Search Results (414)

Ovarian cancer is a highly lethal malignancy, characterised by late-stage diagnosis, marked inter- and intra-tumoural heterogeneity, and frequent development of chemoresistance. Existing preclinical models, including conventional two-dimensional cultures, three-dimensional spheroids, and organoids, only partially recapitulate the structural and functional complexity of the ovarian tumour microenvironment (TME). Tumour-on-chip (CoC) technology has emerged as a promising alternative, enabling the co-culture of tumour and stromal cells within a microengineered platform that incorporates relevant extracellular matrix components, biochemical gradients, and biomechanical cues under precisely controlled microfluidic conditions. This review provides a comprehensive overview of CoC technology relevant to ovarian cancer research, outlining fabrication strategies, device architectures, and TME-integration approaches. We systematically analyse published ovarian cancer-specific CoC models, revealing a surprisingly limited number of studies and a lack of standardisation across design parameters, materials, and outcome measures. Based on these findings, we identify critical technical and biological considerations to inform the rational design of next-generation CoC platforms, with the aim of improving their reproducibility, translational value, and potential for personalised medicine applications. Full article

Breast cancer is the most common malignancy and leading cause of cancer-related mortality among women worldwide. Oestrogen receptor (ER)-positive disease accounts for the majority of cases, where endocrine and targeted therapies have substantially improved survival. Nevertheless, resistance to therapy remains inevitable, emphasising the need for precision strategies informed by molecular profiling. The molecular landscape of ER-positive breast cancer is increasingly complex, characterised by diverse genomic alterations driving resistance and progression. Advances in next-generation sequencing and circulating tumour DNA (ctDNA) technologies enable the dynamic assessment of tumour heterogeneity and clonal evolution, informing prognostication and guiding biomarker-driven therapy. Uniquely, this review integrates molecular phenotyping with clinical treatment algorithms for advanced ER-positive breast cancer, providing a practical framework to translate genomic insights into patient care. Key genomic alterations and targeted strategies with demonstrated clinical benefit, including oral selective ER degraders (SERDs) and PI3K/AKT/mTOR inhibitors in selected biomarker populations, are highlighted. Emerging targets, such as human epidermal growth factor 2 (HER2) mutations, and the potential of ctDNA monitoring to detect resistance and guide therapeutic escalation are also discussed. Incorporating molecular profiling, as recommended by international guidelines, into routine clinical decision making can personalise therapy and optimise patient outcomes. Addressing real-world challenges, including cost and accessibility, will be critical to achieving equitable implementation of precision oncology for patients with ER-positive breast cancer worldwide. Full article

Bladder cancer (BCa) is one of the most diagnosed cancers worldwide. It is classified as non-muscle-invasive (NMIB), confined to the mucosa, and muscle-invasive (MIB), extended to deeper layers or formed metastases. The poor outcomes associated with MIBC indicate the urgent need for candidate biomarkers to improve treatment strategies. Molecular characterisation of both NMIBC and MIBC, and especially the classification of tumours into molecular subtypes, could provide the development of novel therapeutics in high-risk muscle-invasive bladder cancer. A few studies have focused on pathways implicated in MIBC, including growth factors, DNA–RNA modifying enzymes and the differential roles played by the NOTCH receptors. NOTCH1 has been revealed as a tumour suppressor; in contrast, NOTCH2 and NOTCH3 have demonstrated an oncogenic role in BCa. Recent reports have found that NOTCH2 and NOTCH3 are associated with poor prognosis. Moreover, inhibiting these NOTCH receptors effectively restrained BCa growth and metastasis, suggesting the potential value of targeting NOTCH as a promising therapeutic strategy for bladder cancer. Given the crucial role of the NOTCH pathway, we will discuss the different predictive value of the four NOTCH receptors and the potential of NOTCH-combined therapy in BCa. Full article

