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Abstract Despite the favorable effects of immunotherapies in multiple types of cancers, its complete success in CNS malignancies remains challenging. Recently, a successful clinical trial of cytokine-induced killer (CIK) cell immunotherapy in patients with glioblastoma (GBM) has opened a new avenue for adoptive cellular immunotherapies in CNS malignancies. Prompt from these findings, herein, we investigated whether dendritic cells (DC) in combination with cytokine-induced killer cells (DC-CIK) could also provide an alternative and more effective way to improve the efficacy of GBM treatment. The analysis showed that DC-CIK cells exerted a significant cytotoxic effect on the glioblastoma cell lines, especially with the phenotype of stem-like cells (GSCs). In addition, the increased specific lysis of these cells subsequent to DC-CIK co-culture was confirmed with confocal fluorescence microscope. The direct interactions between tumor and effector cells were found to be highly effective in GBM organoids (GBOs). Moreover, a significant increase in apoptosis and elevated levels of IFN-γ (and not TNF-α) secretion were observed as a targeting mechanism of DC-CIK cells against GBM cell models. Overall, we provide important preliminary evidence that DC-CIK cells may have potential in the treatment of CNS malignancies, particularly glioblastoma.

Abstract The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.

ABSTRACT Background Cytokine‐induced killer (CIK) cell therapy has proven successful in clinical trials regarding glioblastoma. Equally important are the hints suggesting peroxisome proliferator‐activated receptors (PPARs) ligands being co‐expressed in the central nervous system (CNS). This provides a rationale about investigating the possible synergistic effect of CIK cells and PPARs. Methodology We investigated neuroblastoma and glioblastoma cell lines with mature CIK cells and the PPARγ antagonist GW‐9662 to assess the effects on cell viability, candidate gene expression (Wnt/β‐catenin signalling, DNMT1) and global methylation levels (5‐methylcytosine, LINE‐1). Results Using a clinical applicable PPAR‐γ inhibitor, we showed that (1) PPARγ‐antagonist GW‐9662 suppressed tumor cell growth in both neuroblastoma and glioblastoma cells, (2) PPARγ inhibition had restricted effect on the expression of Wnt/β‐catenin associated genes, (3) inhibition of PPARγ led to downregulation of DNMT1 expression, supporting their hypothesized interaction in cancer, (4) a partial modulation of global LINE‐1 methylation levels was observed, indicating their role in epigenetic processes, and (5) Combining PPARγ inhibition with CIK cell immunotherapy enhanced cell lysis significantly. Conclusion We provide evidence that PPAR ligands in combination with CIK cell immunotherapy could be a valuable option for malignant CNS tumors.

Abstract Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

Abstract Histone deacetylase (HDAC) inhibitors have enormous therapeutic potential as effective epigenetic regulators, and now with the focus on the selective HDAC6 inhibitor in ongoing clinical trials, more advantages over other non-selective pan-HDAC inhibitors are foreseeable. As it is of paramount importance to understand the complex regulatory web of mutual interactions involving epigenetic machinery and non-coding genome in regulating gene expression, herein, we investigated the intriguing interactions between HDAC6-induced lncRNA (LINC00152) and its possible sponge miRNA (hsa-miR-499a-5p) in multiple myeloma.

Alzheimer's disease (AD) is the leading cause of dementia and is rapidly becoming one of the most costly, fatal diseases, which is typically discovered in the late stage of molecular pathology, at which point medication intervention is irreversible. As a result, there is an urgent need for a low-cost, least-invasive way of screening cognitive impairment, with the goal of identifying persons at risk of AD. Mild cognitive impairment (MCI) has been described as a transitional state between normal cognitive aging and AD. Early detection and timely tracking of MCI can to some extent prevent the progression towards AD. We found a population in Northwestern China has a comparatively high prevalence of MCI. Continued education, consistent exercise, and a secure financial situation can all help older people maintain cognitive function. Due to the critical role of circulating microRNAs in intercellular signaling and the perturbations thereof, their investigation has assumed paramount significance in elucidating various pathological conditions. Numerous investigations have substantiated the significance of circulating miRNAs specifically in MCI. Here, we evaluated miR-483-5p (Area Under the Curve (AUC) is 0.901, sensitivity 79.2 % and specificity 100 %) and miR-502-5p (AUC is 0.872, sensitivity 79.2 % and specificity 83.3 %), which were derived from plasma exosomes and maintained at high levels in elderly people with MCI, could be employed as promising noninvasive biomarkers.

Abstract Objectives The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine‐induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study. Methods We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM‐2 and NCI‐H929). Utilising various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions. Results The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN‐γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings. Conclusions Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis‐CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D‐ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.