As a cold tumor, malignant glioma has strong immunosuppression and immune escape characteristics. The tumor microenvironment (TME) provides the “soil” for the survival of malignant tumors, and cancer-associated fibroblasts (CAFs) are the architects of matrix remodeling in TME. Therefore, CAFs have potent regulatory effects on the recruitment and functional differentiation of immune cells, whereby they synthesize and secrete numerous collagens, cytokines, chemokines, and other soluble factors whose interaction with tumor cells creates an immunosuppressive TME. This consequently facilitates the immune escape of tumor cells. Targeting CAFs would improve the TME and enhance the efficacy of immunotherapy. Thus, regulation of CAFs and CAFs-related genes holds promise as effective immunotherapies for gliomas. Here, by analyzing the Chinese Glioma Genome Atlas and the Cancer Genome Atlas database, the proportion of CAFs in the tumor was revealed to be associated with clinical and immune characteristics of gliomas. Moreover, a risk model based on the expression of CAFs-related six-gene for the assessment of glioma patients was constructed using the least absolute shrinkage and selection operator and the results showed that a high-risk group had a higher expression of the CAFs-related six-genes and lower overall survival rates compared with those in the low-risk group. Additionally, patients in the high-risk group exhibited older age, high tumor grade, isocitrate dehydrogenase wildtype, 1p/19q non-codeletion, O-6-methylguanine-DNA methyltransferase promoter unmethylation and poor prognosis. The high-risk subtype had a high proportion CAFs in the TME of glioma, and a high expression of immune checkpoint genes. Analysis of the Submap algorithm indicated that the high-risk patients could show potent response to anti-PD-1 therapy. The established risk prediction model based on the expression of six CAFs-related genes has application prospects as an independent prognostic indicator and a predictor of the response of patients to immunotherapy.
Glioblastoma (GBM) is the most common malignant craniocerebral tumor. The treatment of this cancer is difficult due to its high heterogeneity and immunosuppressive microenvironment. Ferroptosis is a newly found non-apoptotic regulatory cell death process that plays a vital role in a variety of brain diseases, including cerebral hemorrhage, neurodegenerative diseases, and primary or metastatic brain tumors. Recent studies have shown that targeting ferroptosis can be an effective strategy to overcome resistance to tumor therapy and immune escape mechanisms. This suggests that combining ferroptosis-based therapies with other treatments may be an effective strategy to improve the treatment of GBM. Here, we critically reviewed existing studies on the effect of ferroptosis on GBM therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In particular, this review discussed the potential of ferroptosis inducers to reverse drug resistance and enhance the sensitivity of conventional cancer therapy in combination with ferroptosis. Finally, we highlighted the therapeutic opportunities and challenges facing the clinical application of ferroptosis-based therapies in GBM. The data generated here provide new insights and directions for future research on the significance of ferroptosis-based therapies in GBM.
Introduction Cerebral microbleeds (CMBs) are frequently found in the healthy elderly. However, data on the prevalence and risk factors of CMBs in the general population of China are lacking. Methods A cross-sectional study focusing on the prevalence and risk factors of CMBs was conducted in stroke-free elderly from Shanghai Wuliqiao community. MRI was performed at 3Tesla and cardiovascular risk factors (eg, age, smoking history, and hypertension), cerebral small vessel disease (CSVD) markers (eg, white matter hyperintensities, lacunar infarction, and enlarged perivascular space) and genetic information (eg, APOE, CR1) were recorded. Poisson regression was used to analyze the risk factors of the presence and location of microbleeds. Results A total of 199 participants (70.8±7.2 years old; male 31.2%) were finally included in our analysis. The overall prevalence of CMBs was 12.6% (25/199) and increased with age from 7.5% (55–64 years old) to 19.3% (over 75 years old). Of those with CMBs, most of them (16/25) located in the deep/mixed region and had 1–2 CMBs (18/25). Poisson regression analysis showed that white matter hyperintensities (OR=1.22, 95% CI: 1.16–1.29), APOE ε4+ carrier (OR=2.16, 95% CI: 1.18–3.96) and CR1 non-F/F isoform (OR=7.78, 95% CI: 4.34–13.96) were associated with CMBs. Further analysis found that in addition to the above three risk factors, hypertension (OR=2.98, 95% CI: 1.16–7.64), lacunar infarction (OR=2.39, 95% CI: 1.19–4.81) also increased the risk of deep/mixed CMBs. Conclusion The prevalence of cerebral microbleeds is similar to other countries. Cardiovascular risk factors, CSVD markers, and genetic factors (APOE ε4, CR1 non-F/F isoform) were associated with CMBs, suggesting an interaction of multiple pathogenesis in Chinese stroke-free community population.
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