Background:Low-grade gliomas(LGG)are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults.Currently,LGG treatment involves either or a combination of surgery,radiation therapy,and...Background:Low-grade gliomas(LGG)are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults.Currently,LGG treatment involves either or a combination of surgery,radiation therapy,and chemotherapy.Despite the knowledge of constitutive genetic risk factors contributing to gliomas,the role of single genes as diagnostic and prognostic biomarkers is limited.The aim of the current study is to discover the predictive and prognostic genetic markers for LGG.Methods:Transcriptome data and clinical data were obtained from The Cancer Genome Atlas(TCGA)database.We first performed the tumor microenvironment(TME)survival analysis using the Kaplan-Meier method.An analysis was undertaken to screen for differentially expressed genes.The function of these genes was studied by Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis.Following which a protein-protein interaction network(PPI)was constructed and visualized.Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes.The key genes were selected by an intersection of core and prognostic genes.A clinical correlation analysis of single-gene expression was undertaken.GSEA enrichment analysis was performed to identify the function of key genes.Finally,a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG.Results:A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA.Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment.The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified.Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG.Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration,positively related to macrophage M1 phenotype,and negatively related to activation of NK cells.Conclusions:HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients.It may also be associated with the immune infiltration phenotype in LGG.展开更多
Background:Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in“carrier”or“pathogenic”states.HLA DQ and HLA DR humanized mice have been used as a small animal model to stu...Background:Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in“carrier”or“pathogenic”states.HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S.aureus infection.However,the contribution of HLA DP to S.aureus infection is unknown yet.Methods:In this study,we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes.Neo-floxed IAβ+/-mice were crossbred with Ella-Cre and further crossbred with HLA DP401 or HLA-DRA0101 humanized mice.After several rounds of traditional crossbreeding,we finally obtained HLA DP401-IAβ-/-and HLA DRA-IAβ-/-humanized mice,in which human DP401 or DRA0101 molecule was introduced into IAβ-/-mice deficient in endogenous murine MHC classⅡmolecules.A transnasal infection murine model of S.aureus pneumonia was induced in the humanized mice by administering 2×108CFU of S.aureus Newman dropwise into the nasal cavity.The immune responses and histopathology changes were further assessed in lungs in these infected mice.Results:We evaluated the local and systemic effects of S.aureus delivered intranasally in HLA DP401-IAβ-/-and HLA DRA-IAβ-/-transgenic mice.S.aureus Newman infection significantly increased the m RNA level of IL 12p40 in lungs in humanized mice.An increase in IFN-γand IL-6 protein was observed in HLA DRA-IAβ-/-mice.We observed a declining trend in the percentage of F4/80+macrophages in lungs in HLA DP401-IAβ-/-mice and a decreasing ratio of CD4+to CD8+T cells in lungs in IAβ-/-mice and HLA DP401-IAβ-/-mice.A decreasing ratio of Vβ3+to Vβ8+T cells was also found in the lymph node of IAβ-/-mice and HLA DP401-IAβ-/-mice.S.aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ-/-genetic background mice.Conclusion:These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S.aureus pneumonia and study what role DP molecule plays in S.aureus infection.展开更多
基金the National Natural Science Foundation of China(No.82173384 and 81773161)
文摘Background:Low-grade gliomas(LGG)are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults.Currently,LGG treatment involves either or a combination of surgery,radiation therapy,and chemotherapy.Despite the knowledge of constitutive genetic risk factors contributing to gliomas,the role of single genes as diagnostic and prognostic biomarkers is limited.The aim of the current study is to discover the predictive and prognostic genetic markers for LGG.Methods:Transcriptome data and clinical data were obtained from The Cancer Genome Atlas(TCGA)database.We first performed the tumor microenvironment(TME)survival analysis using the Kaplan-Meier method.An analysis was undertaken to screen for differentially expressed genes.The function of these genes was studied by Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis.Following which a protein-protein interaction network(PPI)was constructed and visualized.Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes.The key genes were selected by an intersection of core and prognostic genes.A clinical correlation analysis of single-gene expression was undertaken.GSEA enrichment analysis was performed to identify the function of key genes.Finally,a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG.Results:A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA.Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment.The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified.Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG.Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration,positively related to macrophage M1 phenotype,and negatively related to activation of NK cells.Conclusions:HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients.It may also be associated with the immune infiltration phenotype in LGG.
基金National Science and Technology Major Project,Grant/Award Number:2016YFD0500208,2017ZX10304402-001-012 and 2017ZX10304402-001-006Shanghai Science and Technology Commission“R&D public service platform and institutional capacity improvement project”,Grant/Award Number:21DZ2291300Shanghai Public Health Clinical Center projects,Grant/Award Number:KY-GW-2021-39,KY-GW-2019-19 and KY-GW-2019-11。
文摘Background:Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in“carrier”or“pathogenic”states.HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S.aureus infection.However,the contribution of HLA DP to S.aureus infection is unknown yet.Methods:In this study,we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes.Neo-floxed IAβ+/-mice were crossbred with Ella-Cre and further crossbred with HLA DP401 or HLA-DRA0101 humanized mice.After several rounds of traditional crossbreeding,we finally obtained HLA DP401-IAβ-/-and HLA DRA-IAβ-/-humanized mice,in which human DP401 or DRA0101 molecule was introduced into IAβ-/-mice deficient in endogenous murine MHC classⅡmolecules.A transnasal infection murine model of S.aureus pneumonia was induced in the humanized mice by administering 2×108CFU of S.aureus Newman dropwise into the nasal cavity.The immune responses and histopathology changes were further assessed in lungs in these infected mice.Results:We evaluated the local and systemic effects of S.aureus delivered intranasally in HLA DP401-IAβ-/-and HLA DRA-IAβ-/-transgenic mice.S.aureus Newman infection significantly increased the m RNA level of IL 12p40 in lungs in humanized mice.An increase in IFN-γand IL-6 protein was observed in HLA DRA-IAβ-/-mice.We observed a declining trend in the percentage of F4/80+macrophages in lungs in HLA DP401-IAβ-/-mice and a decreasing ratio of CD4+to CD8+T cells in lungs in IAβ-/-mice and HLA DP401-IAβ-/-mice.A decreasing ratio of Vβ3+to Vβ8+T cells was also found in the lymph node of IAβ-/-mice and HLA DP401-IAβ-/-mice.S.aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ-/-genetic background mice.Conclusion:These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S.aureus pneumonia and study what role DP molecule plays in S.aureus infection.
