Search Results (2,803)

Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In search of signal transduction pathways with a potential impact in glioma growth and immunotherapy, the Slit guidance ligands (Slits) and their Roundabout (Robo) family of receptors have been revealed as key regulators of tumor cells and their microenvironment. Recent evidence indicates the implication of the Slit/Robo signaling pathway in inflammation, cell migration, angiogenesis, and immune cell infiltration of gliomas, suppressing or promoting the expression of pivotal proteins, such as cell adhesion molecules, matrix metalloproteinases, interleukins, angiogenic growth factors, and immune checkpoints. Herein, we discuss recent data on the significant implication of the Slit/Robo signaling pathway in glioma pathology along with the respective targeting options, including immunotherapy, monoclonal antibody therapy, and protein expression modifiers. Full article

Background: Gliomas, the most prevalent type of primary brain tumor, stand out as one of the most aggressive and lethal types of human cancer. Methods & Results: To uncover potential prognostic markers, we employed the weighted correlation network analysis (WGCNA) on the Chinese Glioma Genome Atlas (CGGA) 693 dataset to reveal four modules significantly associated with glioma clinical traits, primarily involved in immune function, cell cycle regulation, and ribosome biogenesis. Using the least absolute shrinkage and selection operator (LASSO) regression algorithm, we identified 11 key genes and developed a prognostic risk score model, which exhibits precise prognostic prediction in the CGGA 325 dataset. More importantly, we also validated the model in 12 glioma patients with overall survival (OS) ranging from 4 to 132 months using mRNA sequencing and immunohistochemical analysis. The analysis of immune infiltration revealed that patients with high-risk scores exhibit a heightened immune infiltration, particularly immune suppression cells, along with increased expression of immune checkpoints. Furthermore, we explored potentially effective drugs targeting 11 key genes for gliomas using the library of integrated network-based cellular signatures (LINCS) L1000 database, identifying that in vitro, both torin-1 and clofarabine exhibit promising anti-glioma activity and inhibitory effect on the cell cycle, a significant pathway enriched in the identified glioma modules. Conclusions: In conclusion, our study provides valuable insights into molecular mechanisms and identifying potential therapeutic targets for gliomas. Full article

The chemotherapeutic agent vincristine is commonly used for a variety of hematologic cancers, as well as solid tumors of the head and neck, bronchial carcinoma, as part of the procarbazine, lomustine and vincristine (PCV) regimen, for glioma. Damage to nerve tissue (neuropathy) is often dose-limiting and restricts treatment. Nimodipine is a calcium antagonist that has also shown neuroprotective properties in preliminary studies. In this approach here, we investigated the effects of the combination of vincristine and nimodipine on three cancer cell lines (A549, SAS and LN229) and neuronal cells (RN33B, SW10). Fluorescence microscopy, lactate dehydrogenase (LDH) assays and Western blot analyses were used. Nimodipine was able to enhance the cell death effects of vincristine in all tumor cells, while neuronal cells were protected and showed less cell death. There was an opposite change in the protein levels of Ak strain transforming/protein kinase B (AKT) in tumor cells (down) and neuronal cells (up), with simultaneous increased protein levels of cyclic adenosine monophosphate response element-binding protein (CREB) in all cell lines. In the future, this approach may improve tumor response to chemotherapy and reduce unwanted side effects such as neuropathy. Full article

The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia (GAMMs) overwhelmingly constitute the bulk of the recurrent glioblastoma (rGBM) microenvironment, in comparison to the highly cellular and proliferative tumor microenvironment characteristic of primary GBM. These immune cells dynamically interact within the tumor microenvironment and can contribute to disease progression and therapy resistance while also providing novel targets for emerging immunotherapies. Within these varying contexts, histological-based assessments of immune cells in rGBM, including immunohistochemistry (IHC) and immunofluorescence (IF), offer a critical way to visualize and examine the inflammatory landscape. Here, we exhaustively review the available body of literature on the inflammatory landscape in rGBM as identified through histological-based assessments. We highlight the heterogeneity of immune cells throughout the glioma-infiltrated cortex with a focus on microglia and macrophages, drawing insights from canonical and novel immune-cell histological markers to estimate cell phenotypes and function. Lastly, we discuss opportunities for immunomodulatory treatments aiming to harness the inflammatory landscape in rGBM. Full article

