Differences in online gambling expenditure between players from Germany, Spain, Netherlands, Great Britain, US and Canada: A largescale online player tracking study.

We estimate the reduction in tax revenues that would result from the electrification of road transport in Great Britain over the period 2025–2050 and a revenue-neutral distance-based charge to recoup these revenues. Our model uses the assumptions and data from the Common Analytical Scenarios produced by the Department for Transport, 2023a , Department for Transport, 2023b . We find that under fast decarbonisation scenarios the revenues from fuel duty, VAT on the pre-tax price of fuel and on fuel duty, practically disappear, and under slow decarbonisation scenarios, they decrease substantially by 2050. The decrease is between 40% and 50%. Our revenue-neutral distance-based charge is designed to vary with vehicle type and trip purpose (work/non-work), and ranges from 0.4–3.8 pence per km in 2025, to 2.2–34.6 pence per km in 2050, depending on the vehicle type/trip purpose combination, the scenario, and the elasticity assumed. Importantly, although it applies on top of the fuel duties and is payable by both electric vehicles and fossil fuel vehicles, electric vehicles continue to offer significant cost savings. • Revenues from fuel taxes will decrease substantially or practically disappear by 2050. • The revenue-neutral distance-based charge range is 0.4–3.8 p/km in 2025 and 2.2–34.6 p/km in 2050. • The government in Great Britain should introduce a distance-based charge. • The distance-based charge could be levied on all power trains and differentiated by vehicle type/trip purpose. • The distance-based charge could be applied on top of the fuel duties currently in place.

Gambling often co-occurs with tobacco smoking and alcohol use, which likely exacerbates the physical, psychological, and financial harm that each of them cause. Using 2023 Gambling Survey for Great Britain (GSGB; n=9742) data, we ran generalized linear models (adjusted for sex, age, income, housing tenure and ethnicity) to assess associations between i) risk or severity of gambling problems (Problem Gambling severity Index [PGSI], and reported overspend or ignoring spend limits), and ii) attempts to reduce gambling, with alcohol consumption (Alcohol Use Dependence Test for Consumption [AUDIT-C]) and current smoking. A multinomial model explored the association between the same gambling harm predictors and a composite measure of smoking and high-risk drinking. Compared with non-gamblers, AUDIT-C was significantly (all p<0.001) higher across all PGSI response categories in a dose dependent fashion (PGSI 0 β=0.30; PGSI 1-2 β=0.64; PGSI 3-7 β=0.75; PGSI≥8 β=1.40). The odds of current smoking also increased with higher PGSI scores but was only statistically significant for PGSI scores≥8 (ORadj=2.81, 95%CI 1.85, 4.28). Similar associations were apparent for overspending or ignoring limits. Those who attempted to reduce or stop gambling in the past year were more likely to smoke. Disordered gamblers (PGSI≥8) compared with those who do not gamble had greatly increased odds of both smoking and having an AUDIT-C ≥ 8 (high-risk drinking) vs. not smoking and having an AUDIT-C score<8 (ORadj=9.37; 95%CI=4.15-21.14; p<0.001). Increased risk or severity of gambling problems is associated with risky drinking and odds of smoking in a dose dependent fashion. These findings underscore the need for integrated policy and intervention approaches to address gambling-related and substance-related harms together.

Climate change impact on hydrological droughts: Differences between two ensembles of regional climate projections across Great Britain

