Local delivery of carboplatin-loaded hydrogel and calcium carbonate enables two-stage drug release for limited-dose radiation to eliminate mouse malignant glioma.

Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 µL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 µg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.

Comparing spatial distributions of ALA-PpIX and indocyanine green in a whole pig brain glioma model using 3D fluorescence cryotomography.

Significance: ALA-PpIX and second-window indocyanine green (ICG) have been studied widely for guiding the resection of high-grade gliomas. These agents have different mechanisms of action and uptake characteristics, which can affect their performance as surgical guidance agents. Elucidating these differences in animal models that approach the size and anatomy of the human brain would help guide the use of these agents. Herein, we report on the use of a new pig glioma model and fluorescence cryotomography to evaluate the 3D distributions of both agents throughout the whole brain. Aim: We aim to assess and compare the 3D spatial distributions of ALA-PpIX and second-window ICG in a glioma-bearing pig brain using fluorescence cryotomography. Approach: A glioma was induced in the brain of a transgenic Oncopig via adeno-associated virus delivery of Cre-recombinase plasmids. After tumor induction, the pro-drug 5-ALA and ICG were administered to the animal 3 and 24 h prior to brain harvest, respectively. The harvested brain was imaged using fluorescence cryotomography. The fluorescence distributions of both agents were evaluated in 3D in the whole brain using various spatial distribution and contrast performance metrics. Results: Significant differences in the spatial distributions of both agents were observed. Indocyanine green accumulated within the tumor core, whereas ALA-PpIX appeared more toward the tumor periphery. Both ALA-PpIX and second-window ICG provided elevated tumor-to-background contrast (13 and 23, respectively). Conclusions: This study is the first to demonstrate the use of a new glioma model and large-specimen fluorescence cryotomography to evaluate and compare imaging agent distribution at high resolution in 3D.

Targeting ferroptosis opens new avenues in gliomas.

Gliomas are one of the most challenging tumors to treat due to their malignant phenotype, brain parenchymal infiltration, intratumoral heterogeneity, and immunosuppressive microenvironment, resulting in a high recurrence rate and dismal five-year survival rate. The current standard therapies, including maximum tumor resection, chemotherapy with temozolomide, and radiotherapy, have exhibited limited efficacy, which is caused partially by the resistance of tumor cell death. Recent studies have revealed that ferroptosis, a newly defined programmed cell death (PCD), plays a crucial role in the occurrence and progression of gliomas and significantly affects the efficacy of various treatments, representing a promising therapeutic strategy. In this review, we provide a comprehensive overview of the latest progress in ferroptosis, its involvement and regulation in the pathophysiological process of gliomas, various treatment hotspots, the existing obstacles, and future directions worth investigating. Our review sheds light on providing novel insights into manipulating ferroptosis to provide potential targets and strategies of glioma treatment.

Comment on "gemcitabine, PI3kinase-Akt pathway inhibition and radiation in human glioma cell lines" by M.S. Elnaggar et al.1.

The combination of gemcitabine, PI3K-Akt pathway inhibitors, and radiation in human glioma cell lines shows potential to enhance radiation sensitivity in aggressive brain tumors. Inhibiting the overactive PI3K-Akt pathway may increase tumor vulnerability to treatment. However, variability in responses among different glioma cell lines highlights the need for personalized approaches. Future research should focus on identifying biomarkers to tailor treatment for individual patients. Additionally, addressing safety concerns and the challenges of translating preclinical findings into clinical practice is crucial. Further studies should explore the therapy's molecular mechanisms and evaluate its clinical potential.

The Importance of Biotinylation for the Suitability of Cationic and Neutral Fourth-Generation Polyamidoamine Dendrimers as Targeted Drug Carriers in the Therapy of Glioma and Liver Cancer.