In light of the growing significance of molecular biomarkers in central nervous system tumours, in this study, we aimed to comprehensively and quantitatively analyze the mRNA expression levels of DJ-1 (Parkinsonism-associated deglycase 7, PARK7), GDF15 (Growth Differentiation Factor 15), and MFGE8 (Milk Fat Globule-EGF Factor 8 Protein) in glioma and meningioma tissues and to thoroughly evaluate the associations between these gene expression profiles and clinicopathological parameters. Real-time PCR (qRT-PCR) analyses performed on tumour tissues obtained from a total of 27 glioma and 18 meningioma patients revealed that these three genes exhibited significantly elevated expression compared to control samples. Despite their different cellular origins, statistically significant positive correlations were observed between the expression levels of DJ-1, GDF15, and MFGE8 and both tumour grade and the Ki-67 proliferation index (Ki-67 Pi) in both glioma and meningioma cases, indicating that higher gene expression is associated with increased tumour aggressiveness in both tumour types. Receiver operating characteristic (ROC) curve analyses further confirmed the diagnostic and prognostic potential of these genes. Additionally, protein–protein interaction networks involving the target genes were characterised, providing valuable insights into their molecular mechanisms. These findings suggest that DJ-1, GDF15, and MFGE8 may play a role in the aggressiveness, invasion, and proliferation of gliomas and meningiomas. Moreover, integrating these genes as molecular biomarkers into tumour classification systems may provide a foundation for the development of personalised and targeted therapeutic strategies, although further studies are needed to support this. Full article

Objectives: Cancer is a multifactorial disease determined by several factors. Metabolic disorders such as obesity and diabetes significantly contribute to cancer risk by promoting chronic inflammation, insulin resistance, and hormonal dysregulation. Obesity and hyperglycaemia elevate insulin-like growth factor-1 (IGF-1) levels, driving oncogenic pathways such as PI3K/Akt/mTOR, which promote tumour proliferation and survival. Furthermore, cancer cells undergo metabolic reprogramming, characterised by increased reliance on glycolysis (Warburg effect), facilitating tumour growth and therapy resistance. Hence, body weight reduction and glycaemic control may represent potential strategies for cancer prevention and treatment. Irisin, a myokine secreted by skeletal muscle, plays a critical role in cellular metabolism and energy homeostasis. Emerging evidence suggests that irisin may exert tumour-suppressive effects by modulating key metabolic and oncogenic pathways. Methods: A systematic literature search identified studies investigating irisin’s effects in various cancer models. Results: In vitro, irisin exerts dose- and time-dependent anti-proliferative effects in a variety of cancer cell lines, primarily via PI3K/Akt/mTOR inhibition and AMPK activation, leading to cell cycle arrest and apoptosis. Additionally, irisin inhibits epithelial–mesenchymal transition, which suppresses cancer cell migration and invasion. However, conflicting findings, particularly in hepatocellular carcinoma, suggest tissue-specific responses. Similarly, clinical data regarding systemic and tumoural irisin levels remain inconsistent and appear to vary based on cancer type and stage. Conclusions: Irisin represents a promising therapeutic target due to its ability to modulate metabolic and oncogenic pathways. However, further research is needed to elucidate its clinical relevance and optimise its application as an adjunct to existing cancer therapies. Full article