• Developed a national-scale, event-based framework to stress-testing road network resilience to flooding. • Integrated process-based approach to capture congestion, rerouting and isolation effects. • Indirect disruption losses exceed direct asset costs significantly for most flood events. • Single carriageway A roads and suburban bridges are critical for network resilience. • Rapid clearance and early speed restriction removal substantially reduce indirect flood impacts. Road infrastructure is facing increasing flooding risks, causing asset damage and disrupting traffic flows. Effective risk management requires integrated assessments that capture network vulnerability, disruption and recovery. While localised studies have simulated traffic disruptions, national-scale assessments have largely focused on flood exposure rather than systemic disruption analysis. We developed a modelling framework combining process-based flow model of passenger travel-to-work flows and applied it to stress-test Great Britain’s road networks against 17 historical flood events from 1953 to 2024. Results reveal significant variations between direct and indirect damage losses, with single carriageway A roads and suburban bridges emerging as critical points. Notably, indirect losses due to disruption and rerouting can be significantly higher than direct damages depending on hazard event. Early clearance and speed restriction removal are key to mitigating the overall indirect impacts. The model is generalisable and can be applied to stress-test other road networks and flood scenarios worldwide.

Air conditioning and the future electricity system in Great Britain

Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progression. This study provides insights into COPD pathogenesis and provides a theoretical basis for potential therapeutic targets. Mice were exposed to cigarette smoke (CS) for 16 weeks to establish a COPD model. In vitro, alveolar macrophages (AMs) (MH-S) and alveolar epithelial cells (MLE-12) were treated with cigarette smoke extract (CSE). Subsequently, NETs were isolated from phorbol-12-myristate-13-acetate (PMA)-stimulated neutrophils. Lung histopathology, inflammatory markers, and pyroptosis-related proteins were analyzed. Co-immunoprecipitation analysis was used to verify the binding of GSDMD and ubiquitin molecules in cells. Interventions included DNase1 to degrade NET and GSDMD knockdown. In CS-exposed mice, NETs increased the levels of proinflammatory cells and mediators, and lung structure was further disrupted. Pyroptosis of AMs was increased, while phagocytosis of AMs was inhibited. However, treatment with DNAse1 partially reversed the results caused by CS exposure and NET induction. Consistently, NETs aggravated inflammatory response and pyroptosis in the CSE-induced MH-S cell model. Furthermore, NETs significantly caused an increase in ROS, which promoted the activation of GSDMD deubiquitination and subsequent pyroptosis pathway in AMs. DNase1 treatment or GSDMD silencing attenuated pyroptosis, reduced inflammatory mediators, and improved lung function. NETs aggravated CS-induced lung inflammation and injury by activating GSDMD to promote pyroptosis in AMs. Targeting GSDMD or NETs represents a novel therapeutic strategy for COPD. © 2026 The Pathological Society of Great Britain and Ireland.

Malignant germ cell tumors (GCTs) are relatively rare tumors with limited therapeutic options. This study examined the homologous recombination deficiency (HRD) status and genomic characteristics in 14 patients with GCT who underwent next-generation sequencing. HRD was evaluated using the genomic instability score (GIS), which incorporates three components: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LST). Our findings showed that 57.1% (8/14) of participants were HRD positive. Female patients presented a significantly higher prevalence of HRD positivity (87.5%, 7/8) compared with male patients (16.7%, 1/6). HRD positivity in female cases had a mean GIS of 56 (range 48-76), including one patient harboring a germline BRCA2 p.S2670L (c.8009C>T) likely pathogenic mutation. LST demonstrated the strongest correlation with the integrated GIS (R2 = 0.945), followed by LOH (R2 = 0.872). Distinct mutation patterns were observed based on gender. GCTs in male cases predominantly exhibited mutations in TP53 (50% in yolk sac tumors; 50% in teratomas). GCTs in male cases also demonstrated TP53 mutations in one mediastinal yolk sac tumor and one mediastinal teratoma. Male cases showed recurrent alterations in KRAS, PRKDC, and CDKN1B, alongside frequent chromosome 12p amplifications in two cases. One particularly complex mediastinal teratoma in a male patient, featuring rhabdomyosarcomatous transformation, displayed bidirectional intergenic (TWSG1, MANEA-DT)-ROS1fusions, a HRAS-intergenic (RNH1) fusion, and MET focal amplification. These findings suggest a promising therapeutic opportunity with poly (ADP-ribose) polymerase (PARP) inhibitors for female patients with HRD-positive GCTs. Additionally, the complex composition of gene variants found in male patients with GCTs, including ROS1 fusions and MET focal amplification, points toward potential targeted therapeutic strategies. This study underscores the presence of sex-specific therapeutic vulnerabilities in GCTs, which warrant further exploration in larger cohorts. © 2026 The Pathological Society of Great Britain and Ireland.

