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Summary: Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn−/−) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP’s involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn−/− primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Background: Previous studies have reported the critical roles of tumor cells and the tumor microenvironment in tumor prognosis and immunotherapeutic response. However, how Tenascin-XB (TNXB) expression relates to glioma prognosis and to the levels of tumor-infiltrating immune cells in various cancers has remained elusive. Therefore, this work aimed to investigate the expression, prognostic value, biological function and correlation between TNXB expression and the levels of tumor-infiltrating immune cells in glioma tissues.Methods: First, we explored TNXB expression in glioma tissues by using online biological databases. Second, we assessed the clinical importance of TNXB expression with chi-squared tests, Cox regression and Kaplan-Meier curve analyses. Third, we examined the relationship between TNXB expression and the levels of tumor-infiltrating immune cells in glioma tissues in an online database. Additionally, we assessed the associations of TNXB expression with genetic markers of immune cells and common immune-checkpoint molecules.Results: Elevated TNXB expression in glioma tissues correlated with tumor grade, according to several databases. Elevated TNXB expression was significantly associated with negative clinicopathological manifestations and poorer prognosis, on the basis of TCGA (n=510) data. Furthermore, univariate and multivariate Cox regression indicated that TNXB was an independent indicator of glioma prognosis. Pathway enrichment analyses suggested that TNXB participates in the immune response, humoral immune response and interferon-gamma-mediated signaling pathways. Importantly, TNXB expression was significantly associated with higher levels of tumor-infiltrating immune cells in diverse cancers. Furthermore, TNXB expression was strongly associated with genetic markers of immune cells and common immune-checkpoint molecules (e.g., PD-1, PD-L1, CTLA4, TIM-3, LAG3, PDCD1LG2, TIGIT and Siglec-15).Conclusions: TNXB expression correlates with poorer prognosis and higher levels of tumor-infiltrating immune cells in several cancers. In addition, TNXB expression is likely to contribute to the regulation of dendritic cells, exhausted T cells, regulatory T cells and tumor-associated macrophages in gliomas. Consequently, TNXB may serve as an important prognostic marker and may play an immunomodulatory role in tumors.

Abstract Background C5AR2 is recognized as a proinflammatory molecule and activates the inflammatory response in multiple disorders. However, little has been reported on C5AR2 in glioma. This study sought to explore its expression, biological function, and association with clinical pathological indicators, prognosis, and immune infiltration levels in glioma through glioma cohorts. Methods A cohort of 657 patients was screened from the Chinese Glioma Genome Atlas (CGGA). χ2 test was performed to calculate the difference of classified variables. Cox proportional hazard regression modeling was used to identify independent prognostic indicators of glioma patients. A survival plot was generated by the Kaplan–Meier method. The immune cell infiltration score of glioma patients was calculated by TIMER algorithm. Results We observed that high expression of C5AR2 was strongly associated with malignant clinical indicators in 657 patients with glioma, and patients with high C5AR2 expression had worse prognoses. Multivariate Cox analysis showed that C5AR2 could be a new independent prognostic indicator for glioma patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that C5AR2 overexpression correlated with multiple inflammatory and immune biological processes. Additionally, high C5AR2 expression was strongly associated with higher abundance and marker gene expression of multiple tumor immune cells in low‐grade glioma. Finally, a model was constructed to improve the prognostic evaluation of glioma patients. Conclusions The C5AR2 gene is highly expressed in gliomas and is significantly associated with clinical indicators of malignant progression in glioma patients. In glioma, patients with high C5AR2 expression displayed a worse outcome. In glioma tissues, the expression level of C5AR2 highly correlated with the abundance of tumor immune cell infiltration. Additionally, GO and KEGG enrichment analysis revealed that C5AR2 expression may be involved in a variety of immune and inflammatory biological processes.

The evaluation on prognosis of glioma patients is critical for the individualized treatment. Despite of the widely used mRNA expression level and methylation status of prognostic genes in predicting the patients’ prognosis, the clinical application of high-throughput sequencing technology is still limited. Thus, this study aimed to construct a visual and reliable nomogram based on the common clinicopathological parameters for predicting the prognosis of patients diagnosed with high grade glioma (HGG). Notably, age, histopathology, IDH status, 1p/19q status, radiotherapy status, chemotherapy status, and tumor recurrence were identified as seven independent prognostic factors for HGG patients. A comprehensive nomogram based on the seven identified factors was subsequently constructed with the remarkable C-index of 0.732. Calibrations for nomogram showed great consistency between the predictive values and the actual values in 1-, 3-, and 5-year survival rates. Besides, the areas under the ROC curve (AUC) for predicting 1-, 3-, and 5-year survival rates of patients had the values of 0.796 (95% CI: 0.759-0.833), 0.809 (95% CI: 0.770-0.848), and 0.820 (95% CI: 0.771-0.869), respectively. Furthermore, an external cohort (n=89) was used to validate the nomogram. In conclusion, age, histopathology, IDH status, 1p/19q status, radiotherapy status, chemotherapy status, and tumor progression were identified as independent prognostic factors, on which a visual predictive model was constructed with powerful predictive value.