Background: Phosphaturic mesenchymal tumours secreting fibroblast growth factor 23 (hereinafter referred to as FGF23+ PMT) are rare neoplasms that can cause hypophosphataemic osteomalacia, owing to excessive FGF23 production. Mast cells (MCs) play a key role in tumour biology by modulating proliferative activity of atypical cells, resistance to innate and acquired immunity, angiogenesis, and metastatic behaviour. However, MCs associated with FGF23+ PMT have not previously been investigated. This study, to our knowledge, is the first to characterise features of the tumour microenvironment through spatial phenotyping of the immune and stromal landscape, together with histotopographic mapping of intercellular MC interactions with other subcellular populations in FGF23+ PMT. Methods: Histochemical staining (haematoxylin and eosin, toluidine blue, Giemsa solution, picro-Mallory protocol, silver impregnation), as well as monoplex and multiplex immunohistochemical staining with spatial phenotyping, were performed to detect atypical FGF23-secreting cells, immune cells (CD3, CD4, CD8, CD14, CD20, CD38, CD68, or CD163), stromal components (CD31, α-SMA, or vimentin), and specific MC proteases (tryptase, chymase, or carboxypeptidase A3). Bioinformatics analysis using artificial intelligence technologies was applied for spatial profiling of MC interactions with tumour, immunocompetent, and stromal cells in the tumour microenvironment. Results: Bioinformatic analysis of the entire tumour histological section, comprising over 70,000 cells stained using monoplex and multiplex immunohistochemical protocols, enabled identification of more than half of the cell population. The most abundant were CD14+ (30.7%), CD163+ (23.2%), and CD31+ (17.9%) cells. Tumour-associated MCs accounted for 0.7% of the total pool of immunopositive cells and included both mucosal and connective tissue subpopulations, predominantly of the tryptase + chymase-CPA3-specific protease phenotype. This pattern reflected combined multidirectional morphogenetic processes in the patient’s FGF23+ PMT. More than 50% of MCs were colocalized with neighbouring cells of the tumour microenvironment within 20 μm, most frequently with monocytes (CD14+CD68+), M2 macrophages (CD68+CD163+), and endothelial cells (CD31+). In contrast, colocalization with atypical FGF23-secreting cells was rare, indicating minimal direct effects on tumour cell activity. Interaction with T lymphocytes, including CD8+, was also infrequent, excluding their activation and the development of antitumour effects. Mapping of MC histotopography validated the hypothesis of their inductive role in monocyte differentiation into M2 macrophages and probable polarisation of macrophages from M1 into M2, thereby contributing to slow tumour growth. MCs were further involved in extracellular matrix remodelling and participated in the formation of pro-osteogenic niches within the FGF23+ PMT microenvironment, leading to pathological osteoid development. Conclusions: This study demonstrated active MC participation in the evolution of the FGF23+ PMT microenvironment. The findings may be applied in translational medicine to develop novel algorithms for personalised therapy in patients with FGF23-secreting tumours, offering an alternative when surgical removal of the tumour is not feasible. Full article

Background: The novel anti-HER2 antibody 104 (mAb104) targets a unique tumour-specific epitope, lacks normal tissue binding and can internalise into tumour cells, thus supporting its development into antibody drug conjugates (ADCs). Methods: We now describe the binding properties and preclinical activity of mAb104-ADCs developed through the conjugation of mAb104 via linkers to the anti-microtubule drug maytansoinoid ematansine (DM1-SMCC; DM1), topoisomerase I inhibitor, exatecan derivative (MC-GGFG-DX8951; DX8951) or microtubule disruptor monomethyl auristatin E (MC-vc-PAB-MMAE; MMAE). Results: Mab104-ADCs demonstrate dose-dependent cytotoxicity in vitro. The safety of single-dose mAb104-DX8951 was demonstrated in vivo at doses up to 10 mg/kg. MAb104-ADCs also demonstrated potent and prolonged anti-tumour activity in a range of tumour types with variable HER2 expression. Mab104-DX8951 showed significant responses in trastuzumab-resistant HER2-positive breast cancer, low HER2-expressing cancers, as well as HER2-overexpressing cancers. Conclusion: These findings indicate the potential for tumour-specific targeting of HER2-expressing tumours with mAb104-ADCs. Full article

Osteoarthritis (OA) is a multifactorial chronic musculoskeletal disorder characterised by cartilage degradation, synovial inflammation, and subchondral bone remodelling. Conventional diagnostic modalities, including radiographic imaging and symptom-based assessments, primarily detect disease in its later stages, limiting the potential for timely intervention. Inflammatory biomarkers, particularly Interleukin-6 (IL-6), Tumour Necrosis Factor-alpha (TNF-α), and Myeloperoxidase (MPO), have emerged as biologically relevant indicators of disease activity, with potential applications as companion diagnostics in precision medicine. This review examines the diagnostic and prognostic relevance of IL-6, TNF-α, and MPO in OA, focusing on their mechanistic roles in inflammation and joint degeneration, particularly through the activity of fibroblast-like synoviocytes (FLSs). The influence of sample type (serum, plasma, synovial fluid) and analytical performance, including enzyme-linked immunosorbent assay (ELISA), is discussed in the context of biomarker detectability. Advanced statistical and computational methodologies, including rank-based analysis of covariance (ANCOVA), discriminant function analysis (DFA), and Cox proportional hazards modelling, are explored for their capacity to validate biomarker associations, adjust for demographic variability, and stratify patient risk. Further, the utility of synthetic data generation, hierarchical clustering, and dimensionality reduction techniques (e.g., t-distributed stochastic neighbour embedding) in addressing inter-individual variability and enhancing model generalisability is also examined. Collectively, this synthesis supports the integration of biomarker profiling with advanced analytical modelling to improve early OA detection, enable patient-specific classification, and inform the development of targeted therapeutic strategies. Full article

