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A scalable platform for cell typing in the glioma microenvironment can improve tumor subtyping and immune landscape detection as successful immunotherapy strategies continue to be sought and evaluated. DNA methylation (DNAm) biomarkers for molecular classification of tumor subtypes have been developed for clinical use. However, tools that predict the cellular landscape of the tumor are not well-defined or readily available. We developed the Glioma Immune Microenvironment Composition Calculator (GIMiCC), an approach for deconvolution of cell types in gliomas using DNAm data. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries in the biological context of selected genomic regions and validate deconvolution results using independent datasets. We utilize GIMiCC to illustrate that DNAm-based estimates of immune composition are clinically relevant and scalable for potential clinical implementation. In addition, we utilize GIMiCC to identify composition-independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma., (© 2024. The Author(s).)

Brain tumors are among the most fatal and devastating diseases, and they often result in a significant reduction in life expectancy. The devising of treatment plans that can extend the lives of affected individuals hinges on an accurate diagnosis of these tumors. Identifying and analyzing large volumes of magnetic resonance imaging (MRI) data manually proves to be both challenging and time-consuming. As a result, there exists a pressing need for a reliable machine-learning approach to accurately diagnose brain tumors, and numerous methods have already been proposed over the last decade. In this paper, a novel, comprehensive approach is proposed for identifying and classifying a given MR brain image as abnormal. Three common brain diseases, namely glioma, meningioma, and pituitary tumor, are chosen as abnormal brains, and the Figshare MRI brain image dataset was collected from the Kaggle and IEEE websites. The proposed method is initiated by employing 1st-order statistics, 2nd-order statistics, and higher-order transformed (DWT) feature extraction to extract features from images. Then missing data is addressed and handled using KNNImputer, followed by the application of the ExtratreesClassifier and PCA feature selection methods to identify the most relevant features and reduce the dimensions of these features. Subsequently, the reduced features are submitted to seven machine learning models, namely RF, GB, CB, SVM, LGBM, DT, and LR. The strategy of k-fold cross-validation is utilized to enhance the performance of those models. Finally, the models are evaluated using XAI approaches, which ensure transparent decision-making processes and provide insights into the model's predictions. Remarkably, our approach achieves the highest accuracy, precision, recall, F1 score, MCC, Kappa, AUC-ROC, and R2, as well as the lowest loss, among the seven models evaluated, proving its effectiveness and applicability in multiple analytic applications relying on publicly available datasets., (© 2024. The Author(s).)

Background: Second and third surgeries were demonstrated as safe and efficient in recurrent diffuse low-grade glioma (LGG). Here, the feasibility of more than 3 resections is investigated., Methods: Patients who underwent 4 or 5 operations for recurrent initially WHO grade 2 IDH-mutated gliomas were consecutively selected., Results: Twenty-three operations were performed in five patients (all males, mean age 27.2 ± 4 years). Three patients underwent 5 surgeries and two patients underwent 4 surgeries. Twelve procedures (52%) were achieved with awake mapping, including all 4th and 5th operations but one. Repeat electrical mapping detected changes of the cortical maps between at least two awake surgeries in 4 patients. No patients experienced permanent neurological impairment (KPS score ≥ 80 in all cases). The patients returned to work after 22 surgeries among 23 (95.6%). There were 3 oligodendrogliomas and 2 astrocytomas (4 gliomas became malignant at fourth or fifth operation). Although the preoperative tumor volume significantly increased before the fourth (p = 0.026) and fifth operation (p = 0.003) compared with the first operation, there was no significant difference between the residual tumor volume after the fourth or fifth resection versus the first one. The mean delay was 10.6 ± 3.9 years before chemotherapy and 15.4 ± 3.4 years before radiotherapy (one patient never received adjuvant treatment after 21.5 years). The mean follow-up duration was 18.3 ± 3.1 years since the first surgery (2.3 ± 1.8 years since the last surgery). Three patients were still alive at last follow-up., Conclusions: This is the first series showing that to reoperate beyond three times is feasible with a low functional risk and a long survival in multiple LGG recurrences, with the use of awake mapping in 87.5% of 4th and 5th surgeries., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Glioblastoma (GBM) is the most aggressive form of glioma, characterized by high mortality and poor prognosis. Dysregulation of microRNAs (miRNAs) plays a critical role in the progression and metastasis of GBM. This study aimed to investigate the role and molecular mechanism of miR-124-3p in GBM. Levels of miR-124-3p, EPHA2, and ALKBH5 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, migration, invasion, and stemness were assessed using the Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and sphere formation assays, respectively. Bioinformatics prediction, dual-luciferase reporter assays, and RNA pull-down experiments were employed to validate the target of miR-124-3p. RNA binding protein immunoprecipitation (RIP) and methylated RNA immunoprecipitation (Me-RIP) were utilized to evaluate the regulation of miR-124-3p maturation by ALKBH5. The results indicated that overexpression of miR-124-3p inhibited the proliferation, migration, invasion, and stemness of GBM cells. EPHA2 was identified as a direct downstream target of miR-124-3p, and its overexpression reversed the inhibitory effects of miR-124-3p on cellular functions. Furthermore, miR-124-3p targeted EPHA2 to inactivate the Wnt/β-catenin pathway. Additionally, ALKBH5 negatively regulated miR-124-3p by impeding its processing. In conclusion, knockdown of ALKBH5 promoted the processing of pri-miR-124-3p, increasing mature miR-124-3p levels, which inhibited the malignant behaviors of GBM cells by targeting EPHA2. These findings highlight the importance of the ALKBH5/miR-124-3p/EPHA2 axis in GBM., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Brain tumors, particularly Glioblastoma Multiforme (GBM) and Low-Grade Gliomas (LGG), present significant clinical challenges due to their aggressive nature and resistance to conventional treatments. Traditional therapies such as surgery, chemotherapy, and radiation are often limited in efficacy, necessitating novel therapeutic strategies. Nanotechnology, particularly the use of silver nanoparticles (Ag NPs), offers a targeted and potentially more effective approach. This study focuses on the green synthesis of Ag NPs using Podocarpus macrophyllus leaf extract as a reducing agent. The synthesized Ag NPs were characterized for their physicochemical properties, demonstrating a controlled particle size of 13 nm as determined by scanning electron microscopy (SEM). Fourier-transform infrared (FTIR) spectroscopy confirmed the presence of functional groups, and energy-dispersive X-ray (EDX) spectroscopy revealed that silver constituted approximately 90% of the nanoparticle composition. The Ag NPs exhibited promising biological activity, including 90% free radical scavenging (antioxidant) activity, 99.15% inhibition of protein denaturation (anti-inflammatory activity), and 90.56% inhibition of alpha-amylase (anti-diabetic activity). Additionally, the nanoparticles displayed significant anti-hemolytic (89.9% inhibition) and antimicrobial activities, with a 20 mm inhibition zone against Staphylococcus species. Computational analyses further indicated that the NOTCH2 gene, which is upregulated in LGG and GBM, may interact with Ag NPs, suggesting their potential in brain cancer therapy. The green synthesis approach offers a sustainable and bioactive method for producing Ag NPs, underscoring their therapeutic promise for treating GBM and LGG., (© 2024. The Author(s).)

