Edinburgh Cancer Research

Our Scientific Editor reports on the highlights of the Brain Conference 2025, and announces the winner of our Early Career Researcher Award for a paper published in the journal in 2024.

In vitro culturing of effective human-induced pluripotent stem cell-derived skeletal muscle cells (hiPSC-SMCs) has proven to be challenging. Progress is hindered by the limited range of metrics applied to assess experimental success. We present a semi-automated workflow for segmenting, tracking and quantifying migration and fusion behaviour in live and static images of myoblast and myotube cells. Workflow outputs are validated against manually labelled images and the metrics applied to images from case studies of in vitro cultures of primary mouse muscle cells under varying culture media conditions, mouse primary cells undergoing optogenetic stimulation and hiPSC-SMC. We show culture media-dependent differences in cell fusion dynamics and increased acetylcholine receptors in myonuclei under optogenetic stimulation. We show that myoblasts have greater persistence and proliferation in primary mouse cells than hiPSC, and cell–cell fusion occurred earlier but at a steadier rate in primary mouse cells.

The below‐ground growing season often extends beyond the above‐ground growing season in tundra ecosystems and as the climate warms, shifts in growing seasons are expected. However, we do not yet know to what extent, when and where asynchrony in above‐ and below‐ground phenology occurs and whether variation is driven by local vegetation communities or spatial variation in microclimate. Here, we combined above‐ and below‐ground plant phenology metrics to compare the relative timings and magnitudes of leaf and fine‐root growth and senescence across microclimates and plant communities at five sites across the Arctic and alpine tundra biome. We observed asynchronous growth between above‐ and below‐ground plant tissue, with the below‐ground season extending up to 74% (~56 days) beyond the onset of above‐ground leaf senescence. Plant community type, rather than microclimate, was a key factor controlling the timing, productivity, and growth rates of fine roots, with graminoid roots exhibiting a distinct ‘pulse’ of growth later into the growing season than shrub roots. Our findings indicate the potential of vegetation change to influence below‐ground carbon storage as the climate warms and roots remain active in unfrozen soils for longer. Taken together, our findings of increased root growth in soils that remain thawed later into the growing season, in combination with ongoing tundra vegetation change including increased shrub and graminoid abundance, indicate increased below‐ground productivity and altered carbon cycling in the tundra biome.

Introduction The role of female sex hormones and their influence on asthma’s development and natural history remain uncertain. Our study aims to enhance understanding of exogenous sex hormones’ role in asthma development and manifestation, considering phenotypic heterogeneity and focusing on metabolic syndrome-linked asthma that has shown increased severity in females. Methods and analysis A cohort study using primary care data from the Clinical Practice Research Datalink (CPRD) databases linked with additional data sources (Hospital Episode Statistics, ethnicity and deprivation) will include individuals aged 16–70 years, spanning 1 January 2005 to 31 December 2019. We will use appropriate statistical learning methods depending on the outcome: extended Cox regression for late-onset asthma; Poisson or negative binomial regression for asthma exacerbations; binary logistic regression for asthma control; and ordered logistic regression for asthma severity. Asthma exacerbation will be defined based on the American Thoracic Society/European Respiratory Society Task Force definition as the presence of either one of an asthma-related accident and emergency department visit, an asthma-related (unscheduled) hospital admission or an acute course of oral corticosteroids (OCS) with evidence of asthma-related medical event and/or review within 2 weeks of OCS prescription. Poor asthma control in any given month will be defined by the occurrence of an exacerbation episode or use of short-acting beta agonist. Asthma severity will be defined based on the British Thoracic Society asthma severity steps. Asthma phenotypes will be identified using k-means clustering. Analyses will be undertaken using both GOLD and Aurum to ensure coverage across UK nations. Ethics and dissemination CPRD has received ethics approval from the Health Research Authority (East Midlands—Derby, REC reference number 21/EM/065) to support research using anonymised data. Approval to conduct this study was obtained through CPRD’s Research Data Governance process. The results will be disseminated through academic publications and conference presentations, contributing to the understanding and practice of asthma management, particularly in the context of the impacts of exogenous sex steroid hormones.