Glioblastoma (GBM) is a highly aggressive brain tumour characterised by a poor prognosis and resistance to anti-angiogenic treatments. Vasculogenic mimicry (VM), in which tumour cells form vessel-like structures independent of endothelial cells, has emerged as a key mechanism hindering the efficacy of anti-angiogenic therapies. Recent research highlights the central role of RNA-binding proteins (RBPs) in regulating VM through diverse post-transcriptional mechanisms, including mRNA decay induction and translational repression. Several oncogenic RBPs, such as HuR and HNRNPs, promote VM and tumour aggressiveness, while others, including RBMS3, act as suppressors of VM. Despite the prominent oncogenic roles of multiple RBPs, RBP-targeting compounds aimed at suppressing VM in GBM have remained at an early stage due to a number of limitations. This review summarises the role of VM in the treatment resistance of GBM, RBP regulation of VM, and the current landscape and future direction of RBP-targeted therapies aimed at overcoming VM-mediated treatment resistance in GBM. Full article

Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1 presents with café-au-lait macules; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal abnormalities; learning disabilities; and optic pathway gliomas, while NF2 is characterised by bilateral vestibular schwannomas, multiple meningiomas, ependymomas, and peripheral nerve schwannomas. Although germline mutations in the NF1 and NF2 tumour suppressor genes are well established, they do not fully explain the broad clinical variability observed, even among individuals carrying identical mutations. As increasingly recognised in other genetic diseases, epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA (ncRNA) regulation, play a critical role in modulating gene expression and influencing disease severity. Despite important findings, the research remains fragmented, and a unified model is lacking. This review organises the current knowledge, emphasising how epigenetic alterations impact disease behaviour and outlining their potential as prognostic biomarkers and therapeutic targets. A deeper understanding of these mechanisms could lead to improved personalised management and the development of targeted epigenetic therapies for individuals with NF1 and NF2. Full article

Background/Objectives: Romania remains a tuberculosis (TB) hotspot in the European Union, yet host-derived factors of poor outcomes are poorly characterised. We quantified circulating pro-inflammatory cytokines and examined their interplay with behavioural risk factors, the nutritional status, and the clinical course in adults hospitalised with pulmonary TB. We analysed 80 adults with microbiologically confirmed pulmonary TB and 40 respiratory symptom controls; four TB patients (5%) died during hospitalisation, all within 10 days of admission. Methods: A retrospective analytical case–control study was conducted at the Constanța regional TB referral centre (October 2020—October 2023). Patients with smear- or culture-confirmed TB were frequency-matched by sex, 10-year age band, and BMI class to culture-negative respiratory controls at a 2:1 ratio. The patients’ serum interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-1β (IL-1β), and tumour-necrosis-factor-α (TNF-α) were quantified within 24 h of admission; the neutrophil/lymphocyte ratio (NLR) was extracted from full blood counts. Independent predictors of in-hospital mortality were identified by multivariable logistic regression; factors associated with the length of stay (LOS) were modelled with quasi-Poisson regression. Results: The median TNF-α (24.1 pg mL⁻¹ vs. 16.2 pg mL⁻¹; p = 0.009) and IL-1β (5.34 pg mL⁻¹ vs. 3.67 pg mL⁻¹; p = 0.008) were significantly higher in the TB cases than in controls. TNF-α was strongly correlated with IL-1β (ρ = 0.80; p < 0.001), while NLR showed weak concordance with multiplex cytokine patterns. Among the patients with TB, four early deaths (5%) exhibited a tripling of TNF-α (71.4 pg mL⁻¹) and a doubling of NLR (7.8) compared with the survivors. Each 10 pg mL⁻¹ rise in TNF-α independently increased the odds of in-hospital death by 1.8-fold (95% CI 1.1–3.0; p = 0.02). The LOS (median 29 days) was unrelated to the smoking, alcohol, or comorbidity load, but varied across BMI strata: underweight, 27 days; normal weight, 30 days; overweight, 23 days (Kruskal–Wallis p = 0.03). In a multivariable analysis, under-nutrition (BMI < 18.5 kg m⁻²) prolonged the LOS by 19% (IRR 1.19; 95% CI 1.05–1.34; p = 0.004) independently of the disease severity. Conclusions: A hyper-TNF-α/IL-1β systemic signature correlates with early mortality in Romanian pulmonary TB, while under-nutrition is the dominant modifiable determinant of prolonged hospitalisation. Admission algorithms that pair rapid TNF-α testing with systematic nutritional assessment could enable targeted host-directed therapy trials and optimise bed utilisation in high-burden settings. Full article