Risk stratification across the three main clinical subsets of malignant peripheral nerve sheath tumor (MPNST), neurofibromatosis type I (NF1-related), sporadic, and prior radiation therapy (RT), is based mainly on clinicopathologic parameters, such as size, grade, stage, and NF1 status. Moreover, no prior study investigated the additional impact of genomic alterations in the prognosis of high-grade MPNST using clinically validated DNA targeted next-generation sequencing (NGS) panels. Our goal was to integrate clinicopathologic and genomic parameters using an elastic-net penalized Cox proportional hazards machine learning model using OncoCast for risk prediction. Herein we perform comprehensive mutational and copy number profiling using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) on 81 primary localized high-grade MPNSTs (51% NF1-related, 38% sporadic, 11% RT-associated). The most common genomic alterations included NF1 (51% germline, 59% somatic), CDKN2A/B (62%), PRC2 components (SUZ12, EED) (53%), and TP53 (25%). Variables selected by OncoCast as significantly associated with survival were used to construct a three-tier risk stratification model for progression-free survival (PFS) and disease-specific survival (DSS). For PFS, patients with chr16 deletion were classified as high-risk, those with concurrent germline and somatic NF1 alterations as low-risk, and the remainder was assigned to the intermediate-risk group. For DSS, cases with fraction genome altered (FGA) > 50% were defined as high-risk, those with PRC2 abnormalities, CDKN2A deletion, TERT promoter mutation, or chr16 deletion as intermediate-risk, and cases lacking all the aforementioned alterations as low-risk. The high-risk group showed significantly inferior survival compared to the low-risk group (both PFS and DSS p < 0.001). Subgroup analysis showed that among NF1-related MPNST, co-occurring somatic NF1 mutation or WT TP53 was associated with superior PFS. Collectively, genomic alterations detected by clinical NGS panels provide potential new biomarkers for risk stratification that can be integrated with conventional parameters to provide improved prognostication and guide therapeutic strategies. © 2026 The Pathological Society of Great Britain and Ireland.