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of "Astrocytoma, IDH-mutant; High Grade" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors., (© 2024. The Author(s).)

Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma., (© 2024. The Author(s).)

Oncostreams are self-organized structures formed by spindle-like, elongated, self-propelled cells recently described in glioblastomas and especially in gliosarcomas. Cells within these structures either move as large clusters in one main direction, flocks, or as linear, intermingling collections of cells advancing in opposite directions, streams. Round, passive cells are also observed, either inside or segregated from the oncostreams. Here we generalize a recently formulated particle-field approach to investigate the genesis and evolution of these structures, first showing that, in systems consisting only of identical self-propelled cells, both flocks and streams emerge as self-organized dynamic configurations. Flocks are the more stable configurations, while streams are transient and usually originate in collisions between flocks. Stream degradation is easier at low self-propulsion speeds. In systems consisting of both motile and passive cells, the latter block stream formation and accelerate their degradation and flock stabilization. Since the flock appears to be the most effective invasive structure, we thus argue that a phenotype mixture (motile and passive cells) may favor glioblastoma invasion. hlBy relating cellular properties to the observed outcome, our model shows that oncostreams are self-organized structures that result from the interplay between speed, shape, and steric repulsion., (© 2024. The Author(s).)

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to non-invasively image blood-brain barrier leakage, yet its clinical utility has been hampered by issues such as noise and partial volume artifacts. In this retrospective study involving 306 adult patients with diffuse glioma, we applied deep learning-based super-resolution and denoising (DLSD) techniques to enhance the signal-to-noise ratio (SNR) and resolution of DCE-MRI. Quantitative analysis comparing standard DCE-MRI (std-DCE) and DL-enhanced DCE-MRI (DL-DCE) revealed that DL-DCE achieved significantly higher SNR and contrast-to-noise ratio (CNR) compared to std-DCE (SNR, 52.09 vs 27.21; CNR, 9.40 vs 4.71; P < 0.001 for all). Diagnostic performance assessed by the area under the receiver operating characteristic curve (AUROC) showed improved differentiation of WHO grades based on a pharmacokinetic parameter [Formula: see text] (AUC, 0.88 vs 0.83, P = 0.02), while remaining comparable to std-DCE in other parameters. Analysis of arterial input function (AIF) reliability demonstrated that [Formula: see text] exhibited superior agreement compared to [Formula: see text], as indicated by mostly higher intraclass correlation coefficients (Time to peak, 0.79 vs 0.43, P < 0.001). In conclusion, DLSD significantly enhances both the image quality and reliability of DCE-MRI in patients with diffuse glioma, while maintaining or improving diagnostic performance., (© 2024. The Author(s).)

Background: Glioma is a highly heterogeneous and poorly immunogenic malignant tumor, with limited efficacy of immunotherapy. The characteristics of the immunosuppressive tumor microenvironment (TME) are one of the important factors hindering the effectiveness of immunotherapy. Therefore, this study aims to reveal the immune microenvironment (IME) characteristics of glioma and predict different immune subtypes using machine learning methods, providing guidance for immune therapy in glioma., Methods: We first performed unsupervised cluster analysis on the genes and arrays of 693 gliomas in CGGA database and 702 gliomas in TCGA database. Then establish and verify the classification model through Machine Learning (ML). Then, use DAVID to perform functional enrichment analysis for different immune subtypes. Next step, analyze the immune cell distribution, stemness maintenance, mesenchymal phenotype, neuronal phenotype, tumorigenic cytokines, molecular and clinical characteristics of different immune subtypes of gliomas., Results: Firstly, we divide the IME of gliomas in the CGGA database into four different subtypes, namely IM1, IM2, IM3, and IM4; similarly, the IME of gliomas in the TCGA database can also be divided into four different subtypes (IMA, IMB, IMC, and IMD). Next, based on ML, we developed a highly reliable model for predicting different immune subtypes of glioma. Then, we found that Monocytic lineage, Myeloid dendritic cells, NK cells and CD8 T cells had the highest enrichment in the IM1/IMD subtypes. Cytotoxic lymphocytes were highest expressed in the IM4/IMA subtypes. Next step, Enrichment analysis revealed that the IM1-IMD subtypes were mainly closely related to the production and secretion of IL-8 and TNF signaling pathway. The IM2-IMB subtypes were strongly associated with leukocyte activation and NK cell mediated cytotoxicity. The IM3-IMC subtypes were closely related to mitotic nuclear division and mitotic cell cycle process. The IM4-IMA subtypes were strongly associated with Central Nervous System (CNS) development and striated muscle tissue development. Afterwards, Single sample gene set enrichment analysis (ssGSEA) showed that stemness maintenance phenotypes were mainly enriched in the IM4/IMA subtypes; Neuronal phenotypes were closely associated with the IM2/IMB subtypes; and mesenchymal phenotypes and tumorigenic cytokines were highly correlated with the IM2 /IMB subtypes. Finally, we found that compared with patients in the IM2/IMB and IM4/IMA subtypes, the IM1/IMD and IM3/IMC subtypes have the highest proportion of GBM patients, the shortest average overall survival of patients and the lowest proportion of patients with IDH mutation and 1p36/19q13 co-deletion., Conclusions: We developed a highly reliable model for predicting different immune subtypes of glioma by ML. Then, we comprehensively analyzed the immune infiltration, molecular and clinical features of different immune subtypes of gliomas and defined gliomas into four subtypes: immunogenic subtype, adaptive immune resistance subtype, mesenchymal subtype, and immune tolerance subtype, which represent different TMEs and different stages of tumor development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

High-grade gliomas are the most prevalent neurooncological desease in adults, their incidence increases with age, peaking in the seventh decade. This paper aims to address how to select patients for surgical resection by identifying pre-surgical predictors of 12-month mortality in newly diagnosed HGG patients aged ≥ 75 years. A prognostic score will be proposed to guide surgical decisions based on expected survival. Retrospective observational single-center cohort study was carried out at the "Città della Salute e della Scienza-Molinette" University Hospital in Turin, Italy. All consecutive patients aged ≥ 75 years newly diagnosed with HGG were included, regardless of whether they underwent surgical resection. Clinical, radiological, histological and molecular data were collected.Variables potentially available at the time of diagnosis were considered to develop a multivariable logistic regression predictive model, with 12-months overall survival as the dependent variable. 102 patients aged 75 years or older received a new diagnosis of high-grade glioma, of whom 68 underwent surgical resection. Patients undergoing surgery were slightly younger (76.9 vs 79.0 years, p = 0.007) and had better performance status (median KPS 80 vs 70). Most tumors undergoing surgery were localized in cortical or subcortical non-motor areas (p < 0.001) and less frequently deep-seated (p = 0.023) or multifocal (p < 0.001). A predictive model, the DAK-75 score, was developed: the AUROC of the final model was 0.822 (95% CI 0.741-0.902). The score includes clinical presentation, tumor location, and KPS, ranging from 0 to 20, categorizing risk scores into low-risk and high-risk groups (< or > 8). Higher scores corresponded to fewer surgical patients and higher one-year mortality rates (92.2% vs 47.1%, p < 0.001). DAK-75 score may represent a valuable tool in the decision-making process for neurosurgical intervention in elderly patients diagnosed with HGG. Further studies are needed to externally and prospectively validate the scoring system., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