In this study, we hypothesized that biotinylated and/or glycidol-flanked fourth-generation polyamidoamine (PAMAM G4) dendrimers could be a tool for efficient drug transport into glioma and liver cancer cells. For this purpose, native PAMAM (G4) dendrimers, biotinylated (G4B), glycidylated (G4gl), and biotinylated and glycidylated (G4Bgl), were synthesized, and their cytotoxicity, uptake, and accumulation in vitro and in vivo were studied in relation to the transport mediated by the sodium-dependent multivitamin transporter (SMVT). The studies showed that the human temozolomide-resistant glioma cell line (U-118 MG) and hepatocellular carcinoma cell line (HepG2) indicated a higher amount of SMVT than human HaCaT keratinocytes (HaCaTs) used as a model of normal cells. The G4gl and G4Bgl dendrimers were highly biocompatible in vitro (they did not affect proliferation and mitochondrial activity) against HaCaT and U-118 MG glioma cells and in vivo (against Caenorhabditis elegans and Wistar rats). The studied compounds penetrated efficiently into all studied cell lines, but inconsistently with the uptake pattern observed for biotin and disproportionately for the level of SMVT. G4Bgl was taken up and accumulated after 48 h to the highest degree in glioma U-118 MG cells, where it was distributed in the whole cell area, including the nuclei. It did not induce resistance symptoms in glioma cells, unlike HepG2 cells. Based on studies on Wistar rats, there are indications that it can also penetrate the blood-brain barrier and act in the central nervous system area. Therefore, it might be a promising candidate for a carrier of therapeutic agents in glioma therapy. In turn, visualization with a confocal microscope showed that biotinylated G4B penetrated efficiently into the body of C. elegans, and it may be a useful vehicle for drugs used in anthelmintic therapy.

Beyond surgical resection: evaluating stereotactic brachytherapy iodine-125 for low-grade gliomas: a systematic review and meta-analysis.

Stereotactic Brachytherapy Iodine-125 (SBT I-125) has been investigated by some studies for the treatment of lowgrade gliomas. We performed a meta-analysis to assess the efficacy and safety of SBT I-125 Brachytherapy for treatment of patients with Low-Grade Gliomas. PubMed, Cochrane, Web of Science, and EMBASE databases were searched for randomized and observational studies. This systematic review and meta-analysis was conducted according to the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. We used relative risk (RR) with 95% confidence intervals and random effects model to compare the effects of I-125 SBT treatment on the interest outcomes. We evaluated heterogeneity using I2 statistics; we considered heterogeneity to be significant if the p-value was less than 0.05 and I2 was higher than 35%. We performed statistical analysis using the software R (version 4.2.3). A total of 20 studies with a cohort of 988 patients with low grade gliomas who received SBT I-125 as a treatment option. The pooled analysis evidenced: (1) Complication rate of 10% (95% CI: 7-12%; I² = 60%); (2) 5-year PFS of 66% (99% CI: 45-86%; I²= 98%); (3) 10-year PFS was 66% (99% CI: 45-86%; I²= 98%); (4) Malignant transformation rate of 26% (95% CI: 8-45%; I²=0); (5) Mortality of 33% (95% CI: 15-51%; I² = 0%). Our systematic review and meta-analysis of SBT I-125 for low-grade gliomas have revealed significant concerns regarding its safety and efficacy. Despite a proportion of patients remaining progression-free, elevated rates of complications and mortality cast doubt on the intervention's reliability. Future research should prioritize long-term follow-up studies, standardized protocols, and comparative effectiveness research.

Elevated α-1,2-mannosidase MAN1C1 in glioma stem cells and its implications for immunological changes and prognosis in glioma patients.

Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor, and the presence of glioma stem cells (GSCs) has been linked to its resistance to treatments and recurrence. Additionally, aberrant glycosylation has been implicated in the aggressiveness of cancers. However, the influence and underlying mechanism of N-glycosylation on the GSC phenotype and GBM malignancy remain elusive. Here, we performed an in-silico analysis approach on publicly available datasets to examine the function of N-glycosylation-related genes in GSCs and gliomas, accompanied by a qRT-PCR validation experiment. We found that high α-1,2-mannosidase MAN1C1 is associated with immunological functions and worse survival of glioma patients. Differential gene expression analysis and qRT-PCR validation revealed that MAN1C1 is highly expressed in GSCs. Furthermore, higher MAN1C1 expression predicts worse outcomes in glioma patients. Also, MAN1C1 expression is increased in the perinecrotic region of GBM and is associated with immunological and inflammatory functions, a hallmark of the GBM mesenchymal subtype. Further analysis confirmed that MAN1C1 expression is closely associated with infiltrating immune cells and disrupted immune response in the GBM microenvironment. These suggest that MAN1C1 is a potential biomarker for gliomas and may be important as an immunotherapeutic target for GBM.

Machine learning predicts cuproptosis-related lncRNAs and survival in glioma patients.