Late-onset Fuchs endothelial corneal dystrophy (FECD) is the most common primary disease of the corneal endothelium and the leading indication for corneal transplantation in Western countries. It is characterized by progressive accumulation, over two to three decades, of extracellular matrix (ECM) components in Descemet's membrane (DM), leading to the formation of abnormal excrescences, known as guttae, and additional DM layers. Clinical forms and evolutionary profiles vary widely among patients. FECD is strongly associated with intronic CTG trinucleotide repeats (TNRs) in the transcription factor 4 (TCF4) gene. We analysed 500 DMs removed during keratoplasty for FECD across 25 European centres to identify different anatomopathological forms of the disease. Following flat mounting and dehydration, the samples were digitized using transmitted light microscopy and independently assessed by three independent readers. A total of ten parameters - six related to guttae and four on other forms of ECM - were scored. Principal component analysis and an unsupervised clustering method separated three clusters from these parameters. In addition, manual classification was performed by grouping samples with major common features. The number of TNRs in TCF4 was analysed by short tandem repeat (STR)- and triplet repeat primed-polymerase chain reaction (TP-PCR) for 109 patients. We found that (1) five FECD phenotypes exist; (2) guttae and other ECM structures were radially arranged in 95% of samples; (3) 33% of samples exhibited peripheral radial striae that corresponded to a hypertrophied form of similar structures present in healthy corneas; and (4) patients with fewer than 50 TNRs had only two out of five phenotypes and had a significantly higher number of peripheral radial striae (94% versus 49%, p < 0.001). Taken together, these new findings demonstrate the existence of different FECD phenotypes; reveal that lesions affect both the centre and the periphery of the endothelium; and suggest that radial deposits may be produced by pathological cells migrating from the periphery towards the centre. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The integration of artificial intelligence into pathology is transforming the assessment of histological and immunohistochemical (IHC) slides, offering opportunities to reduce variability and streamline diagnostics. In practical terms, most available tools and research models emulate the diagnostic capabilities of pathologists by detecting, grading, and classifying tumours and other diseases. More recent applications have moved beyond mimicry, aiming to predict established biomarkers, such as microsatellite instability or IHC-based markers, and to tackle even more ambitious tasks, such as directly predicting patient prognosis from H&E whole slide images. Remarkably, novel computational tools are now being designed as companion diagnostic assays, linking the automated evaluation of specific IHC biomarkers to the prediction of response to specific drugs, potentially marking a new chapter in the evolution of digital and computational pathology. The TROPION-PanTumor01 trial recently demonstrated the superiority of a supervised machine learning model (termed the quantitative continuous score [QCS] by the vendor) in assessing TROP2 IHC compared with human scoring, promising better stratification of patients with non-small cell lung cancer for treatment with datopotamab deruxtecan. The same approach has shown promise in refining HER2 (human epidermal growth factor receptor 2) and PD-L1 (programmed death-ligand 1) evaluations, revealing patient subgroups that may benefit from targeted therapies. Moreover, other similar approaches are progressively reaching the market, posing significant opportunities and challenges for clinicians involved in the care of patients with cancer. This Perspective is promoted by the European Society of Digital and Integrative Pathology (ESDIP, founded in 2016, and having long-standing experience in computational pathology, esdipath.org) and the European Interdisciplinary Society of Artificial Intelligence for Cancer Research (ESAC, a recently established initiative, founded in 2024, esac-network.eu), both bringing together clinicians, engineers and other professionals dedicated to the development and clinical translation of computational approaches aimed at improving patient care. It aims to provide an informed overview of novel computational pathology companion diagnostic tools, with a particular focus on the background that practicing pathologists and oncologists need to have with these tools, when transitioning from research to clinical practice, irrespective of their prior familiarity with computational approaches. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The conceptualization of mitochondria, previously restricted to their function as cellular 'powerhouses', has evolved to recognize their function as central coordinating hubs for the orchestration of cancer cell metabolism, signaling, and fate determination. Within the context of lung cancer, encompassing both non-small cell lung cancer and small cell lung cancer, these organelles undergo profound functional and structural dysregulation integral to tumor initiation, progression, and most critically, therapeutic resistance. This review presents a synthesis of the burgeoning field of mitochondrial inhibitors as a strategic approach for lung cancer treatment, achieved by synthesizing detailed mechanistic and preclinical data into an evidence-graded framework. This document first provides a delineation of the fundamental dysregulation of mitochondrial functions in lung cancer, inclusive of metabolic reprogramming toward oxidative phosphorylation dependency, particularly in distinct genetic contexts (e.g., LKB1, SWI/SNF-mutant). Subsequent sections systematically categorize and analyze the major classes of mitochondrial inhibitors predicated upon their mechanisms of action, including electron transport chain inhibitors, pro-apoptotic agents (e.g., B-cell lymphoma 2/B-cell lymphoma xL inhibitors), and modulators of metabolism and dynamics. A critical focus is applied to the role of these agents in the supersession of acquired resistance to established therapies, such as epidermal growth factor receptor-tyrosine kinase inhibitors, chemotherapy, and immunotherapy. The translational landscape is consolidated herein by summarizing key clinical trials (including terminations precipitated by toxicity) and distinguishing small cell lung cancer specific vulnerabilities. Finally, the significant challenges of on-target, off-tumor toxicity and the crucial necessity for predictive biomarkers are addressed. Through the synthesis of these disparate fields into a unified, clinically oriented framework, it is posited that targeting mitochondrial vulnerabilities possesses the potential to overcome longstanding therapeutic hurdles in lung cancer. © 2026 The Pathological Society of Great Britain and Ireland.

