Comorbidity Index(CCI),smoking status,and pathological tumor-node-metastasis(TNM)stage,especially for patients with non-squamous cell NSCLC and without targeted therapy.Conclusion:Tα1 as adjuvant immunomodulatory therapy can significantly improve DFS and OS in patients with NSCLC after R0 resection,except for patients with squamous cell carcinoma and those receiving targeted therapy.The duration of Tα1 treatment is recommended to be>24 months.
基金This work was supported by National Natural Science Foundation of China(32271445,52073193,and 82202322)National Science and Technology Major Project of China(2023YFB3810004)+2 种基金1‧3‧5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China)the Sichuan Science and Technology Program(2023NSFSC1592,China),the China Postdoctoral Science Foundation(2021M692255,China)the Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH094,China).Thanks to Guiping Yuan for her help of TEM images,and Zhiqian Li,Zhengju Chen,Yan Wang,Xiangyi Ren,Cong Li,Lei Wu and Yaping Wu(Histology and Imaging Platform,Research Core Facility,West China Hospital,Sichuan University)for their help in confocal imaging studies and Qiaorong Huang,Wentong Meng and Xue Li(Laboratory of Stem Cell Biology,West China Hospital,Sichuan University)for their help in flow cytometer.
文摘Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.
基金supported by the National Natural Science Foundation of China (Grants 31771549 to Y.C.,82103251 to J.Z.,82203153 to K.Z.,and 82203574 to S.W.)the 1.3.5 Project for Disciplines of Excellence (Grants ZYGD18021,ZYJC18009,ZYJC21002,and ZYJC21015)+1 种基金the China Postdoctoral Science Foundation (Grants 2020TQ0210 and 2021M692268 to J.Z.)Natural Science Foundation of Sichuan Province (Grant 2022NSFSC1438 to J.Z.).
文摘Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKl)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiting clinical efficacy.We found that TET2 was poly-ubiquitinated by E3 ligase CUL7^(FBXW11) and degraded in EGFR-TKI resistant NSCLC ells.Genetic perturbationof TET2 rendered parental cells more tolerant to TKI treatment.TET2 was stabilized by MEK1 phosphorylation at Ser 1107,while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7^(FBXW11),Loss of TET2 resulted in the upregulation of TNF/NF-kB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-kB attenuate the TKI resistance both in vitro and in vivo.Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2,and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency.Therefore,combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.