Mast cell tumours (MCT) are the most common cutaneous neoplasms in dogs, with variable behaviours and patient survival time. Both indolent and aggressive forms have been described, but much remains to be explored regarding prognosis and therapy. Evidence has highlighted the influence of microbiota on multiple health and disease processes, including certain types of cancer in humans. However, knowledge remains scarce regarding microbiota biology and its interactions in both humans and canine cancer patients. This study aimed to characterise the faecal microbiota of dogs with MCT and compare it with that of healthy individuals. Twenty-eight dogs diagnosed with MCT and twenty-eight healthy dogs were enrolled in the study. Faecal samples were collected and analysed by Illumina sequencing of 16S rRNA genes. Alpha diversity was significantly lower in dogs with cancer, and the species diversity InvSimpson Indexwas reduced (p = 0.019). Principal coordinate analysis showed significant differences in the bacterial profile of the two groups: there was a significant lower abundance of the genera Alloprevotella, Holdemanella, Erysipelotrichaceae_UCG-003, and Anaerobiospirillum and, conversely, a significant increase in the genera Escherichia-Shigella and Clostridium sensu stricto 1 in diseased dogs. At the phylum level, Bacteroidota was significantly reduced in diseased dogs (25% in controls vs. 19% in MCT dogs). In conclusion, sequencing analysis provided an overview of the bacterial profile and showed statistical differences in the microbial communities of dogs with MCT compared with healthy dogs, suggesting a link between the gut microbiota and MCT in this species. Full article

Background/Objectives: Paclitaxel (PTX) is widely used in the treatment of a variety of solid tumours due to its broad-spectrum anti-tumour activity, but its use in brain gliomas is limited by insufficient blood–brain tumour barrier (BBTB) penetration and systemic toxicity. The aim of this study was to develop a Solutol HS-15-based micellar nanoparticle (PSM) to enhance the brain glioma targeting of PTX and reduce toxicity. Methods: PSMs were prepared by solvent injection and characterised for particle size, encapsulation rate, haemolysis rate and in vitro release properties. A C6 in situ glioma mouse model was used to assess the brain targeting and anti-tumour effects of the PSM by in vivo imaging, tissue homogenate fluorescence analysis and bioluminescence monitoring. Meanwhile, its safety was evaluated by weight monitoring, serum biochemical indexes and histopathological analysis. Results: The particle size of PSMs was 13.45 ± 0.70 nm, with an encapsulation rate of 96.39%, and it demonstrated excellent cellular uptake. In tumour-bearing mice, PSMs significantly enhanced brain tumour targeting with a brain drug concentration 5.94 times higher than that of free PTX. Compared with Taxol, PSMs significantly inhibited tumour growth (terminal luminescence intensity <1 × 10⁶ p/s/cm²/Sr) and did not cause significant liver or kidney toxicity or body weight loss. Conclusions: PSMs achieve an efficient accumulation of brain gliomas through passive targeting and EPR effects while significantly reducing the systemic toxicity of PTX. Its simple preparation process and excellent therapeutic efficacy support its use as a potential clinically translational candidate for glioma treatment. Full article