G protein subunit Gamma 5 (GNG5) has been found to be involved in regulating glioma progression. However, its function and mechanism in glioblastoma (GBM) progression need to be further elucidated. GBM cell proliferation, apoptosis, invasion and stemness were assessed by cell counting kit 8 assay, EdU assay, flow cytometry, transwell assay and sphere formation assay. The mRNA and protein levels of GNG5 and Yin Yang 1 (YY1) were determined by quantitative real-time PCR and western blot (WB). Detection of the glucose consumption, lactate production and ATP/ADP ratios were used to assess cell glycolysis. Besides, Wnt/β-catenin pathway-related protein levels were examined by WB. Mice xenograft model was also constructed to explore GNG5 roles in vivo. GNG5 was highly expressed in GBM, and its silencing inhibited GBM cell proliferation, invasion, stemness and glycolysis, while promoted apoptosis. Transcription factor YY1 could bind to the GNG5 promoter region and induce its expression. GNG5 overexpression reversed the inhibitory effects of YY1 silencing on GBM cell growth, invasion, stemness and glycolysis. YY1/GNG5 axis could activate the Wnt/β-catenin pathway, and Wnt/β-catenin pathway agonists SKL2001 could revert the effects of GNG5 silencing on GBM cell progression. Furthermore, GNG5 facilitated GBM tumor growth by mediating the Wnt/β-catenin pathway. YY1-mediated GNG5 promoted GBM progression through the Wnt/β-catenin pathway., (© 2024. The Author(s).)

Glioblastomas (GBMs) are the most aggressive types of central nervous system tumors. Although certain genomic alterations have been identified as prognostic biomarkers of GBMs, the histomorphological features that predict their prognosis remain elusive. In this study, following an integrative diagnosis of 227 GBMs based on the 2021 World Health Organization classification system, the cases were histologically fractionated by cellular variations and abundance to evaluate the relationship between cellular heterogeneity and prognosis in combination with O-6-methylguanine-DNA methyltransferase gene promoter methylation (mMGMTp) status. GBMs comprised four major cell types: astrocytic, pleomorphic, gemistocytic, and rhabdoid cells. t-distributed stochastic neighbor embedding analysis using the histological abundance of heterogeneous cell types identified two distinct groups with significantly different prognoses. In individual cell component analysis, the abundance of gemistocytes showed a significantly favorable prognosis but confounding to mMGMTp status. Conversely, the abundance of epithelioid cells was correlated with the unfavorable prognosis. Linear model analysis showed the favorable prognostic utility of quantifying gemistocytic and epithelioid cells, independent of mMGMTp. The evaluation of GBM cell histomorphological heterogeneity is more effective for prognosis prediction in combination with mMGMTp analysis, indicating that histomorphological analysis is a practical and useful prognostication tool in an integrative diagnosis of GBMs., (© 2024. The Author(s).)

Currently used drugs for glioblastoma (GBM) treatments are ineffective, primarily due to the significant challenges posed by strong drug resistance, poor blood-brain barrier (BBB) permeability, and the lack of tumor specificity. Here, we report two cationic fluorescent anticancer agents (TriPEX-ClO 4 and TriPEX-PF 6 ) capable of BBB penetration for efficient GBM therapy via paraptosis and ferroptosis induction. These aggregation-induced emission (AIE)-active agents specifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated paraptosis and GPX4-mediated ferroptosis. Specifically, they rapidly induce substantial mitochondria-derived vacuolation, accompanied by reactive oxygen species generation, decreased mitochondrial membrane potential, and intracellular Ca 2+ overload, thereby disrupting metabolisms and inducing nonapoptotic cell death. In vivo imaging revealed that TriPEX-ClO 4 and TriPEX-PF 6 successfully traversed the BBB to target orthotopic glioma and initiated effective synergistic therapy postintravenous injection. Our AIE drugs emerged as the pioneering paraptosis inducers against drug-resistant GBM, significantly extending survival up to 40 days compared to Temozolomide (20 days) in drug-resistant GBM-bearing mice. These compelling results open up new venues for the development of fluorescent anticancer drugs and innovative treatments for brain diseases.

Despite advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors without an artificial extracellular scaffold. MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAF V600K -mutant and BRAF-wildtype MBM sample were collected directly from the operating room. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Organoid growth was observed within 3-4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment., (© 2024. The Author(s).)

Glioblastoma (GBM) is the most prevalent primary brain tumor. Recent research emphasizes the crucial role of microRNAs (miRs) in GBM pathogenesis, and targeting miRs offers an effective approach for precise GBM therapy. However, inhibiting a single miR may not be sufficient due to the compensatory mechanisms of GBM. Herein, we developed a miR-nanosponge capable of specifically capturing multiple miRs involved in tumor growth, migration, invasion, angiogenesis, and the creation of an immunosuppressive microenvironment, thereby offering a comprehensive treatment for GBM. Coated with BV2 cell membrane (BM) for enhanced blood-brain barrier (BBB) crossing and GBM targeting, the BM@miR-nanosponge targets miR-9, miR-21, miR-215, and miR-221, significantly inhibiting GBM progression and modulating the immune system for a thorough GBM eradication. The BM@miR-nanosponge notably extended the median survival time of GBM-bearing mice and outperformed the standard treatment drug temozolomide (TMZ). This study introduces a comprehensive miR-based strategy for GBM treatment and highlights the importance of targeting multiple miRs associated with tumor survival for effective therapy.