The naked mole-rat (NMR; Heterocephalus glaber) is a subterranean rodent native to the arid regions of the Horn of Africa. The NMR is the longest-lived rodent and is known for its distinctive physiological and social traits. This species has become a notable model organism for studying aging, cancer biology, behavioral ecology, and reproduction. Recently, NMRs have gained attention because their gastrointestinal tract features an exceptionally strong intestinal barrier, a large number of goblet cells, a thicker mucin layer, and reduced gut permeability. The NMR gut microbiome, similar to that observed in human centenarians, is highly diverse and characterized by a high microbial load. In fact, Hart et al (2026) demonstrated that spontaneous infection with Citrobacter braakii in the NMR causes clinical symptoms and histopathological changes that are very similar to those observed in human colitis. If left untreated, the disease can progress and become fatal. However, probiotic treatment can reverse the clinical and histopathological phenotypes. These findings indicate that, in addition to serving as a powerful model for aging, cancer, and reproduction, the NMR may also serve as a powerful tool for studying human diseases such as gut dysbiosis, gut barrier dysfunction, and colitis. © 2026 The Pathological Society of Great Britain and Ireland.

Lung cancer is the leading cause of global cancer-related morbidity and mortality, with tobacco smoking as its strongest risk factor. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-regulated transcription factor frequently dysregulated in non-small cell lung cancer (NSCLC), leading to aggressive disease and resistance to therapy. In this study, we analyzed circulating cell-free tumor DNA from a real-world cohort to characterize clinicopathological features and identify risk factors associated with oncogenic NRF2 activation in inoperable NSCLC. Key findings were further validated using retrospective datasets. Our results demonstrate that NRF2 pathway-mutated NSCLC represents a smoking-associated, high-risk molecular subtype frequently accompanied by detrimental SMARCA4 mutations. Importantly, these co-occurring mutations cumulatively worsen clinical outcomes independently of other risk factors. We show that NRF2-mutated tumors generally exhibit lower leukocyte infiltration, while high tumor mutation burden independently correlates with increased cytotoxic T lymphocyte density, regardless of NRF2 status. Furthermore, our data indicate that NRF2 activation can be reliably identified through immunohistochemical detection of protein expression of markers AKR1B10 and AKR1C1, both of which correlate with inferior outcomes. As mutations in NRF2-regulating tumor suppressors KEAP1 and CUL3 are not confined to specific hotspot regions, our findings advocate for a multimodal profiling approach combining somatic mutation assessment with protein or transcriptomic evaluation of NRF2 targets. This comprehensive strategy effectively identifies oncogenic NRF2 hyperactivity, enhancing diagnostic accuracy and clinical decision-making in NSCLC management. