Objective:The combination of epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)and immune checkpoint inhibitors(ICIs)leads to an increased incidence of severe immune-related adverse events(irAEs)....Objective:The combination of epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)and immune checkpoint inhibitors(ICIs)leads to an increased incidence of severe immune-related adverse events(irAEs).However,the mechanisms underlying macrophages in irAEs have not been elucidated.Methods:An osimertinib and ICI-induced irAE mouse model was constructed.Lung micro-CT scans were used to assess the degree of inflammatory infiltration.Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues.Flow cytometry was used to detect the percentages of T cells,NK cells,and macrophages and the expression of EGFR.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum interleukin(IL)-6,alanine transaminase(ALT),ferritin,and tumor necrosis factor(TNF)-αlevels.Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq.Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state.Results:Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6,ALT,and ferritin levels.RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group.Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6,ALT,and ferritin levels in the combination treatment group.Conclusions:An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages,which led to the release of relevant cytokines.展开更多
The observation of oxygen(O)-and nitrogen(N)-bearing molecules gives an idea about the complex prebiotic chemistry in the interstellar medium.Recent millimeter and submillimeter wavelength observations have shown the ...The observation of oxygen(O)-and nitrogen(N)-bearing molecules gives an idea about the complex prebiotic chemistry in the interstellar medium.Recent millimeter and submillimeter wavelength observations have shown the presence of complex O-and N-bearing molecules in the star formation regions.So,the investigation of those molecules is crucial to understanding the chemical complexity in the star-forming regions.In this article,we present the identification of the rotational emission lines of N-bearing molecules ethyl cyanide(C_(2)H_(5)CN)and cyanoacetylene(HC_(3)N),and O-bearing molecule methyl formate(CH_(3)OCHO)toward high-mass protostar IRAS18089–1732 using the Atacama Compact Array.We also detected the emission lines of both the N-and O-bearing molecule formamide(NH_(2)CHO)in the envelope of IRAS 18089–1732.We have detected the v=0 and 1 state rotational emission lines of CH_(3)OCHO.We also detected the two vibrationally excited states of HC_(3)N(v7=1 and v7=2).The estimated fractional abundances of C_(2)H_(5)CN,HC_(3)N(v7=1),HC_(3)N(v7=2),and NH_(2)CHO toward IRAS 18089–1732 are(1.40±0.5)×10^(-10),(7.5±0.7)×10^(-11),(3.1±0.4)×10^(-11),and(6.25±0.82)×10^(-11)respectively.Similarly,the estimated fractional abundances of CH_(3)OCHO(v=0)and CH_(3)OCHO(v=1)are(1.90±0.9)×10^(-9)and(8.90±0.8)×10^(-10),respectively.We also created the integrated emission maps of the detected molecules,and the observed molecules may have originated from the extended envelope of the protostar.We show that C_(2)H_(5)CNand HC_(3)N are most probably formed via the subsequential hydrogenation of the CH_(2)CHCNand the reaction between C_(2)H_(2)and CN on the grain surface of IRAS 18089–1732.We found that NH_(2)CHO is probably produced due to the reaction between NH_(2)and H_(2)CO in the gas phase.Similarly,CH_(3)OCHO is possibly created via the reaction between radical CH_(3)O and radical HCO on the grain surface of IRAS 18089–1732.展开更多
基金funded by grants from the National Natural Science Foundation of China(Grant Nos.82003288,U20A20375,82372779,and 82103001)Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-009A).
文摘Objective:The combination of epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)and immune checkpoint inhibitors(ICIs)leads to an increased incidence of severe immune-related adverse events(irAEs).However,the mechanisms underlying macrophages in irAEs have not been elucidated.Methods:An osimertinib and ICI-induced irAE mouse model was constructed.Lung micro-CT scans were used to assess the degree of inflammatory infiltration.Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues.Flow cytometry was used to detect the percentages of T cells,NK cells,and macrophages and the expression of EGFR.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum interleukin(IL)-6,alanine transaminase(ALT),ferritin,and tumor necrosis factor(TNF)-αlevels.Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq.Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state.Results:Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6,ALT,and ferritin levels.RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group.Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6,ALT,and ferritin levels in the combination treatment group.Conclusions:An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages,which led to the release of relevant cytokines.
基金the Swami Vivekananda Merit-cum-Means Scholarship(SVMCM)for financial support for this research。
文摘The observation of oxygen(O)-and nitrogen(N)-bearing molecules gives an idea about the complex prebiotic chemistry in the interstellar medium.Recent millimeter and submillimeter wavelength observations have shown the presence of complex O-and N-bearing molecules in the star formation regions.So,the investigation of those molecules is crucial to understanding the chemical complexity in the star-forming regions.In this article,we present the identification of the rotational emission lines of N-bearing molecules ethyl cyanide(C_(2)H_(5)CN)and cyanoacetylene(HC_(3)N),and O-bearing molecule methyl formate(CH_(3)OCHO)toward high-mass protostar IRAS18089–1732 using the Atacama Compact Array.We also detected the emission lines of both the N-and O-bearing molecule formamide(NH_(2)CHO)in the envelope of IRAS 18089–1732.We have detected the v=0 and 1 state rotational emission lines of CH_(3)OCHO.We also detected the two vibrationally excited states of HC_(3)N(v7=1 and v7=2).The estimated fractional abundances of C_(2)H_(5)CN,HC_(3)N(v7=1),HC_(3)N(v7=2),and NH_(2)CHO toward IRAS 18089–1732 are(1.40±0.5)×10^(-10),(7.5±0.7)×10^(-11),(3.1±0.4)×10^(-11),and(6.25±0.82)×10^(-11)respectively.Similarly,the estimated fractional abundances of CH_(3)OCHO(v=0)and CH_(3)OCHO(v=1)are(1.90±0.9)×10^(-9)and(8.90±0.8)×10^(-10),respectively.We also created the integrated emission maps of the detected molecules,and the observed molecules may have originated from the extended envelope of the protostar.We show that C_(2)H_(5)CNand HC_(3)N are most probably formed via the subsequential hydrogenation of the CH_(2)CHCNand the reaction between C_(2)H_(2)and CN on the grain surface of IRAS 18089–1732.We found that NH_(2)CHO is probably produced due to the reaction between NH_(2)and H_(2)CO in the gas phase.Similarly,CH_(3)OCHO is possibly created via the reaction between radical CH_(3)O and radical HCO on the grain surface of IRAS 18089–1732.
