Search Results (552)

A body of evidence suggests that upregulating O-GlcNAcylation, a reversible post-translational modification of serine and threonine residues on target proteins, is beneficial in neurological diseases. However, this phenomenon is currently underexplored in the pharmacotherapy of epilepsy. Therefore, we aimed to explore the potential effects of combining N-acetylglucosamine (GlcNAc), a precursor for O-GlcNAcylation, and a centrally acting benzodiazepine (diazepam) on oxidative stress, a known driver of epilepsy, and some epileptogenesis-associated genes. Mice (n = 10) were randomly assigned to treatment groups and treated with varied oral doses (100, 200, and 400 mg/kg) of GlcNAc in combination with diazepam (1 mg/kg) for 14 days. Following this, seizure was chemically induced with 70 mg/kg pentylenetetrazol intraperitoneally. Brains of treated mice were excised for antioxidant assays and to determine the expression of genes associated with epileptogenesis: potassium chloride co-transporter (KCC4), interleukin (IL-6), tumour necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF). Our findings suggest that GlcNAc, when concurrently administered with diazepam, prevents oxidative stress and reduces the gene expression of IL-6, a cytokine associated with neuroinflammation and seizures, whilst increasing the gene expression of KCC4, an ion co-transporter that promotes antiepileptogenesis. Full article

Bitter taste receptors (TAS2Rs) are increasingly recognised as extraoral chemosensors that modulate diverse biological processes, including cancer cell behaviour and drug responsiveness. Many TAS2R ligands correspond to therapeutic compounds; however, their contribution to the response of brain tumours to chemotherapy remains unexplored. Here, we investigated whether the bitter taste signalling pathway is modulated by temozolomide (TMZ), the standard chemotherapeutic agent for glioblastoma, with an impact on treatment efficacy in glioblastoma cells. We show that TMZ elicits intracellular Ca²⁺ responses compatible with activation of G-protein-coupled receptor signalling and induces anti-proliferative and pro-apoptotic effects in multiple human glioblastoma cell lines. Pharmacological inhibition of bitter taste receptors, as well as genetic silencing of the taste transduction G protein GNAT3, significantly attenuated TMZ-induced cytotoxicity, suggesting that bitter taste signalling is involved in this process. In silico ligand prediction combined with receptor expression profiling identified TAS2R43 as a candidate modulator of these effects, and TAS2R43 knockdown markedly reduced TMZ-induced loss of cell viability and apoptosis. Moreover, TMZ enhanced intracellular accumulation of the ABC transporter substrate doxorubicin, suggesting modulation of multidrug efflux mechanisms. Collectively, our findings identify TAS2R43 as a potential biomarker that warrants further validation to improve responses to TMZ and other ABC transporter-limited anticancer drugs. Full article

Paediatric medulloblastoma is the most common malignant brain tumour in children, exhibiting substantial biological heterogeneity that drives variable treatment outcomes. Despite advances in multimodal therapy, treatment-related morbidity remains a critical concern, underscoring the need for biomarkers to guide precision therapy. This review synthesises current knowledge on biomarkers of treatment response, encompassing molecular, epigenetic, transcriptomic, protein, and imaging-based markers. WNT-activated tumours show excellent prognosis and are candidates for therapy de-escalation; SHH-driven tumours demonstrate age-dependent outcomes influenced by TP53 status; Group 3 tumours carry the poorest prognosis; and Group 4 tumours display highly variable outcomes. DNA methylation profiles, transcriptional programs, and non-coding RNAs provide additional predictive insights. Protein biomarkers and advanced imaging, including liquid biopsy and radiomics, offer minimally invasive approaches for real-time monitoring of treatment efficacy. The review also addresses challenges such as intra-tumour heterogeneity, limited tissue availability, technical variability, and ethical considerations in paediatric oncology. Finally, we explore future directions, highlighting integrative, longitudinal, and ethically grounded biomarker strategies that have the potential to optimise therapy, minimise long-term toxicity, and improve both survival and quality of life for children with medulloblastoma. Full article

Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant forms of brain cancer, posing challenges to modern oncology. Current treatments, including surgery, radiation, and chemotherapy (e.g., Temozolomide or TMZ), often fail due to the inevitable development of drug resistance. TMZ resistance remains a major therapeutic challenge for the reasons that it is the first-line treatment. Recent studies indicate a rising GBM tumour burden and a trend towards earlier age of onset. It highlights the urgent need for evidence-based policymaking and intensified research to address this most difficult-to-treat malignancy in clinical settings. Ferroptosis, a newly recognized type of controlled cell death induced by iron-dependent lipid peroxidation, has emerged as a potential approach to overcome apoptosis resistance and restore drug sensitivity in GBM. This mechanism is modulated by key molecules that can be specifically targeted to either enhance oxidative stress or inhibit antioxidant defences, ultimately leading to tumour cell death. This review conducts a meta-analysis of preclinical evidence to better understand the potential of activating ferroptosis as a key target for developing nanoparticles to resensitize TMZ-resistant GBM cells. Current evidence indicates that combining ferroptosis induction with strategically engineered nanocarrier systems can serve as a novel and effective therapeutic approach to overcome TMZ resistance and advance precision-based GBM treatment. Full article

Background: Breast cancer brain metastases (BCBM) lack effective treatments, contributing to breast cancer-related morbidity and mortality. Integrating translational animal models and advanced non-invasive imaging can accelerate the development of urgently needed therapies. Method: In this study, we developed an intracarotid method mimicking BCBM and compared it to the stereotactic model in terms of animal welfare, tumour establishment, and blood–brain barrier (BBB) permeability. BCBM was established through intracarotid or stereotactic inoculation of BT474 and MDA-MB-231.Luc2 cells in NMRI nude mice. We utilised magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) to monitor tumour growth and BBB permeability, supported by fluorescent immunohistochemistry for validation. Finally, light sheet microscopy (LSM) was employed to visualise tumour establishment in intact brains. Results: Both inoculation methods achieved a survival rate > 70%, with animals recovering within a week post-surgery. MRI and BLI effectively visualised tumour growth with stereotactic implantation, resulting in single tumours, while intracarotid inoculation led to micro-seeding of up to seven tumours in one brain. Tumour growth was rapid and homogenous in the stereotactic model, whereas the intracarotid model exhibited slower, heterogenous growth. Notably, BBB permeability was significantly higher in small tumours in the stereotactic model when compared to the intracarotid model (p = 0.003). Ex vivo analyses validated these findings with the identification of multiple metastasis in the intracarotid model and single tumours in the stereotactic model. Conclusions: We developed an animal model that closely mimics BCBM, highlighting extravasation and micro-seeding while maintaining animal welfare. Our established imaging protocols enable longitudinal evaluations of BBB permeability and treatment response, creating a translational platform for testing novel anti-cancer therapies. Full article

Background: Non-invasive approaches to brain tumour detection and diagnosis are limited by the absence of clinically validated circulating biomarkers. This study utilised a miniaturised tissue perfusion model to maintain human brain tumour tissue ex vivo with the aim of identifying tissue-derived proteins with potential biomarker utility. Methods: 55 tumour samples from 11 different brain tumours (glioblastoma n = 4, low-grade glioma n = 4, brain metastases n = 3) were micro-dissected and maintained ex vivo on a continuous-flow perfusion device for 168 h. Proteomic analysis of tumour effluent was performed by reversed-phase capillary liquid chromatography-mass spectrometry. Two candidate proteins—extracellular matrix protein 1 (ECM1) and cathepsin D—were quantified using ELISA. Results: All tumour subtypes retained tissue viability over 168 h of perfusion. Proteomic profiling identified 90 tissue-derived proteins in the tumour effluent. Many proteins corresponded to previously described cancer biomarkers such as glial fibrillary acidic protein (GFAP) while others, including Serpin A12 and collapsin response mediator protein-2 (CRMP2), had not yet been described in a brain tumour context. ELISA confirmed significantly higher ECM1 levels in high-grade glioma effluent compared with low-grade glioma (p = 0.0407), whereas cathepsin D levels did not differ significantly between tumour types. Conclusions: The ex vivo perfusion model effectively preserved primary and metastatic human brain tumour tissue and enabled direct characterisation of tumour-secreted proteins. The proteins identified here warrant further validation as tumour biomarkers in patient serum or cerebrospinal fluid. Full article