Background: Glioblastoma multiforme (GBM) is among the most aggressive and challenging brain tumors, with limited treatment options. Cimicifuga foetida, a traditional Chinese medicine, has shown promise due to its bioactive components. This study investigates the anti-glioma effects of a methanolic extract of C. foetida (CF-ME) in GBM cell lines. Methods: The effects of CF-ME and its index compounds (caffeic acid, cimifugin, ferulic acid, and isoferulic acid) on GBM cell viability were assessed using MTT assays on U87 MG, A172, and T98G cell lines. The ability of CF-ME to induce cell cycle arrest, apoptosis, and autophagy and inhibit metastasis was evaluated using flow cytometry, Western blotting, and functional assays. Additionally, the synergistic potential of CF-ME with temozolomide (TMZ) was explored. Results: CF-ME significantly reduced GBM cell viability in a dose- and time-dependent manner, induced G1 phase cell cycle arrest, promoted apoptosis via caspase activation, and triggered autophagy. CF-ME also inhibited GBM cell invasion, migration, and adhesion, likely by modulating epithelial–mesenchymal transition (EMT) markers. Combined with TMZ, CF-ME further enhanced reduced GBM cell viability, suggesting a potential synergistic effect. However, the individual index compounds of CF-ME exhibited only modest inhibitory effects, indicating that the full anti-glioma activity may result from the synergistic interactions among its components. Conclusions: CF-ME exhibited potent anti-glioma activity through multiple mechanisms, including cell cycle arrest, apoptosis, autophagy, and the inhibition of metastasis. Combining CF-ME with TMZ further enhanced its therapeutic potential, making it a promising candidate for adjuvant therapy in glioblastoma treatment. Full article

In recent years, various drug delivery systems circumventing the blood–brain barrier have emerged for treating brain tumors. This study aimed to improve the efficacy of brain tumor treatment in boron neutron capture therapy (BNCT) using cerebrospinal fluid (CSF) circulation to deliver boronophenylalanine (BPA) to targeted tumors. Previous experiments have demonstrated that boron accumulation in the brain cells of normal rats remains comparable to that after intravenous (IV) administration, despite BPA being administered via CSF at significantly lower doses (approximately 1/90 of IV doses). Based on these findings, BNCT was conducted on glioma model rats at the Kyoto University Research Reactor Institute (KUR), with BPA administered via CSF. This method involved implanting C6 cells into the brains of 8-week-old Wistar rats, followed by administering BPA and neutron irradiation after a 10-day period. In this study, the rats were divided into four groups: one receiving CSF administration, another receiving IV administration, and two control groups without BPA administration, with one subjected to neutron irradiation and the other not. In the CSF administration group, BPA was infused from the cisterna magna at 8 mg/kg/h for 2 h, while in the IV administration group, BPA was intravenously administered at 350 mg/kg via the tail vein over 1.5 h. Thermal neutron irradiation (5 MW) for 20 min, with an average fluence of 3.8 × 10¹²/cm², was conducted at KUR’s heavy water neutron irradiation facility. Subsequently, all of the rats were monitored under identical conditions for 7 days, with pre- and post-irradiation tumor size assessed through MRI and pathological examination. The results indicate a remarkable therapeutic efficacy in both BPA-administered groups (CSF and IV). Notably, the rats treated with CSF administration exhibited diminished BPA accumulation in normal tissue compared to those treated with IV administration, alongside maintaining excellent overall health. Thus, CSF-based BPA administration holds promise as a novel drug delivery mechanism in BNCT. Full article

The serotonin 5-HT₆ receptor (5-HT₆R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT₆R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT₆R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT₆R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug–drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio rerio model. Two antagonists with an affinity constant K_i < 50 nM (PR 68 K_i = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug–drug interactions. Full article