Gliomas are the most common tumor in the central nervous system in adults, with glioblastoma (GBM) representing the most malignant form, while low-grade glioma (LGG) is a less severe. The prognosis for glioma remains poor even after various treatments, such as chemotherapy and immunotherapy. Cuproptosis is a newly defined form of programmed cell death, distinct from ferroptosis and apoptosis, primarily caused by the accumulation of the copper within cells. In this study, we compared the difference between the expression of cuproptosis-related genes in GBM and LGG, respectively, and conducted further analysis on the enrichment pathways of the exclusive expressed cuproptosis-related mRNAs in GBM and LGG. We established two prediction models for survival status using xgboost and random forest algorithms and applied the ROSE algorithm to balance the dataset to improve model performance.

Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.

Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.

Blood based metabolic markers of glioma from pre-diagnosis to surgery.

Gliomas are highly complex and metabolically active brain tumors associated with poor prognosis. Recent reports have found altered levels of blood metabolites during early tumor development, suggesting that tumor development could be detected several years before clinical manifestation. In this study, we performed metabolite analyses of blood samples collected from healthy controls and future glioma patients, up to eight years before glioma diagnosis, and on the day of glioma surgery. We discovered that metabolites related to early glioma development were associated with an increased energy turnover, as highlighted by elevated levels of TCA-related metabolites such as fumarate, malate, lactate and pyruvate in pre-diagnostic cases. We also found that metabolites related to glioma progression at surgery were primarily high levels of amino acids and metabolites of amino acid catabolism, with elevated levels of 11 amino acids and two branched-chain alpha-ketoacids, ketoleucine and ketoisoleucine. High amino acid turnover in glioma tumor tissue is currently utilized for PET imaging, diagnosis and delineation of tumor margins. By examining blood-based metabolic progression patterns towards disease onset, we demonstrate that this high amino acid turnover is also detectable in a simple blood sample. These findings provide additional insight of metabolic alterations during glioma development and progression.

A nomogram with Ki-67 in the prediction of postoperative recurrence and death for glioma.

This study examined to evaluate the predictive value of a nomogram with Ki-67 in overall and disease-free survival in glioma patients, a total of 76 patients diagnosed with glioma by pathology in Tengzhou Central People's Hospital were enrolled. The baseline data and follow ups were retrospectively collected from medical records. The associations between Ki-67 and survival status were examined using log-rank test, univariate and multivariate Cox proportional hazard regression models. Calibrations were performed to validate the established nomograms. Ki-67 negative group showed of a longer OS survival time and a longer PFS survival time with log-rank test (x2 = 16.101, P < 0.001 and x2 = 16.961, P < 0.001). Age older than 50 years (HR = 2.074, 95% CI 1.097-3.923), abnormal treatment (HR = 2.932, 95% CI 1.343-6.403) and Ki-67 positive (HR = 2.722, 95% CI 1.097-6.755) were the independent predictive factors of death. High grade pathology (HR = 2.453, 95% CI 1.010-5.956) and Ki-67 positive (HR = 2.200, 95% CI 1.043-4.639) were the independent predictive factors of recurrence. The C-index for the nomogram of OS and PFS were 0.745 and 0.723, respectively. The calibration results showed that the nomogram could predict the overall and disease-free 1-year survival of glioma patients. In conclusion, the nomograms with Ki-67 as independent risk factor for OS and PFS could provide clinical consultation in the treatment and follow-up of malignant glioma.

[Clinicopathological and molecular characteristics of pediatric gliomas: analysis of 111 cases].