Upon infection with herpes simplex virus 1 (HSV-1), the virus deploys multiple strategies to evade the host's innate immune response. However, the mechanisms governing this phenomenon remain elusive. Here, we find that HSV-1 leads to a decrease in overall m6A levels by selectively reducing METTL14 protein during early infection in glioma cells. Specifically, the HSV-1-encoded immediate-early protein ICP0 interacts with METTL14 within ND10 bodies and serves as an E3 ubiquitin protein ligase, targeting and ubiquitinating METTL14 at the lysine 156 and 162 sites. Subsequently, METTL14 undergoes proteasomal degradation. Furthermore, METTL14 stabilizes ISG15 mRNA mediated by IGF2BP3 to promote antiviral effects. Notably, METTL14 suppression significantly enhances the anti-tumor effect of oncolytic HSV-1 (oHSV-1) in mice bearing glioma xenografts. Collectively, these findings establish that ICP0-guided m6A modification controls the antiviral immune response and suggest that targeting METTL14/ISG15 represents a potential strategy to enhance the oncolytic activity of oHSV-1 in glioma treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Interleukin-18, a member of the interleukin - 1 family of cytokines, is upregulated in glioma. However, its effects on glioma remain unclear. This study aimed to explore the role and underlying mechanisms of interleukin-18 expression in glioma. Here, we demonstrated that interleukin-18 enhanced resistance to temozolomide by increasing proliferation and inhibiting apoptosis in cultured glioma cells. Further in vivo studies revealed that interleukin-18 promoted temozolomide resistance in BALB/c nude mice bearing tumor. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT signaling pathway in glioma cells, and PI3K inhibition could reduce the temozolomide resistance promoted by interleukin-18. We found that interleukin-18 upregulated CD274 expression in glioma, revealing its potential effects on the microenvironment. Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibody. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice bearing tumor. Combined treatment with anti-interleukin-18 and anti-PD-1 monoclonal antibody showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumor. Collectively, these data present that interleukin-18 promotes temozolomide chemoresistance in glioma cells via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma., (© 2024. The Author(s).)

Ultrasmall gold nanoparticles (1.5 nm) were covalently conjugated with doxorubicin (AuDox) and AlexaFluor647 (AuAF647) to assess their biodistribution and their efficiency toward brain tumors (glioblastoma). A thorough characterization by transmission electron microscopy, small-angle X-ray scattering, and differential centrifugal sedimentation confirmed their uniform ultrasmall nature which makes them very mobile in the body. Each nanoparticle carried either 13 doxorubicin molecules (AuDox) or 2.7 AlexaFluor-647 molecules (AuAF647). The firm attachment of the ligands to the nanoparticles was demonstrated by their resilience to extensive washing, followed by centrifugation. The particles easily entered mammalian cells (HeLa, T98-G, brain endothelial cells, and human astrocytes) due to their small size. The intravenously delivered fluorescing AuAF647 nanoparticles crossed the blood-brain barrier with ∼23% accumulation in the brain tumor in an orthotopic U87 brain tumor model in nude mice. This was confirmed by elemental analysis (gold; inductively coupled plasma optical emission spectroscopy) in various organs. The doxorubicin-loaded AuDox nanoparticles inhibited brain tumor growth and prolonged animal survival without adverse side effects. Most of the nanoparticles (84%) had been excreted from the animal after 24 h, indicating a high mobility in the body.

Pilocytic astrocytoma (PA) is classified as a Grade I benign neuroglial tumor. The extent of surgical resection is a critical factor influencing the prognosis for patients with PA. In prior researches of PA, the extent of surgical resection is generally categorized into GTR, STR and biopsy. In some researches on brain tumor surgeries, the extent of resection also includes GTL. There is no existing research specifically comparing the efficacy of GTR versus GTL in PA treatment. In this study, the data we used are from the SEER database. We categorized the extent of resection into GTL, GTR, STL, STR, biopsy, and no surgery based on SEER classification of surgical procedures, to investigate the impact of extent of resection on PA patient survival. A multivariate logistic regression model was utilized to acquire odds ratios (OR) for different extent of resection. Survival outcomes across different extent of resection (GTL, GTR, STL, STR, biopsy, no surgery) were assessed using Kaplan-Meier survival curve analysis, with curve comparisons conducted via log-rank tests. The impact of various risk factors on survival was assessed using the Cox proportional hazards model. The hazard ratio (HR) was employed to quantify the influence of one or more factors on overall survival throughout the follow-up period. Multivariate Cox analysis revealed that age, tumor location, extent of resection, as well as the application of radiotherapy and chemotherapy, all significantly impacted prognosis. Compared to GTL, GTR did not significantly increase the risk of mortality (HR 1.17; 95% CI 0.73-1.86, p = 0.5). Furthermore, there was no statistically significant difference between the Kaplan-Meier survival curves of the two groups (p = 0.18). We employed propensity score matching (PSM) to balance the differences in baseline characteristics of patients receiving chemotherapy or radiotherapy. A total of 4429 patients were included in this study. Age, diagnosis period, race, tumor size, and tumor location as influential on the extent of resection. Age, tumor location, extent of resection, and application of radiotherapy and chemotherapy influenced the survival of PA patients. The Kaplan-Meier survival curves revealed that the long-term survival rate for GTR is slightly higher than that for GTL. The PSM analysis revealed that the application of radiotherapy and chemotherapy was associated with the reduction of overall survival in PA patients. In conclusion, there was no significant difference in survival between GTR and GTL, so GTR with less damage was preferred. The application of radiotherapy and chemotherapy can reduce overall survival of patients with PA., (© 2024. The Author(s).)

Background and Purpose: Progression-free survival (PFS) remains to be validated as an outcome measure for diffuse WHO grade 2 gliomas, and knowledge about the relationships between PFS, post-progression survival (PPS), and overall survival (OS) in this subset of tumors is limited. We sought to assess correlations between PFS and OS, and identify factors associated with PFS, PPS, and OS in patients treated for diffuse supratentorial WHO grade 2 gliomas., Material and Methods: We included 319 patients from three independent observational cohorts. The correlation between PFS and OS was analyzed using independent exponential distributions for PFS and time from progression to death. Cox proportional hazards models were used to determine the effects of covariates on PFS, PPS, and OS., Results: The overall correlation between PFS and OS was rs0.31. The correlation was rs 0.37 for astrocytomas and rs 0.19 for oligodendrogliomas. Longer PFS did not predict longer PPS. Patients with astrocytomas had shorter PFS, PPS, and OS. Larger preoperative tumor volume was a risk factor for shorter PFS, while older age was a risk factor for shorter PPS and OS. Patients who received early radio- and chemotherapy had longer PFS, but shorter PPS and OS., Interpretation: We found a weak correlation between PFS and OS in WHO grade 2 gliomas, with the weakest correlation observed in oligodendrogliomas. Our analyses did not demonstrate any association between PFS and PPS. Critically, predictors of PFS are not necessarily predictors of OS. There is a need for validation of PFS as an endpoint in diffuse WHO grade 2 gliomas.

Glioblastomas (aka Glioblastoma multiformes (GBMs)) are the most deadly of the adult brain tumors. Even with aggressive treatment, the prognosis is extremely poor. The large GTPase Guanylate-Binding Protein-1 (GBP-1) contributes to the poor prognosis of GBM by promoting migration and invasion. GBP-1 is substantially localized to the cytosolic side of the outer membrane of mitochondria in GBM cells. Because mitochondrial dynamics, particularly mitochondrial fission, can drive cell migration and invasion, the potential interactions between GBP-1 and mitochondrial dynamin-related protein 1 (Drp1) were explored. Drp1 is the major driver of mitochondrial fission. While GBP-1 and Drp1 both had punctate distributions within the cytoplasm and localized to regions of the cytoplasmic side of the plasma membrane of GBM cells, the proteins were only molecularly co-localized at the mitochondria. Subcellular fractionation showed that the presence of elevated GBP-1 promoted the movement of Drp1 from the cytosol to the mitochondria. The migration of U251 cells treated with the Drp1 inhibitor, Mdivi-1, was less inhibited in the cells with elevated GBP-1. Elevated GBP-1 in GBM cells resulted in shorter and wider mitochondria, most likely from mitochondrial fission. Mitochondrial fission can drive several important cellular processes, including cell migration, invasion, and metastasis.