Glial brain tumours, including astrocytoma IDH (Isocitrate Dehydrogenase) mutant and glioblastoma IDH wild-type, are highly malignant brain tumours with poor clinical outcomes. Genomic instability, encompassing microsatellite (MIN) and chromosomal instability (CIN), drives tumour heterogeneity and evolution. In this study, genomic instability was analysed in 85 patients using AP-PCR (Arbitrarily Primed Polymerase Chain Reaction) by comparing tumour and normal tissue (blood) DNA profiles of the same patient. Both types of alterations were present in all analysed samples, contributing almost equally to the total level of genomic instability. The dominant pattern of genomic instability in our cohort was low overall instability, predominantly manifesting as low-degree microsatellite instability. A general decrease in genomic instability was observed with increasing tumour grade. Glioblastoma IDH wild-type was more prevalent in older patients, whereas astrocytoma IDH mutant predominated in younger individuals. Notably, low genomic instability (both MIN and CIN) was associated with poorer survival in patients over 50 years of age. Females, compared to males, exhibited higher MIN in grade 2 tumours and elevated CIN in grade 4 tumours. Our results confirm that genomic instability contributes to tumour progression, MIN being the pivotal factor, and could serve as a prognostic biomarker in malignant gliomas. Full article

Glioblastoma (GBM) is an aggressive brain tumour known for its ability to resist the current treatment protocols. A major reason for this resistance is a minor group of cells within the tumour called glioblastoma stem cells (GSCs). These cells drive tumour growth, invasion, and recurrence after therapy. GSCs survive and expand within a specific microenvironment that protects and supports them. Three of the most important niches are: hypoxic (low oxygen) regions, which trigger survival pathways and make GSCs more resistant to treatment; perivascular areas near blood vessels, which provide nutrients and signals that maintain stem-like properties; and immune-related zones, where inflammatory and suppressive signals help GSCs escape the body’s defences. Together, these environments allow GSCs to thrive and contribute to the tumour’s persistence. This review highlights how hypoxia, blood vessel niches, and immune interactions work together to sustain GSCs and promote GBM progression. A clearer understanding of these supportive environments may lead to new treatment approaches aimed at disrupting GSC survival and improving patient outcomes. Full article

Understanding the interactions of nanomaterials with complex tumour models is essential for advancing their use in nanomedicine. Calcium fluoride nanoparticles doped with neodymium and yttrium (CaF₂:Nd³⁺,Y³⁺) exhibit promising properties for biomedical applications, particularly for optical sensing and tagging. This study investigates their interaction with 3D cell spheroids derived from breast cancer, from Michigan Cancer Foundation-7 (MCF-7) and brain cancer, from Uppsala 87 Malignant Glioma (U-87 MG) cell lines as tumour models. Specific protocols have been developed in Total-reflection X-Ray Fluorescence (TXRF) to evaluate nanoparticles’ internalisation and diffusion within spheroids by quantifying the concentrations of Ca, Nd, and Y taken up by the cells. Minimal background interference enabled precise multi-element detection in low-volume biological samples, yielding very low detection limits and minimal uncertainties. The study demonstrates the effectiveness of TXRF for quantifying rare-earth-doped nanoparticles in 3D cancer models and reveals that, although both cell lines permit nanoparticle diffusion into cells, higher accumulation is observed in glioblastoma cell spheroids. A Weibull diffusion model was applied to help understand the observed internalisation kinetics of nanoparticles into U-87 MG and MCF-7 spheroids. The relevant differences suggest cell-line-dependent uptake behaviour, potentially influenced by differences in cellular architecture, the porosity of the generated spheroid, and its intercellular 3D microstructure. These findings highlight the importance of tumour-specific interactions in the investigation of nanoparticle systems for targeted cancer diagnostics and therapeutics. Full article