Objective: To summarize the clinical, pathological and molecular characteristics of various types of pediatric glioma, and to explore the differences in the morphology and clinical significance among various types of pediatric glioma. Methods: Based on the fifth edition of the World Health Organization classification of central nervous system tumors, this study classified or reclassified 111 pediatric gliomas that were diagnosed at Guangzhou Medical University Affiliated Women and Children's Medical Center from January 2020 to June 2023. The clinical manifestations, imaging findings, histopathology, and molecular characteristics of these tumors were analyzed. Relevant literature was also reviewed. Results: The 111 patients with pediatric glioma included 56 males and 55 females, with the age ranging from 10 days to 13 years (average age, 5.5 years). Clinically, manifestations presented from 5 days to 8 years before the diagnosis, including epilepsy in 16 cases, increased intracranial pressure in 48 cases and neurological impairment in 66 cases. MRI examinations revealed tumor locations as supratentorial in 43 cases, infratentorial in 65 cases, and spinal cord in 3 cases. There were 73 cases presented with a solid mass and 38 cases with cystic-solid lesions. The largest tumor diameter ranged from 1.4 to 10.6 cm. Among the 111 pediatric gliomas, there were 6 cases of pediatric diffuse low-grade glioma (pDLGG), 63 cases of circumscribed astrocytoma glioma (CAG), and 42 cases of pediatric diffuse high-grade glioma (pDHGG). Patients with pDLGG and CAG were younger than those with pDHGG. The incidence of pDLGG and CAG was significantly lower in the midline of the infratentorial region compared to that of pDHGG. They were more likely to be completely resected surgically. The pDLGG and CAG group included 4 cases of pleomorphic xanthoastrocytoma, showing histological features of high-grade gliomas. Among the high-grade gliomas, 13 cases were diffuse midline gliomas and also showed histological features of low-grade glioma. Immunohistochemical studies of H3K27M, H3K27ME3, p53, ATRX, BRAF V600E, and Ki-67 showed significant differences between the pDLGG and CAG group versus the pDHGG group (P<0.01). Molecular testing revealed that common molecular variations in the pDLGG and CAG group were KIAA1549-BRAF fusion and BRAF V600E mutation, while the pDHGG group frequently exhibited mutations in HIST1H3B and H3F3A genes, 1q amplification, and TP53 gene mutations. With integrated molecular testing, 2 pathological diagnoses were revised, and the pathological subtypes of 35.3% (12/34) of the pediatric gliomas that could not be reliably classified by histology were successfully classified. Conclusions: There are significant differences in clinical manifestations, pathological characteristics, molecular variations, and prognosis between the pDLGG, CAG and pDHGG groups. The integrated diagnosis combining histology and molecular features is of great importance for the accurate diagnosis and treatment of pediatric gliomas.

GAD1 ameliorates glioma progression through regulating cuproptosis via RAS/MAPK pathway.

Glioma represents a primary malignant tumor occurring in the central nervous system. Glutamate decarboxylase (GAD1) plays a significant role in tumor development; however, its function of GAD1 and underlying mechanisms in glioma progression remain unclear. Differentially expressed genes (DEGs) obtained from the GSE12657 and GSE15209 datasets that intersected with cuproptosis-related genes and pivot genes were identified using comprehensive bioinformatics methods. The elesclomol (ES) treatment was used to induce cuproptosis in U251 cells, which was validated by detecting intracellular copper levels and cuproptosis marker expression. Lentivirus-mediated gene overexpression was performed to explore the effects of GAD1 using functional assays in vitro and in a mouse xenograft model. The RAS agonist ML098 was used to verify the effect of GAD1 on the RAS/MAPK pathway in glioma cells. A total of 87 cuproptosis-related DEGs and seven hub genes were obtained, with five genes upregulated and two were downregulated in gliomas. Overexpression of GAD1 inhibited proliferation, invasion, and migration, promoted apoptosis of glioma cells, and suppressed tumorigenesis in vivo. In addition, GAD1 overexpression enhanced the sensitivity of glioma cells to cuproptosis. Additionally, ML098 treatment attenuated the inhibitory effect of GAD1 overexpression on the malignant phenotype of ES-treated cells. GAD1 plays an anti-oncogenic role in glioma by regulating apoptosis via inhibition of the RAS/MAPK pathway.

Microenvironmental regulation of tumor-associated neutrophils in malignant glioma: from mechanism to therapy.

Glioma is the most common primary intracranial tumor in adults, with high incidence, recurrence, and mortality rates. Tumor-associated neutrophils (TANs) are essential components of the tumor microenvironment (TME) in glioma and play a crucial role in glioma cell proliferation, invasion and proneural-mesenchymal transition. Besides the interactions between TANs and tumor cells, the multi-dimensional crosstalk between TANs and other components within TME have been reported to participate in glioma progression. More importantly, several therapies targeting TANs have been developed and relevant preclinical and clinical studies have been conducted in cancer therapy. In this review, we introduce the origin of TANs and the functions of TANs in malignant behaviors of glioma, highlighting the microenvironmental regulation of TANs. Moreover, we focus on summarizing the TANs-targeted methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of TANs in the malignant glioma microenvironment.

PITAR, a DNA damage-inducible cancer/testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA.

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 Associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.

[An MRI multi-sequence feature imputation and fusion mutual-aid model based on sequence deletion for differentiation of high-grade from low-grade glioma].