Background: Gliomas, including the most severe form known as glioblastomas, are primary brain tumors arising from glial cells, with significant impact on adults, particularly men aged 45 to 70. Recent advancements in the WHO (World Health Organization) classification now correlate genetic markers with glioma phenotypes, enhancing diagnostic precision and therapeutic strategies. Aims and Methods: This scoping review aims to evaluate the current state of deep learning (DL) applications in the genetic characterization of adult gliomas, addressing the potential of these technologies for a reliable virtual biopsy. Results: We reviewed 17 studies, analyzing the evolution of DL algorithms from fully convolutional networks to more advanced architectures (ResNet and DenseNet). The methods involved various validation techniques, including k-fold cross-validation and external dataset validation. Conclusions: Our findings highlight significant variability in reported performance, largely due to small, homogeneous datasets and inconsistent validation methods. Despite promising results, particularly in predicting individual genetic traits, the lack of robust external validation limits the generalizability of these models. Future efforts should focus on developing larger, more diverse datasets and integrating multidisciplinary collaboration to enhance model reliability. This review underscores the potential of DL in advancing glioma characterization, paving the way for more precise, non-invasive diagnostic tools. The development of a robust algorithm capable of predicting the somatic genetics of gliomas or glioblastomas could accelerate the diagnostic process and inform therapeutic decisions more quickly, while maintaining the same level of accuracy as the traditional diagnostic pathway, which involves invasive tumor biopsies. Full article

The registration of preoperative and follow-up brain MRI, which is crucial in illustrating patients’ responses to treatments and providing guidance for postoperative therapy, presents significant challenges. These challenges stem from the considerable deformation of brain tissue and the areas of non-correspondence due to surgical intervention and postoperative changes. We propose a stepwise corrected attention registration network grounded in convolutional neural networks (CNNs). This methodology leverages preoperative and follow-up MRI scans as fixed images and moving images, respectively, and employs a multi-level registration strategy that establishes a precise and holistic correspondence between images, from coarse to fine. Furthermore, our model introduces a corrected attention module into the multi-level registration network that can generate an attention map at the local level through the deformation fields of the upper-level registration network and pathological areas of preoperative images segmented by a mature algorithm in BraTS, serving to strengthen the registration accuracy of non-correspondence areas. A comparison between our scheme and the leading approach identified in the MICCAI’s BraTS-Reg challenge indicates a 7.5% enhancement in the target registration error (TRE) metric and improved visualization of non-correspondence areas. These results illustrate the better performance of our stepwise corrected attention registration network in not only enhancing the registration accuracy but also achieving a more logical representation of non-correspondence areas. Thus, this work contributes significantly to the optimization of the registration of brain MRI between preoperative and follow-up scans. Full article

Background/Objectives: Glioblastomas (GBMs) are the most malignant and intractable of all cancers, with an unfavorable clinical prognosis for affected patients. The objective was to analyze the sensitivity of GBM cells to the antimicrobial peptides (AMPs) cathelicidin (LL-37) and protegrin-1 (PG-1), both alone and in combination with chemotherapy, to predict overall survival (OS) in the patients. Methods: The study was conducted on 27 GBM patients treated in the neurosurgical department of the Almazov Medical Research Centre (Saint Petersburg, Russia) from 2021 to 2024. The cytotoxic effects of chemotherapy, AMPs, and their combinations on brain tumor cells were assessed by an MTT assay using a 50% inhibitory concentration (IC₅₀). Results: In GBM cells from the patients, LL-37 and PG-1 exhibited strong anticancer effects, surpassing those of chemotherapy drugs. These LL-37 and PG-1 anticancer effects were associated with a statistically significant increase in life expectancy and OS in GBM patients. These findings were confirmed by experiments on rats with C6 glioma, where the intranasal administration of LL-37 (300 μM) and PG-1 (600 μM) increased the life expectancy of the animals to 69 and 55 days, respectively, compared to 24 days in the control group (HR = 4.139, p = 0.0005; HR = 2.542, p = 0.0759). Conclusions: Additionally, the combination of LL-37 and PG-1 with chemotherapy drugs showed that a high IC₅₀ of LL-37 with cisplatin (cutoff > 800 μM) in GBM cells was associated with increased life expectancy (19 vs. 5 months, HR = 4.708, p = 0.0101) and OS in GBM patients. These combinations could be used in future GBM treatments. Full article

The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin’s functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin’s function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation. Full article