Glioblastoma, a fatal brain cancer with limited treatments and poor prognosis, could benefit from targeting the L-type amino acid transporter I (LAT1). LAT1 is essential for cancer cells to acquire necessary amino acids. Tetrahydrocurcumin (THC), a key curcumin derivative, shows potential for glioblastoma treatment. However, its effectiveness is hindered by poor physicochemical and pharmacokinetic properties. Therefore, this study aims to improve the therapeutic efficacy of THC against glioblastoma by chemically modifying it to target LAT1. A novel series of THC-amino acid conjugates were synthesized by conjugating five amino acids: glycine, leucine, isoleucine, and phenylalanine to THC via carbamate bonds. The therapeutic efficacy of THC-amino acid conjugates was further examined in C6 glioma cells, including the role of LAT1 in their therapeutic effects. Among the conjugates tested, THC conjugated with two phenylalanines (THC-di-Phe) showed remarkably higher cytotoxicity against C6 glioma cells (35.8 μM) compared to THC alone (110.7 μM). THC-di-Phe induced cellular death via necrosis and apoptosis, outperforming THC. Additionally, THC-di-Phe inhibited C6 cell proliferation and migration more effectively than THC. Co-incubation of THC-di-Phe with the LAT1 inhibitor 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) further increased cellular death. THC-di-Phe also significantly inhibited the P70SK/S6 pathway, regulated by LAT1 inhibitors, more effectively than THC and displayed a similar binding mode with both JX-075 and BCH to the active site of LAT1. Findings suggest the potential role of THC-di-Phe as a LAT1 inhibitor and provide novel insight into its use as a potent antitumor agent in glioma with increased therapeutic efficacy.

Glioblastoma is the most aggressive and fatal brain cancer, characterized by a high growth rate, invasiveness, and treatment resistance. The presence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) poses a challenging task for chemotherapeutics, resulting in low efficacy, bioavailability, and increased dose-associated side effects. Despite the rigorous treatment strategies, including surgical resection, radiotherapy, and adjuvant chemotherapy with temozolomide, overall survival remains poor. The failure of current chemotherapeutics and other treatment regimens in glioblastoma necessitates the development of new drug delivery methodologies to precisely and efficiently target glioblastoma. Nanoparticle-based drug delivery systems offer a better therapeutic option in glioblastoma, considering their small size, ease of diffusion, and ability to cross the BBB. Liposomes are a specific category of nanoparticles made up of fatty acids. Furthermore, liposomes can be surface-modified to target a particular receptor and are nontoxic. This review discusses various methods of liposome modification for active/directed targeting and various liposome-based therapeutic approaches in the delivery of current chemotherapeutic drugs and nucleic acids in targeting the glioblastoma and tumor microenvironment.

Glioblastoma Multiforme (GBM), designated as grade IV by the World Health Organization, is the most aggressive and challenging brain tumor within the central nervous system. Around 80% of GBM patients have a poor prognosis, with a median survival of 12-15 months. Approximately 90% of GBM cases originate from normal glial cells via oncogenic processes, while the remainder arise from low-grade tumors. GBM is notorious for its heterogeneity, high recurrence rates, invasiveness, and aggressive behavior. Its malignancy is driven by increased invasive migration, proliferation, angiogenesis, and reduced apoptosis. Throughout various stages of central nervous system (CNS) development, pivotal signaling pathways, including Wnt/β-catenin, Sonic hedgehog signaling (Shh), PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, STAT3, NF-КB, TGF-β, and Notch signaling, orchestrate the growth, proliferation, differentiation, and migration of neural progenitor cells in the brain. Numerous upstream and downstream regulators within these signaling pathways have been identified as significant contributors to the development of human malignancies. Disruptions or aberrant activations in these pathways are linked to gliomagenesis, enhancing the invasiveness, progression, and aggressiveness of GBM, along with epithelial to mesenchymal transition (EMT) and the presence of glioma stem cells (GSCs). Traditional GBM treatment involves surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ). However, most patients experience tumor recurrence, leading to low survival rates. This review provides an overview of the major cell signaling pathways involved in gliomagenesis. Furthermore, we explore the signaling pathways leading to therapy resistance and target key molecules within these signaling pathways, paving the way for the development of novel therapeutic approaches., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Treatment of glioblastoma is ineffective. Myx-M011L-KO/EGFP, a myxoma virus actively inducing apoptosis in BTICs linked to recurrence, offers innovative treatment. We loaded this construct into adipose-derived stem cells (ADSCs) to mitigate antiviral host responses and enable systemic delivery. The apoptotic and cytotoxic effects of the construct were studied using murine and human glioblastoma cell lines. Before implementing systemic delivery, we delivered the construct locally using ADSC to verify elimination of orthotopic murine glioma lesions. vMyx-M011L-KO/EGFP was cytotoxic to a murine cell line, preventing effective virus multiplication. In three human glioma cell lines, viral replication did occur, coupled with cell killing. The knock-out construct induced apoptotic cell death in these cultures. ADSCs infected ex vivo were shown to be sufficiently migratory to assure transfer of the therapeutic cargo to murine glioma lesions. Virus-loaded ADSCs applied to the artificial blood-brain barrier (BBB) yielded viral infection of glioma cells grown distally in the wells. Two rounds of local administration of this therapeutic platform starting 6 days post tumor implantation slowed down growth of orthotopic lesions and improved survival (total recovery < 20%). ADSCs infected ex vivo with vMyx-M011L-KO/EGFP show promise as a therapeutic tool in systemic elimination of glioma lesions.

In recent years, CD9 has been extensively studied as a potential biomarker for cancer. However, the biological role of CD9 in gliomas remains unclear. This study investigates the function of CD9 in gliomas and its molecular mechanisms. Utilizing pan-cancer analysis with TCGA, CGGA, and GEO databases, differential expression of CD9 was observed in 11 tumor types within the TCGA cohort, and it was associated with patient survival rates. Analysis of the CGGA glioma database revealed that patients with high CD9 expression had lower survival rates. The area under the ROC curve (AUC) for GSE16011 was greater than 0.7, indicating a high discriminative ability. Through gene set enrichment analysis (GSEA), immune-related analysis, and CD9 mutation detection, CD9 was found to have the strongest correlation with neutrophil involvement (cor = 0.30, P < 0.05), and the high CD9 expression group exhibited higher rejection responses and TIDE scores, suggesting a lower likelihood of successful immunotherapy. The high CD9 expression group was more sensitive to 81 drugs, indicating potential therapeutic effects for gliomas. Furthermore, overexpression of CD9 in gliomas may be associated with gene mutations. Down-regulation or up-regulation of CD9 expression in the glioblastoma cell line LN229 showed that CD9 could positively regulate the migratory ability of LN229 cells. Further, several marker genes, such as VEGFR-2, TGF-β1, CASP1 and PI3K, were down regulated in CD9 knockdown cell lines and up regulated in CD9 overexpression cell lines, compared with control cell line. This study preliminarily explores the role of CD9 in gliomas and its prognostic value, providing new insights for personalized treatment strategies in glioma therapy., (© 2024. The Author(s).)

