ROS regulation in gliomas: implications for treatment strategies.

Gliomas are one of the most common primary malignant tumours of the central nervous system (CNS), of which glioblastomas (GBMs) are the most common and destructive type. The glioma tumour microenvironment (TME) has unique characteristics, such as hypoxia, the blood-brain barrier (BBB), reactive oxygen species (ROS) and tumour neovascularization. Therefore, the traditional treatment effect is limited. As cellular oxidative metabolites, ROS not only promote the occurrence and development of gliomas but also affect immune cells in the immune microenvironment. In contrast, either too high or too low ROS levels are detrimental to the survival of glioma cells, which indicates the threshold of ROS. Therefore, an in-depth understanding of the mechanisms of ROS production and scavenging, the threshold of ROS, and the role of ROS in the glioma TME can provide new methods and strategies for glioma treatment. Current methods to increase ROS include photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), etc., and methods to eliminate ROS include the ingestion of antioxidants. Increasing/scavenging ROS is potentially applicable treatment, and further studies will help to provide more effective strategies for glioma treatment.

Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer.

Lung cancer is one of the most common malignant tumours worldwide, with the highest mortality rate. Approximately 1.6 million deaths owing to lung cancer are reported annually; of which, 85% of deaths occur owing to non-small-cell lung cancer (NSCLC). At present, the conventional treatment methods for NSCLC include radiotherapy, chemotherapy, targeted therapy and surgery. However, drug resistance and tumour invasion or metastasis often lead to treatment failure. The ubiquitin-proteasome pathway (UPP) plays an important role in the occurrence and development of tumours. Upregulation or inhibition of proteins or enzymes involved in UPP can promote or inhibit the occurrence and development of tumours, respectively. As regulators of UPP, ubiquitin-specific proteases (USPs) primarily inhibit the degradation of target proteins by proteasomes through deubiquitination and hence play a carcinogenic or anticancer role. This review focuses on the role of USPs in the occurrence and development of NSCLC and the potential of corresponding targeted drugs, PROTACs and small-molecule inhibitors in the treatment of NSCLC.

MSC Senescence-Related Genes Are Associated with Myeloma Prognosis and Lipid Metabolism-Mediated Resistance to Proteasome Inhibitors.

Background: Complex carcinogenic mechanisms and the existence of tumour heterogeneity in multiple myeloma (MM) prevent the most commonly used staging system from effectively interpreting the prognosis of patients. Since the microenvironment plays an important role in driving tumour development and MM occurs most often in middle-aged and elderly patients, we hypothesize that ageing of bone marrow mesenchymal stem cells (BM-MSCs) may be associated with the progression of MM. Methods: In this study, we collected the transcriptome data on MM from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Differentially expressed genes in both senescent MSCs and MM tumour cells were considered relevant damaged genes. GO and KEGG analyses were applied for functional evaluation. A PPI network was constructed to identify hub genes. Subsequently, we studied the damaged genes that affected the prognosis of MM. Least absolute shrinkage and selection operator (lasso) regression was used to identify the most important features, and a risk model was created. The reliability of the risk model was evaluated with the other 3 GEO validation cohorts. In addition, ROC analysis was used to evaluate the novel risk model. An analysis of immune checkpoint-related genes, tumour immune dysfunction and exclusion (TIDE), and immunophenotypic scoring (IPS) were performed to assess the immune status of risk groups. pRRophetic was utilized to predict the sensitivity to administration of chemotherapeutic agents. Results: We identified that MAPK, PI3K, and p53 signalling pathways were activated in both senescent MSCs and tumour cells, and we also located hub genes. In addition, we constructed a 14-gene prognostic risk model, which was analysed with the ROC and validated in different datasets. Further analysis revealed significant differences in predicted risk values across the International Staging System (ISS) stage, sex, and 1q21 copy number. A high-risk group with higher immunogenicity was predicted to have low proteasome inhibitor sensitivity and respond poorly to immunotherapy. Lipid metabolism pathways were found to be significantly different between high-risk and low-risk groups. A nomogram was created by combining clinical data, and the optimization model was further improved. Finally, real-time qPCR was used to validate two bortezomib-resistant myeloma cell lines, and the test confirmed that 10 genes were detected to be expressed in resistant cell lines with the same trend as in the high-risk cohort compared to nonresistant cells. Conclusion: Fourteen genes related to ageing in BM-MSCs were associated with the prognosis of MM, and by combining this genotypic information with clinical factors, a promising clinical prognostic model was established.