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initiating AD-like skin symptoms and disease-specific molecular alterations, we generated Tg mice overexpressing a mutant form of acid ceramidase (aCDase) under the control of the involucrin promoter, resulting in targeted expression in the upper epidermis. By 3 weeks of age, Tg mice developed noninflammatory, scaly skin characterized by severely compromised barrier integrity and water-holding capacity, along with significantly elevated epidermal aCDase activity and markedly reduced ceramide levels in the SC. Compared to WT controls, Tg mice also exhibited increased epidermal innervation and reduced intraepidermal semaphorin 3a protein levels. Additionally, Tg skin showed substantial changes in the expression of AD-associated biomarkers involved in barrier impairment, pruritus, and Th2 polarization. These included increased levels of Il10, Il17a, S100a7, S100a8, and S100a9 and decreased levels of Cxcl10, Ifng, Il2, Il13, Il33, Sema3a, and Tlr9. Repeated topical application of mite antigens induced allergic responses in Tg mice, but not in WT mice. These responses were characterized by prominent eosinophil infiltration in the dermis and significantly elevated serum IgE levels. Allergen-challenged ear skin from Tg mice also demonstrated significantly increased expression of inflammatory mediators related to AD, including Ccl17, Ccl22, Ccl26, Ccl27, Il3, Il13, Il22, and Il33. These findings establish Tg mice as a pathophysiologically relevant model of AD, presenting key features such as xerotic, pruritic skin, impaired barrier and water-retention functions, and Th2-dominant allergic inflammation. This model provides important insights into ceramide-dependent mechanisms in AD pathogenesis and offers a useful platform for therapeutic development. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Emergency general surgery (EGS) is an essential part of general surgery. However, the service configuration for EGS in the United Kingdom (UK) and Ireland varies significantly. This study aims to clarify current and desired future roles of EGS surgeons in the UK and Ireland, particularly regarding operative procedures. An e-survey, designed by the Association of Surgeons of Great Britain and Ireland (ASGBI) Moynihan Academy, was distributed to ASGBI members at two national conferences in 2023. Data collection included the operative roles of EGS surgeons and factors influencing the appeal of a dedicated EGS career. The study was conducted and reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). There were 132 of 347 (response rate 38.0%) complete responses analysed. Respondents identified a core set of procedures that could be safely performed by EGS surgeons, regardless of dedicated EGS service configuration. A minority of respondents stated that EGS surgeons - rather than a surgeon with a specialist interest - should operate on specific conditions: emergency colonic resection for cancer (65 of 132 [49.2%]) or for inflammatory bowel disease (49 of 132 [37.1%]), laparoscopic cholecystectomy plus intraoperative cholangiogram with or without common bile duct exploration (45 of 132 [34.1%]), operations for gastric volvulus (45 of 132 [34.1%), operations for Boerhaave's (37 of 132 [28.0%]) and operations for bariatric complications (34 of 132 [25.8%]). Factors that might improve future EGS careers included pragmatic job planning, minimally invasive elective surgical opportunities and dedicated continuing professional development. This study outlines the operative role of EGS surgeons within the broader general surgical profession and highlights controversies regarding whether EGS surgeons should perform specific complex operations.

Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) and the cannabinoid receptors CB1 and CB2 during AP. A severity-dependent decrease in circulating 2-AG was found both in patients and a murine AP model. Restoring 2-AG - by avoiding its degradation via monoacylglycerol lipase inhibitor or direct 2-AG administration - reduced local and systemic inflammation, modulated peritoneal macrophage polarization, and mitigated lung injury. Notably, endocannabinoid system effects were consistent across sexes. Both cannabinoid receptors were involved in disease pathophysiology. Genetic Cnr1 knockout and pharmacological CB2 blockade showed distinct and complementary roles of both receptors in regulating inflammation, immune infiltration, and pulmonary damage. These findings highlight a protective role for 2-AG and highlight the endocannabinoid system - and cannabinoid receptors in particular - as a promising therapeutic target to modulate inflammation and reduce systemic complications in acute pancreatitis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The extracellular matrix (ECM) plays a pivotal role in facilitating tumour development, invasiveness, metastasis, and immunoevasive processes through dynamic ECM remodelling processes. Testican-1 (SPOCK1), an excretory matricellular proteoglycan, is suggested to exert a role in the facilitation of ECM remodelling processes through interacting with matrix metalloproteases (MMPs) and even its less known forms. The structural mechanisms of interactions between testican-1 and MMPs were studied, and their roles in tumour-promotion pathway processes were also examined using a computational approach and immunofluorescence validated by colocalisation technique analysis. A computational analysis using docking, molecular dynamics (MD), and systems biology analysis was employed. HDock and GROMACS were chosen to analyse binding affinity and testican-1 stability with 28 different MMPs. H-bond, free energy, and root mean square fluctuation (RMSF) analyses were performed to confirm the interactions in the testican-1-MMP complexes. The systems biology toolkit implemented in this study consisted of STRING, BioGRID, and Cytoscape, which were employed for testican-1 interaction network and pathway analysis. Kaplan-Meier survival analysis using the GEPIA2 tool was utilised to correlate SPOCK1 gene expression and clinical survival measures for various malignancies. The docking analysis showed robust interactions between testican-1 and MMP23, MMP25, and MMP28. Additionally, testican-1-MMP complexes were confirmed to form stable interfaces based on comprehensive MD analysis, suggesting solid binding interfaces with the MMP-unique domain of testican-1. Our systems biology experiment indicated testican-1 as a central hub for interactions between immunoevasive and ECM remodelling processes. SPOCK expression was also shown to correlate with significant survival measures for different malignancies, revealing clinical implications in cancer. The testican-1-MMP computational analysis suggests testican-1 plays a pivotal role as a therapeutic target for a wide range of malignancies. SPOCK-MMP interactions could be targeted to interrupt tumour-promoting processes by arresting dynamic changes in the ECM, thereby improving patient survival. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are classified as having no specific molecular profile (NSMP). These patients have poor responses to chemotherapy, MEK inhibitors, and hormonal therapies, highlighting the need for alternative strategies. This study aimed to identify novel therapeutic targets in NSMP LGSOC. A high-throughput drug screen of 3,436 compounds (including FDA-approved, clinically tested, and investigational agents) was conducted across 12 LGSOC and one control ovarian epithelial cell line. EGFR inhibitors emerged as selective hits in NSMP cell lines and were further tested in two NSMP and two MAPK-mutant lines in combination with standard-of-care chemotherapy agents, carboplatin and paclitaxel. EGFR expression was assessed using RNA sequencing, DNA methylation profiling, and immunohistochemistry in primary tumors, followed by survival analysis based on expression levels. Unsupervised clustering of drug response data revealed subtype-specific vulnerabilities, with EGFR inhibitors showing marked cytotoxicity in all five NSMP lines (robust Z-score ≤ -2), and minimal activity in MAPK- and USP9X-mutant lines. EGFR inhibitors (avitinib, AV-412) showed selective, low-dose synergy with standard-of-care chemotherapy in NSMP models, with minimal and inconsistent effects in MAPK-mutant lines. NSMP tumors showed elevated EGFR mRNA and EGFR protein expression, associated with poor survival, advanced disease stage, and peritoneal involvement, and inversely correlated with MAPK mutations. These findings position EGFR overexpression as a defining and targetable feature of NSMP LGSOC and support further preclinical validation of EGFR inhibitors as a treatment strategy for this understudied cancer subtype. © 2026 The Pathological Society of Great Britain and Ireland.

In Great Britain, donkey work has shifted from beach donkey rides towards a greater diversity of economic activities, such as wellness industries, films and exhibits. This research investigates the distribution, health and welfare of donkeys in licensed activities in Great Britain. Local authority data were used to map the population of donkeys working under licence. Data on the welfare status of donkeys relinquished, retired or removed to The Donkey Sanctuary from licensed commercial businesses were analysed descriptively. Donkeys are engaged in a diverse range of licensed activities throughout Great Britain and are frequently one of the main draws of some commercial businesses. Most donkeys relinquished or removed from licensed premises were found to have health and welfare issues. The welfare data include only those donkeys relinquished or removed to The Donkey Sanctuary, which may not be representative of the population of donkeys in all commercial operations. The study finds that licensing does not necessarily protect donkeys from poor welfare outcomes, despite some licences requiring mandatory veterinary oversight. In addition, the licensing system and those finding themselves working within it, may need further resourcing to support those trying to license, regulate and enforce commercial activities.