Astrocytomas that harbor recurrent genomic alterations in MYB or MYBL1 are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in MYB or MYBL1. In this report, we examine 14 consecutive cases in which a MYB or MYBL1 alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, MYB- or MYBL1-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the MYB or MYBL1 genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the MYB(L1) genes, regardless of the presence of a productive fusion. In addition, QKI, a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising >1000 CNS tumors of various types, regardless of whether a genomic alteration in QKI was present. Overall, the results show that truncations, in the absence of a productive fusion, of the MYB(L1) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, MYB- or MYBL1-altered, especially for cases that are tested on panels designed to focus on fusion detection., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain., (© 2024. The Author(s).)

Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. In this study, we utilized pathomics analysis to explore the expression of CD40LG and its predictive value for the prognosis of GBM patients. We analyzed the expression differences of CD40LG in GBM tissue and normal brain tissue, along with performing survival prognosis analysis. Additionally, histopathological sections of GBM were used to screen for pathological features. Subsequently, SVM and LR pathomics models were constructed, and the models' performance was evaluated. The pathomics model was employed to predict CD40LG expression and patient prognosis. Furthermore, we investigated the potential molecular mechanisms through enrichment analysis, WGCNA analysis, immune correlation analysis, and immune checkpoint analysis. The expression level of CD40LG was significantly increased in GBM. Multivariate analysis demonstrated that high expression of CD40LG is a risk factor for overall survival (OS) in GBM patients. Five pathological features were identified, and SVM and LR pathomics models were constructed. Model evaluation showed promising predictive effects, with an AUC value of 0.779 for the SVM model, and the Hosmer-Lemeshow test confirmed the model's prediction probability consistency (P > 0.05). The LR model achieved an AUC value of 0.785, and the Hosmer-Lemeshow test indicated good agreement between the LR model's predicted probabilities and the true value (P > 0.05). Immune infiltration analysis revealed a significant correlation between the pathomics score (PS) and the degree of infiltration of activated DC cells, T cells CD4 naïve, Macrophages M2, Macrophages M1, and T cells CD4 memory resting. Our results demonstrate that the pathomics model exhibits predictability for CD40LG expression and GBM patient survival. These findings can be utilized to assist neurosurgeons in selecting optimal treatment strategies in clinical practice., (© 2024. The Author(s).)

Purpose: Solitary fibrous tumors (SFTs) are a rare type of mesenchymal tumors. The World Health Organization reclassified SFTs in 2021. Currently, guidelines concerning treatment and follow-up are lacking. We performed a retrospective case series with reclassification of SFTs, according to the most recent WHO classification, to explore tumor-behavior. The purpose is to build a framework for long-term patient surveillance., Methodology: A retrospective case study was performed according to the PROCESS guidelines. Inclusion criteria were: patients operated on between 2013 and 2023 in two neurosurgical centers with the diagnosis of 'hemangiopericytoma' or SFT on histopathological stains. Patients were excluded if the original stains of the primary tumor were unavailable. The following demographic, radiologic and therapeutic parameters were included in the review: age, sex, original and reclassified anatomopathological diagnosis, location, extent of resection, use of postoperative radiotherapy, location of and time to recurrence, location of-and time to metastasis, and survival. Histological material was re-examined by experienced neuropathologists., Results: Ten patients were identified with a solitary fibrous tumor of the central nervous system (CNS) (three females) between 2013 and 2023. Age at diagnosis ranged from 38 up to 81. Eight patients were treated by gross total resection (GTR) and postoperative radiotherapy (RT) was applied in five cases. Initial WHO grading consisted of three grade I, two grade II, and six grade III lesions. Reclassification according to the WHO 2021 classification of CNS tumors resulted in seven reclassifications, all towards a lower grade. Four patients showed local recurrence, six to eight years after diagnosis, and five patients developed systemic metastases, nine to 13 years after diagnosis., Discussion: Although rare, SFT should be included in the differential diagnosis of intracranial tumors with extra-axial growth patterns. The current histological grade according to the WHO 2021 does not seem to account for local recurrence rate or systemic metastasis. When a solitary fibrous tumor is presumed, gross total resection is the recommended treatment. Lifelong patient follow-up is necessary due to the risk of delayed recurrence and distant metastasis, even after gross-total resection. We would advocate for the use of CT thorax-abdomen or full body PET in the detection of systemic metastases at diagnosis and during follow-up, however optimal intervals remain unclear., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of anti-inflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor since its cytoprotective functions are considered to be the principle cellular defense mechanism against exogenous and endogenous insults, such as xenobiotics and oxidative stress. However, hyperactivation of the Nrf2 pathway supports the survival of normal as well as malignant cells, protecting them against oxidative stress, and therapeutic agents. Plants possess a pool of secondary metabolites with potential chemotherapeutic/chemopreventive actions. Modulation of Nrf2/ARE and downstream activities in a Keap1-dependant manner, with the aid of plant-derived secondary metabolites exhibits promise in the management of brain tumors. Current article highlights the effects of Nrf2/Keap1/ARE cascade on brain tumors, and the potential role of secondary metabolites regarding the management of the same., (© 2024. The Author(s).)

Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is palliative. Targeting BM-initiating cells (BMICs) is a feasible strategy to treat BM, but druggable targets are limited. Here, we apply Connectivity Map analysis to lung-, breast-, and melanoma-pre-metastatic BMIC gene expression signatures and identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We show that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Metabolomic analyses and CRISPR knockout studies confirm that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employs a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation., Competing Interests: Declaration of interests A.M.K., J.W.J., C.V., J.M., and S.K.S. are listed as co-inventors for a PCT patent that has been filed, relating to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sonodynamic therapy (SDT) has garnered significant attention in cancer treatment, however, the low-yield reactive oxygen species (ROS) generation from sonosensitizers remains a major challenge. In this study, titanium boride nanosheets (TiB 2 NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). Compared with commonly-used TiO 2 nanoparticles, the obtained TiB 2 NSs exhibited much higher ROS generation efficiency under ultrasound (US) irradiation due to their narrower band gap (2.50 eV). Importantly, TiB 2 NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron-hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB 2 NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB 2 @CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB 2 @CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity. Our work highlighted a new type of multifunctional titanium-based sonosensitizer with photo-enhanced sonodynamic efficiency for GBM treatment. STATEMENT OF SIGNIFICANCE: Titanium boride nanosheets (TiB 2 NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). The obtained TiB 2 NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron-hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB 2 NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB 2 @CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB 2 @CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The co-occurrence of chromosome 10 loss and chromosome 7 gain in gliomas is the most frequent loss-gain co-aneuploidy pair in human cancers. This phenomenon has been investigated since the late 1980s without resolution. Expanding beyond previous gene-centric studies, we investigated the co-occurrence in a genome-wide manner, taking an evolutionary perspective. Mining of large-scale tumor aneuploidy data confirmed the previous finding of a small-scale longitudinal study that the most likely order is chromosome 10 loss, followed by chromosome 7 gain. Extensive analysis of genomic and transcriptomic data from both patients and cell lines revealed that this co-occurrence can be explained by functional rescue interactions that are highly enriched on chromosome 7, which could potentially compensate for any detrimental consequences arising from the loss of chromosome 10. Transcriptomic data from various normal, noncancerous human brain tissues were analyzed to assess which tissues may be most predisposed to tolerate compensation of chromosome 10 loss by chromosome 7 gain. The analysis indicated that the preexisting transcriptomic states in the cortex and frontal cortex, where gliomas arise, are more favorable than other brain regions for compensation by rescuer genes that are active on chromosome 7. Collectively, these findings suggest that the phenomenon of chromosome 10 loss and chromosome 7 gain in gliomas is orchestrated by a complex interaction of many genes residing within these two chromosomes and provide a plausible reason why this co-occurrence happens preferentially in cancers originating in certain regions of the brain.  Significance: Increased expression of multiple rescuer genes on the gained chromosome 7 could compensate for the downregulation of several vulnerable genes on the lost chromosome 10, resolving the long-standing mystery of this frequent co-occurrence in gliomas., (©2024 American Association for Cancer Research.)

Purpose: Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in the brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated., Experimental Design: We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n = 41), astrocytoma WHO grade 2 (n = 7), and healthy controls (n = 20) and compared TSPO-PET signals of the non-lesion (i.e., contralateral) hemisphere. Back-translation into syngeneic SB28 glioblastoma mice was used to characterize Pet alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain., Results: Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions., Conclusions: Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Pediatric central nervous system tumors are the most common solid tumors in children and leading cause of cancer-related morbidity and mortality. Various factors may influence the practice of blood transfusion during this tumor diagnosis. The primary aim of this study was to determine the factors that may influence intraoperative blood transfusion in pediatric patients undergoing surgery for intracranial tumors and to predict patients who may require blood transfusion., Methods: A retrospective study was performed in all pediatric patients younger than 15 years who underwent craniotomy for brain tumor removal from January 2018 to December 2023 in our institution. Preoperative, intraoperative and postoperative data were collected from medical and store anesthesia records. The predictors of intraoperative blood transfusion were determined using multivariate logistic regression., Results: A total of 138 patients were enrolled in the study, of whom 62 (44.9%) required intraoperative blood transfusion. In multivariate regression analysis age < 4 years and operating time > 490 min were determined as independent variables in terms of need for intraoperative blood transfusion. It was determined that the need for transfusion was higher in patient who were operated on urgently and patients with comorbidities (p = 0.023, p = 0.005)., Conclusion: In conclusion, the findings obtained in this study suggest that age and surgical duration are independent risk factors for intraoperative blood transfusion in pediatric patients undergoing surgery for intracranial tumors. Particularly, in younger patients and prolonged surgeries, closer monitoring and awareness may enhance early detection, leading to the prevention of complications., (© 2024. The Author(s).)

Gliomas exhibit significant molecular diversity and poor prognosis. In this issue of Cancer Cell, Curry et al. apply Patch-seq on human glioma samples uncovering hybrid cells with glial and neuronal features, capable of firing action potentials in isocitrate dehydrogenase mutant gliomas. These findings highlight the importance of neural features in tumor biology and progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The ability of disseminated cancer cells to colonize the brain is highly dependent on initial survival cues, often evoking early microenvironmental adaptations. In this issue of Cancer Cell, Gan et al. unveil disparate tumor architectures in early stage HER2+ breast cancer and triple-negative breast cancer brain metastases that shape stromal interactions, providing a rationale for subtype-dependent patient stratification., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis., Competing Interests: Declaration of interests N.S.M. has consulted for AstraZeneca. D.P. is on the scientific advisory board of Insitro. J.M. holds company stock of Scholar Rock, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis and limited treatment options. Drug delivery by stimuli-responsive nanocarriers holds great promise for improving the treatment modalities of GBM. At the beginning of the review, we highlighted the stimuli-active polymeric nanocarriers carrying therapies that potentially boost anti-GBM responses by employing endogenous (pH, redox, hypoxia, enzyme) or exogenous stimuli (light, ultrasonic, magnetic, temperature, radiation) as triggers for controlled drug release mainly via hydrophobic/hydrophilic transition, degradability, ionizability, etc. Modifying these nanocarriers with target ligands further enhanced their capacity to traverse the blood-brain barrier (BBB) and preferentially accumulate in glioma cells. These unique features potentially lead to more effective brain cancer treatment with minimal adverse reactions and superior therapeutic outcomes. Finally, the review summarizes the existing difficulties and future prospects in stimuli-responsive nanocarriers for treating GBM. Overall, this review offers theoretical guidelines for developing intelligent and versatile stimuli-responsive nanocarriers to facilitate precise drug delivery and treatment of GBM in clinical settings.

Prior studies have described the complex interplay that exists between glioma cells and neurons; however, the electrophysiological properties endogenous to glioma cells remain obscure. To address this, we employed Patch-sequencing (Patch-seq) on human glioma specimens and found that one-third of patched cells in IDH mutant (IDH mut ) tumors demonstrate properties of both neurons and glia. To define these hybrid cells (HCs), which fire single, short action potentials, and discern if they are of tumoral origin, we developed the single cell rule association mining (SCRAM) computational tool to annotate each cell individually. SCRAM revealed that HCs possess select features of GABAergic neurons and oligodendrocyte precursor cells, and include both tumor and non-tumor cells. These studies characterize the combined electrophysiological and molecular properties of human glioma cells and describe a cell type in human glioma with unique electrophysiological and transcriptomic properties that may also exist in the non-tumor brain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Monitoring tumor evolution and predicting survival using non-invasive liquid biopsy is an unmet need for glioblastoma patients. The era of proteomics and metabolomics blood analyzes, may help in this context. A case-control study was conducted. Patients were included in the GLIOPLAK trial (ClinicalTrials.gov Identifier: NCT02617745), a prospective bicentric study conducted between November 2015 and December 2022. Patients underwent biopsy alone and received radiotherapy and temozolomide. Blood samples were collected at three different time points: before and after concomitant radiochemotherapy, and at the time of tumor progression. Plasma samples from patients and controls were analyzed using metabolomics and proteomics, generating 371 omics features. Descriptive, differential, and predictive analyses were performed to assess the relationship between plasma omics feature levels and patient outcome. Diagnostic performance and longitudinal variations were also analyzed. The study included 67 subjects (34 patients and 33 controls). A significant differential expression of metabolites and proteins between patients and controls was observed. Predictive models using omics features showed high accuracy in distinguishing patients from controls. Longitudinal analysis revealed temporal variations in a few omics features including CD22, CXCL13, EGF, IL6, GZMH, KLK4, and TNFRSP6B. Survival analysis identified 77 omics features significantly associated with OS, with ERBB2 and ITGAV consistently linked to OS at all timepoints. Pathway analysis revealed dynamic oncogenic pathways involved in glioblastoma progression. This study provides insights into the potential of plasma omics features as biomarkers for glioblastoma diagnosis, progression and overall survival. Clinical implication should now be explored in dedicated prospective trials., (© 2024. The Author(s).)