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions. The brain was removed 24 h after the i-PDT and analyzed pathologically. The optical fiber was able to puncture the tumor center in all cases, enabling i-PDT to be performed. Histological analysis showed that tumor necrosis was induced in areas close to the light source, correlating with the irradiation energy dose, whereas apoptosis was induced at some distance from the light source. Irradiation using high energy levels resulted in tissue swelling from strong tumor necrosis, and irradiation at 75 J/cm² was most suitable for inducing apoptosis. An experimental system of i-PDT using TPS was established using malignant glioma cells transplanted into the rat brain. Tumor cell death, which correlated with the light propagation, was induced in tumor tissue. Full article

Glioblastoma multiforme (GBM) represents the deadliest form of brain cancer, characterized by complex interactions within its microenvironment. Despite the understanding of GBM biology, GBM remains highly resistant to any therapy. Therefore, defining innovative biomarkers in GBM can provide insights into tumor biology and potential therapeutic targets. In this study, we explored the potential of GPRC5A to serve as a pertinent biomarker for GBM. We utilized the GBM-TCGA dataset and presented the reproducible bioinformatics analysis for our results. We identified that GPRC5A expression was significantly upregulated in GBM compared to normal tissues, with higher levels correlating with poor overall survival (OS) and progression-free interval (PFI). Moreover, it was associated with key genetic mutations, particularly NF1 and PTEN mutations, and strongly correlated with the mesenchymal stem-like phenotype. GPRC5A was also predominantly associated with aggressive GBM features, including hypoxia, high extracellular matrix (ECM) environments, and extensive stromal and immune infiltrations. Its strong correlation with mesenchymal markers and hypoxic regions underscores its potential as a biomarker and therapeutic target in GBM. These findings provide valuable insights into the role of GPRC5A in GBM pathology and its potential impact as a target for GBM stratifications and treatment strategies. Full article

11C-Methionine (MET) is a widely utilized amino acid tracer in positron emission tomography (PET) imaging of primary brain tumors. 11C-MET PET offers valuable insights for tumor classification, facilitates treatment planning, and aids in monitoring therapeutic response. Its tracer properties allow better delineation of the active tumor volume, even in regions that show no contrast enhancement on conventional magnetic resonance imaging (MRI). This review focuses on the role of MET-PET in brain glioma imaging. The introduction provides a brief clinical overview of the problems of high-grade and recurrent gliomas. It discusses glioma management, radiotherapy planning, and the difficulties of imaging after chemoradiotherapy (pseudoprogression or radionecrosis). The mechanism of MET-PET is described. Additionally, the review encompasses the application of MET-PET in the context of primary gliomas, addressing its diagnostic precision, utility in tumor classification, prognostic value, and role in guiding biopsy procedures and radiotherapy planning. Full article

Glioblastoma multiforme (GBM) represents one of the most critical oncological diseases in neurological practice, being considered highly aggressive with a dismal prognosis. At a worldwide level, new therapeutic methods are continuously being researched. Magnetic hyperthermia (MHT) has been investigated for more than 30 years as a solution used as a single therapy or combined with others for glioma tumor assessment in preclinical and clinical studies. It is based on magnetic nanoparticles (MNPs) that are injected into the tumor, and, under the effect of an external alternating magnetic field, they produce heat with temperatures higher than 42 °C, which determines cancer cell death. It is well known that iron oxide nanoparticles have received FDA approval for anemia treatment and to be used as contrast substances in the medical imagining domain. Today, energetic, efficient MNPs are developed that are especially dedicated to MHT treatments. In this review, the subject’s importance will be emphasized by specifying the number of patients with cancer worldwide, presenting the main features of GBM, and detailing the physical theory accompanying the MHT treatment. Then, synthesis routes for thermally efficient MNP manufacturing, strategies adopted in practice for increasing MHT heat performance, and significant in vitro and in vivo studies are presented. This review paper also includes combined cancer therapies, the main reasons for using these approaches with MHT, and important clinical studies on human subjects found in the literature. This review ends by describing the most critical challenges associated with MHT and future perspectives. It is concluded that MHT can be successfully and regularly applied as a treatment for GBM if specific improvements are made. Full article