OBJECTIVE: To evaluate the performance of magnetic resonance imaging (MRI) multi-sequence feature imputation and fusion mutual model based on sequence deletion in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). METHODS: We retrospectively collected multi-sequence MR images from 305 glioma patients, including 189 HGG patients and 116 LGG patients. The region of interest (ROI) of T1-weighted images (T1WI), T2-weighted images (T2WI), T2 fluid attenuated inversion recovery (T2_FLAIR) and post-contrast enhancement T1WI (CE_T1WI) were delineated to extract the radiomics features. A mutual-aid model of MRI multi-sequence feature imputation and fusion based on sequence deletion was used for imputation and fusion of the feature matrix with missing data. The discriminative ability of the model was evaluated using 5-fold cross-validation method and by assessing the accuracy, balanced accuracy, area under the ROC curve (AUC), specificity, and sensitivity. The proposed model was quantitatively compared with other non-holonomic multimodal classification models for discriminating HGG and LGG. Class separability experiments were performed on the latent features learned by the proposed feature imputation and fusion methods to observe the classification effect of the samples in twodimensional plane. Convergence experiments were used to verify the feasibility of the model. RESULTS: For differentiation of HGG from LGG with a missing rate of 10%, the proposed model achieved accuracy, balanced accuracy, AUC, specificity, and sensitivity of 0.777, 0.768, 0.826, 0.754 and 0.780, respectively. The fused latent features showed excellent performance in the class separability experiment, and the algorithm could be iterated to convergence with superior classification performance over other methods at the missing rates of 30% and 50%. CONCLUSION: The proposed model has excellent performance in classification task of HGG and LGG and outperforms other non-holonomic multimodal classification models, demonstrating its potential for efficient processing of non-holonomic multimodal data.

A comparative study of PEO-PBO content on the targeting and anti-glioma activity of annonaceous acetogenins-loaded nanomicelles.

Annonaceous acetogenins (ACGs) have great potential in the treatment of gliomas, but are extremely insoluble and difficult for delivery in vivo. Poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) is an amphiphilic polymer and can reduce the clearance of nanoparticles by mononuclear phagocyte system. To explore an efficient and safe nanomedicine for glioma, ACGs-loaded nanomicelles (ACGs/EB-NCs) was constructed using PEO-PBO as a carrier, and the effect of PEO-PBO content on the targeting and anti-glioma activity were also compared. ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs, the three nanomicellels prepared with different ACGs/EB feeding ratios, had average particle sizes of 148.8±0.5 nm, 32.7±4.1 nm, and 27.1±0.3 nm, respectively. The three ACGs/EB-NCs were spherical in shape, with drug loading content close to the theoretical drug loading content, encapsulation efficiency greater than 97 %, and good stability in physiological media. The cumulative release rates of ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs were 78.2 %, 63.4 %, and 56.3 % within 216 hours, respectively. The inhibitory effects of three ACGs/EB-NCs on U87 MG cells were similar and stronger than free ACGs (P<0.05), with half inhibitory concentration of 0.17, 0.18, and 0.16 ng/mL (P>0.05), respectively. In U87 MG tumor­bearing mice, ACGs/EB5-NC, ACGs/EB10-NCs and ACGs/EB20-NCs showed a similar tumor inhibition rate of 61.1±5.9 %, 56.2±8.6 % and 64.3±9.4 % (P>0.05), with good safety. Three ACGs/EB-NCs exhibited excellent liver escape ability and tumor targeting ability, with the tumor targeting index greater than 1.5. Three ACGs/EB-NCs were successfully prepared with strong anti-glioma activity and tumor targeting properties, which are expected to provide new options for the clinical treatment of gliomas. The content of PEO-PBO in micelles did not have a significant effect on the tumor targeting and anti-glioma activity of ACGs/EB-NCs.

Pre-Clinical Models for CAR T-Cell Therapy for Glioma.

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors.

Emerging and Biological Concepts in Pediatric High-Grade Gliomas.

Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors.

Lipid metabolic rewiring in glioma­associated microglia/macrophages (Review).

Gliomas are the most prevailing brain malignancy in both children and adults. Microglia, which are resident in the central nervous system (CNS), are distributed throughout the brain and serve an important role in the immunity of the CNS. Microglial cells exhibit varying phenotypic and metabolic properties during different stages of glioma development, making them a highly dynamic cell population. In particular, glioma­associated microglia/macrophages (GAMs) can alter their metabolic characteristics and influence malignancies in response to the signals they receive. The significance of macrophage metabolic reprogramming in tumor growth is becoming increasingly acknowledged in recent years. However, to the best of our knowledge, there is currently a scarcity of data from investigations into the lipid metabolic profiles of microglia/macrophages in the glioma setting. Therefore, the present review aims to provide a thorough review of the role that lipid metabolism serves in tumor­associated macrophages. In addition, it outlines potential targets for therapy based on lipid metabolism. The present review aims to serve as a reference source for future investigations into GAMs.