Central nervous system tumors, classified by the WHO into four grades based on their aggressiveness, present significant challenges in treatment, particularly low-grade gliomas (LGGs) which, despite their slower growth, can progress to high-grade gliomas. Lucca B. Palavani and colleagues evaluated the efficacy and safety of SBT I-125 brachytherapy for LGMs in a systematic review and meta-analysis of 20 studies involving 988 patients. The analysis revealed an overall complication rate of 10%, with headaches and cyst formation being the most frequent issues. The five-year progression-free survival (PFS) rate was 66%, while the ten-year PFS rate was 30%, and the rate of malignant transformation was 26%. The mortality rate was 33%. Despite these findings, significant limitations were noted, including data insufficiencies, study heterogeneity, lack of randomized controlled trials, and potential publication bias. Inconsistencies in follow-up durations further hindered the evaluation of long-term efficacy and safety. Recent advancements in automated tumor assessment, such as Cheng et al.'s deep learning-based pipeline, are revolutionizing glioma management by enhancing the accuracy and consistency of tumor volume and RANO measurements. These innovations facilitate improved glioma grading, genetic mutation prediction, surgical planning, real-time intraoperative guidance, and histopathological analysis. Integrating such advanced tools into clinical practice can significantly enhance the precision and efficiency of glioma management. In conclusion, while SBT I-125 brachytherapy shows promise, concerns regarding safety and efficacy underscore the need for further research with standardized methodologies. Incorporating advanced automated assessment tools could improve treatment evaluation and patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This case report delves into the case of a 56-year-old female patient presenting with progressive cephalalgia syndrome, nausea, vomiting, and gait disorders, diagnosed with a high-grade thalamic glioma. Glioma is the most common form of central nervous system (CNS) neoplasm that originates from glial cells. Gliomas are diffusely infiltrative tumors that affect the surrounding brain tissue. Glioblastoma is the most malignant type, while pilocytic astrocytomas are the least malignant brain tumors. In the past, these diffuse gliomas were classified into different subtypes and grades based on histopathologies such as a diffuse astrocytoma, oligodendrogliomas, or mixed gliomas/oligoastrocytomas. Currently, gliomas are classified based on molecular and genetic markers. After the gross total resection, a postoperative brain CT scan was conducted, which confirmed the quasi-complete resection of the tumor. The successful gross total resection of the tumor in this case, coupled with significant neurological improvement postoperatively, illustrates the potential benefits of aggressive surgical management for thalamic gliomas. This report advocates for further research to assess the efficacy of such interventions in malignant cases and to establish standardized treatment protocols, considering the heterogeneity in prognostic outcomes and the advancements in molecular diagnostics that offer deeper insights into glioma oncogenesis and progression.

Background: Gliomas are the highly aggressive brain tumor and also the most devastating human tumors. The latent TGF binding proteins (LTBP) had been found to be involved in malignant biological process and could be used as potent biomarkers in several solid tumors. While the role of LTBP family in human glioma remain to be elucidated., Methods: Normalized gene expression and corresponding clinical data of 2407 gliomas samples in public datasets were downloaded from Gliovis. Kaplan-Meier methods and Cox regression analysis was used for survival analyses.Western blot (WB) and Immunohistochemical (IHC) testing were employed to test LTBPs protein level in 154 gliomas samples. Correlation between LTBP2 expression and immune infiltration was evaluated by immunofluorescence (IF) and IHC in glioma tissues. CCK8 and flow cytometric analysis were used to detect the effect of LTBP2 on glioma cells. Orthotopic glioma- mouse models were utilized to evaluate effects in vivo., Results: LTBP2 mRNA level was dramatically higher in glioma samples compared with non-tumor brain tissues in XENA-TCGA&#95;GTEx, Gill and Gravendeel datasets (all P < 0.01), and its expression positively correlated with glioma WHO grade, IDH1/2 wildtype and mesenchymal subtypes. These results were confirmed by In-house cohort which was detected by WB and IHC. We found that gliomas patients with high LTBP2 level had shorter OS than those with low LTBP2 level. LTBP2 expression significantly associated with glioma immune score (Spearman r = 0.68, P < 0.01)) and strongly correlated with infiltration degreee of macrophages both in lower grade gliomas (LGG) and GBM. Knocking down LTBP2 obviously reduced proliferation and enhanced sensitivity to temozolomide in U87 and U251 cells. Nude mice with lower expression of LTBP2 had slower tumor growth, and accompanied by less tumor-associated macrophages (TAMs) infiltration detected by IHC staining in vivo. Finally, low LTBP2 expression glioma patients who received chemotherapy survived longer than patients with high LTBP2 expression., Conclusion: LTBP2 could be used as a prognostic marker, and high LTBP2 expression related to abundant TAMs infiltration and with a worse response to chemotherapy., (© 2024. The Author(s).)

Background: Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies., Results: Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients., Conclusion: The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies., (© 2024. The Author(s).)

Lower-grade gliomas (LGGs) exhibit diverse clinical behaviors and varying immune infiltration levels. Mitochondria have been implicated in numerous cancer pathogenesis and development, including LGGs. However, the precise biological functions of mitochondrial genes in shaping the immune landscape and the prognostic significance of LGGs remain elusive. Utilizing the Mito-Carta3.0 database, we curated a total of 1136 genes implicated in mitochondrial functions. By leveraging the expression profiles of 1136 genes related to mitochondria, we successfully categorized LGGs into four distinctive mitochondria-related transcriptome (MRT) subtypes. Our thorough analysis conclusively demonstrated that these subtypes exhibited marked disparities. To enable a personalized and integrated evaluation of LGG patients, we developed a prognostic signature known as MRT-related prognostic signature (MTRS). MTRS demonstrated correlation with mitochondria-related transcriptome (MRT) subtypes, allowing the assessment of patients' prognosis and immune microenvironment. We conducted a detailed exploration of the single-cell distribution of MTRS in lower-grade gliomas and verified the core genes of MTRS within the spatial transcriptome of these tumors. Furthermore, our study pinpointed MGME1 as the pivotal gene in the model, functioning as an oncogene that exerts influence on cell proliferation and migration capabilities. Our research highlights the importance of mitochondrial transcriptomic features in LGGs, offering paths for tailored therapies., (© 2024. The Author(s).)