Incomplete or faulty MRI sequences are common in clinical practice and can impair AI-based analyses that rely on complete multi-contrast data. The relative effectiveness of classical generative adversarial networks (GANs) versus modern diffusion and transformer-based models for clinically usable MRI synthesis remains unclear. This study evaluates cross-modality MRI synthesis using the BraTS 2019 brain tumour dataset, focusing on T1-to-T2 translation. We assess paired and unpaired CycleGAN models and compare them with two stronger but computationally intensive baselines, a conditional denoising diffusion probabilistic model (DDPM) and a transformer-enhanced GAN, using identical data splits and preprocessing pipelines. Inter-modality correlation was evaluated to estimate the achievable similarity between modalities. Conceptually, modality synthesis may be viewed as a representation-learning approach that compensates for missing imaging information by reconstructing clinically relevant features from available contrasts. Paired CycleGAN achieved correlations of $r\approx 0.92–0.93$ and SSIM $\approx 0.90–0.92$, approaching natural T1–T2 correlation ($r\approx 0.95$) while maintaining very fast inference (<50 ms/slice). Unpaired CycleGAN achieved $r\approx 0.74–0.78$ and SSIM $\approx 0.82–0.85$, producing clinically interpretable reconstructions without voxel-level supervision. DDPM achieved the highest fidelity (SSIM $\approx 0.93–0.95$, $r\approx 0.94$) but required substantially greater computational resources, while transformer-enhanced GAN performance was intermediate. Qualitative analysis showed that CycleGAN and DDPM best preserved tumour and tissue boundaries, whereas unpaired CycleGAN occasionally over-smoothed subtle lesions. These findings highlight the trade-off between fidelity and efficiency in cross-modality MRI synthesis, suggesting paired CycleGAN for time-sensitive clinical workflows and diffusion models as a computationally expensive accuracy upper bound. Full article

Glioblastoma (GB) is one of the most aggressive brain tumours, with a high mortality rate. Tumour heterogeneity, GB’s invasive nature, the blood–brain barrier (BBB) and resistance development offer significant challenges in devising an effective strategy to manage GB. Clinicians rely on tumour resection, radiotherapy and temozolomide (TMZ) chemotherapy, but their efficacy is hindered due to poor BBB penetration. EGFR (epidermal growth factor receptor), NF-κB, angiogenic pathways, RAS/RAF/MAPK, PI3K/Akt/mTOR, etc., play an important role in GB progression. Development in nanotechnology, pharmaceutical science and genetic engineering enables the design of drug candidates with superior efficacy and safety profiles. This review delves into recent advancements in nanoparticles, hydrogels, extracellular vesicles, microneedles and other drug delivery platforms used in GB treatment. These novel drug delivery systems achieved superior BBB penetration, tumour targeting, and controlled release and better survival outcomes in preclinical setups. This review also discusses the major translational challenges, including those of large-scale production, tumour heterogeneity, off-target effects and M2 macrophage induction. Innovative strategies focusing on drug delivery as a biological decision-making process, integrating tumour stress responses into drug carrier and system-level design principles, are discussed, outlining future prospects. Full article

Background and Objectives: Melanoma is an aggressive cutaneous malignancy with a high recurrence rate even after complete resection. Circulating tumour DNA (ctDNA) has emerged as a promising biomarker for detecting minimal residual disease (MRD), assessing tumour burden, and predicting recurrence. This study aims to evaluate the clinical utility of ctDNA analysis in determining completeness of melanoma resection and disease staging. Materials and Methods: A systematic review was conducted in accordance with PRISMA guidelines, searching PubMed and Web of Science for studies published between January 2017 and February 2025. Eligible studies assessed ctDNA before, during, or after melanoma resection to evaluate surgical completeness and staging. Studies without perioperative ctDNA assessment or which focused solely on immunotherapy efficacy were excluded. Results: Fourteen studies with 1077 patients met the inclusion criteria. Preoperative ctDNA detection correlated with advanced stage, greater tumour burden, and poorer survival. Postoperative ctDNA persistence was strongly associated with recurrence, often detectable months before clinical relapse. In most patients remaining disease-free, ctDNA cleared within weeks after surgery. ctDNA levels reflected metastatic spread, though sensitivity was lower for brain lesions. Across studies, undetectable postoperative ctDNA was consistently linked to longer recurrence-free survival. Conclusions: Perioperative ctDNA analysis shows promise as a prognostic biomarker for detecting residual disease and anticipating relapse in melanoma. However, heterogeneity in patient cohorts, study design, and ctDNA detection methods limits immediate clinical application. Large, standardized prospective trials are needed to validate ctDNA for perioperative management. Full article