Background: Boiling histotripsy (BH) uses high-amplitude, short-pulse focused ultrasound to disrupt tissue mechanically. Oncolytic virotherapy using reovirus has shown modest clinical benefit in pancreatic cancer patients. Here, reovirus and BH were used to treat pancreatic tumours, and their effects on the immune transcriptome of these tumours were characterised. Methods: Orthotopic syngeneic murine pancreatic KPC tumours grown in immune-competent subjects, were allocated to control, reovirus, BH and combined BH and reovirus treatment groups. Acoustic cavitation was monitored using a passive broadband cavitation sensor. Treatment effects were assessed histologically with hematoxylin and eosin staining. Single-cell multi-omics combining whole-transcriptome analysis with the expression of surface-expressed immune proteins was used to assess the effects of treatments on tumoural leukocytes. Results: Acoustic cavitation was detected in all subjects exposed to BH, causing cellular disruption in tumours 6 h after treatment. Distinct cell clusters were identified in the pancreatic tumours 24 h post-treatment. These included neutrophils and cytotoxic T cells overexpressing genes associated with an N2-like and an exhaustion phenotype, respectively. Reovirus decreased macrophages, and BH decreased regulatory T cells compared to controls. The combined treatments increased neutrophils and the ratio of various immune cells to Treg. All treatments overexpressed genes associated with an innate immune response, while ultrasound treatments downregulated genes associated with the transporter associated with antigen processing (TAP) complex. Conclusions: Our results show that the combined BH and reovirus treatments maximise the overexpression of genes associated with the innate immune response compared to that seen with each individual treatment, and illustrate the anti-immune phenotype of key immune cells in the pancreatic tumour microenvironment. Full article

Background/Objectives: The surgical management of trigeminal schwannomas (TSs) has evolved considerably, with increasing interest in minimally invasive approaches. We performed a meta-regression analysis to characterise temporal trends in surgical strategies for TS and to explore factors influencing outcomes. Methods: This systematic review and meta-regression followed the PRISMA 2020 guidelines. Comparative studies published in English reporting surgical treatment of TS were included. Outcomes assessed were the extent of resection (EOR), improvement or worsening of trigeminal symptoms, and postoperative complications. Meta-analyses of pooled frequencies were performed, and meta-regression analyses evaluated associations between surgical approach, tumour localization, year of publication, and outcomes. Surgical approaches were categorized as microsurgical antero-lateral (M-AL-Apr), retrosigmoid (RSA), endoscopic endonasal (EEA), and endoscopic transorbital (ETOA). Tumour localization was stratified using the Samii classification. Results: Fifteen studies (583 surgeries) were included. Endoscopic approaches accounted for 20.1% of cases, with increasing use over time (β = 0.12—p < 0.001), largely driven by transorbital access for Samii type A and C tumours. The use of M-AL-Apr declined. The pooled gross-total resection (GTR) rate was 73% (I² = 78.8%). The stratified meta-regression identified a temporal decrease in GTR for Samii type C tumours alone, while resection rates for types A, B, and D remained stable, likely reflecting the increasing proportion of anatomically complex cases in recent series Trigeminal impairment improved postoperatively in 17% (I² = 84.5%), while worsening of trigeminal symptoms was rare (β = 0.07%—I² = 0%). Complication rates were 11.6% (I² = 32.7%) but with a temporal increase (β = 0.041, p = 0.047). Tumour type was the dominant predictor of EOR, functional outcomes, and complications. Conclusions: Surgical management of TS has evolved towards minimally invasive techniques, particularly endoscopic routes, reflecting advances in technology and a focus on functional preservation. Tumour anatomy remains the key determinant of surgical outcomes, highlighting the importance of tailored, anatomy-driven surgical planning. Full article