GBM Immunotherapy: Macrophage Impacts.

BACKGROUND: Glioblastoma (GBM) is an extremely aggressive form of brain tumor with low survival rates. Current treatments such as chemotherapy, radiation, and surgery are problematic due to tumor growth, invasion, and tumor microenvironment. GBM cells are resistant to these standard treatments, and the heterogeneity of the tumor makes it difficult to find a universal approach. Progression of GBM and acquisition of resistance to therapy are due to the complex interplay between tumor cells and the TME. A significant portion of the TME consists of an inflammatory infiltrate, with microglia and macrophages being the predominant cells. METHODS: Analysis of the literature data over a course of 5 years suggest that the tumor-associated macrophages (TAMs) are capable of releasing cytokines and growth factors that promote tumor proliferation, survival, and metastasis while inhibiting immune cell function at the same time. RESULTS: Thus, immunosuppressive state, provided with this intensively studied kind of TME cells, is supposed to promote GBM development through TAMs modulation of tumor treatment-resistance and aggressiveness. Therefore, TAMs are an attractive therapeutic target in the treatment of glioblastoma. CONCLUSION: This review provides a comprehensive overview of the latest research on the nature of TAMs and the development of therapeutic strategies targeting TAMs, focusing on the variety of macrophage properties, being modulated, as well as molecular targets.

Advances of Genome Editing with CRISPR/Cas9 in Neurodegeneration: The Right Path towards Therapy.

The rate of neurodegenerative disorders (NDDs) is rising rapidly as the world's population ages. Conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia are becoming more prevalent and are now the fourth leading cause of death, following heart disease, cancer, and stroke. Although modern diagnostic techniques for detecting NDDs are varied, scientists are continuously seeking new and improved methods to enable early and precise detection. In addition to that, the present treatment options are limited to symptomatic therapy, which is effective in reducing the progression of neurodegeneration but lacks the ability to target the root cause-progressive loss of neuronal functioning. As a result, medical researchers continue to explore new treatments for these conditions. Here, we present a comprehensive summary of the key features of NDDs and an overview of the underlying mechanisms of neuroimmune dysfunction. Additionally, we dive into the cutting-edge treatment options that gene therapy provides in the quest to treat these disorders.

Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells.

Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.