Introduction: Significant studies have substantiated the evidence for complete resection of intrinsic brain tumours in recent years. However, achieving this through a single surgery is not always possible due to tumour localisation in eloquent areas. Therefore, the present analysis aimed to evaluate surgical outcomes in a cohort of patients undergoing planned two-stage glioma surgery. Methods: Patients who underwent surgery for diffusely infiltrating brain tumours between 2013 and 2023 at the Department of Neurosurgery at Düsseldorf University Hospital were screened for undergoing two-stage surgery, defined by a priori-considered surgical re-intervention up to 6 weeks after the initial surgery. Results: Of 1558 patients with glioma, 447 underwent multiple surgeries, of whom 36 underwent planned two-stage surgery during the course of their disease. Two-stage surgery was performed mostly as glioma surgery at first diagnosis (75%). The mean time between the first and second surgery was 11.67 days (±7.59). Two-stage surgery was performed due to various reasons, mostly in localisations that required multifocal approaches (47.2%), due to non-compliance during initial awake surgery (30.6%), or cases with primary debulking for subsequent awake-surgery approaches (22.2%). Tumours were mainly located in the left hemisphere (50%) (right hemisphere 25%, or bilateral 25%) and motor- or speech-eloquent in 61.11%. Tumours were 72.2% IDH-wildtype. An intended complete resection result was achieved in 58.88% after the second surgery, changing from 93.94% submaximal resection to 58.88% supramaximal and maximal resection after the second surgery. Second surgery significantly reduced residual tumour volume of both T1-CE (Wilcoxon signed-rank test, Z = −4.62, p < 0.001) and T2-nCE (Z = −4.62, p < 0.001). In contrast, functional (KPS: Z = −0.93, p = 0.350) and neurological status (NIHSS: Z = −0.89, p = 0.372) did not significantly change. Perioperative complications of the second surgery occurred in nine (25%) cases, requiring surgical intervention under general anaesthesia or ICU treatment (Clavien–Dindo grade IIIb/IV) in six (16.67%) cases. Conclusion: Planned two-stage surgery was mostly performed as a surgical strategy in eloquent locations to achieve supramaximal or maximal resection. A two-staged surgery significantly extended resection results without neurological and functional deterioration. Despite relevant complication rates, primary debulking followed by staged resection as well as two-staged multifocal approaches may yield a favourable risk–benefit profile. Full article

Adult glioblastoma multiforme (GBM) is the most common primary malignant brain tumour caused by multiple molecular factors. N⁶-methyl-adenosine (m⁶A) is an abundant RNA modification that governs cellular RNA metabolism. We hypothesise that changes in m⁶A-modified RNA and regulatory machinery such as the writer proteins, Methyltransferase 3 (METTL3) and WT1-associating protein (WTAP), the demethyltransferase protein, and Alpha-ketoglutarate dependent dioxygenase (FTO), are driving factors of GBM development and treatment resistance. Here, we investigated m⁶A-RNA spatial and quantitative abundance and expression of m⁶A effector proteins directly in GBM tissue and patient-derived low-passage primary adult GBM and low-grade glioma (LGG) cells, and explored the consequences of m⁶A-RNA disruption on GBM invasive capabilities, self-renewal and responsiveness to temozolomide (TMZ). We observed that METTL3, WTAP and FTO transcript and protein expression were significantly increased in cells derived from invasive regions of GBM tumours, and elevated WTAP and FTO expression significantly correlated with poor GBM patient survival. We further found that the abundance of m⁶A-modified RNA in GBM tumours was significant higher in rim and invasive tissue, as well as significantly higher in patient-derived cells from GBM tumour invasive regions. Functional depletion of these effector proteins significantly altered m⁶A levels on and the expression of the pluripotency stem cell marker SOX2 while also impairing self-renewal and cell invasion behaviour and increasing sensitivity to TMZ. The targeting of RNA modification regulatory mechanisms reveals novel therapeutic strategies aimed at improving clinical outcomes for GBM patients. Full article