Background and Aim Children and young people (CYP) with severe, sub‐optimally controlled asthma and co‐existing allergic senitization to indoor aeroallergens, such as pet dander and house dust mite (HDM), would likely benefit from reduced allergen exposure. Multiple allergen remediation interventions exist and are often suggested to families in secondary care asthma clinics in the United Kingdom. Evidence suggests remediation uptake is low or partial but there is sparse evidence to explain why. This study aims to explain how families in this situation make decisions about home‐based allergen remediations. Methods In‐depth qualitative interviews with CYP and mothers were analyzed, and a grounded theory approach was used to develop a theory to explain decision‐making processes and behaviors. Results Ten CYP aged 11−15 years and 11 mothers were interviewed. The core finding was that families iteratively respond to changes in how certain they are in their asthma management decisions and actions. For allergen remediation uptake, this certainty varied depending on seeing an outcome‐exposure relationship, understanding asthma severity, variability, and asthma control at the time of remediation decision‐making. Understanding the mechanistic role of allergen exposures in asthma was challenging for families, and ongoing bi‐directional communication with clinicians was essential in supporting long‐term decision‐making. Conclusion The theory explains the often elongated, reactive process of allergen remediation decision making and implementation. It also explains other elements of family management of asthma, and their interconnections. Families' iterative responsiveness suggests opportunities to intervene and promote earlier, preventative behavior change.

We address the question of when it is permissible to interfere in the “transformative choices” of others—choices whether or not to undergo experiences that provide us with knowledge we can only get by undergoing them, and which as a result transform our core values and preferences. In doing so, we criticise Farbod Akhlaghi’s recent (2023) claim to have discovered a new moral right, such that interference in the transformative choices of others is permissible when and only when the chooser’s “right to revelatory autonomy” (RRA) is outweighed. In building our case for a more plausible answer to the question, we challenge all aspects of Akhlaghi’s account. We first argue that it fares no better epistemically than other accounts he rejects, and that it fails to provide a more plausible explanation of permissible interference. We then examine RRA itself closely, showing that on its most plausible reading it is both over-inclusive (since it cannot hold in relation to a wide range of transformative choices) and under-inclusive (since it would hold for many choices unlikely to be transformative in the relevant sense). While Akhlaghi’s core insight—that our practices of interference (including by attempts to rationally persuade) in the transformative choices of others are much less likely to be justified than we standardly take them to be—is both true and important, the deontic innovation with which he tries to illuminate this point serves only to obscure it.

Background Guidelines and evidence identify that children and young people (CYP) who die from asthma frequently have a severe preceding attack. There is no agreed name or case definition for the most severe form of asthma attack. We aimed to resolve this using a structured literature, guideline and multimedia review to inform an international electronic Delphi (eDelphi) process. Methods A scoping literature, international guideline and anecdotal evidence (multimedia reporting) review provided items and potential names for round 1 of 3 for an eDelphi. Likert scoring of 1–5, with ≥70% combined score of 4 and 5 provided consensus. Free text enabled additional items and names to be offered. Participants were consultants providing acute asthma care in paediatric and adult respiratory, emergency or critical care medicine from 25 countries. In the final round, participants were provided with a stem definition with two further add-on options. Results Fifty-two studies were identified by scoping review (from 586 studies) with 27 international guidelines providing 41 items and 4 potential names to round 1. 104 participants completed all 3 rounds, offering an additional 10 items and 3 names for round 2. Near-fatal asthma (NFA) was the preferred name in round 3 (66.7%). The 22 items reaching round 2 consensus were placed within stem text where a definition was agreed (83/104, 79.8%). Conclusions This study provides a preferred name and consensus definition of NFA in CYP. This research can enable better characterisation and delivery of care to this vulnerable population.

Objective Taking a qualitative approach, we aimed to understand how London’s Ultra Low Emission Zone (ULEZ) might work to change behaviour and improve health in the context of the school journey. Design Primary qualitative study embedded within an existing natural experimental study. Setting A population-level health intervention implemented across London. Participants Purposive sampling was used to recruit children (aged 10–11 years) from ethnically and socioeconomically diverse backgrounds within an existing cohort study, Children’s Health in London and Luton. Methods In-person and online interviews were conducted with 21 families and seven teachers from the children’s schools between November 2022 and March 2023. Verbatim transcripts were analysed drawing on Braun and Clarke’s reflexive thematic analysis and guided by realist evaluation principles to identify contexts, mechanisms and outcomes using NVivo. Results Common context, mechanism, outcome (CMO) configurations were identified reflecting congruent narratives across children, parents and teachers, for example, current active travellers (context) reported reductions in pollution (mechanism) leading to improvements in health, including alleviated symptoms of asthma (outcome). These CMOs were broadly captured by two themes: (i) how you travelled before the ULEZ matters: the impact of travel mode on experiences of the ULEZ and (ii) your context matters: the role of socioeconomic position in experiences of the ULEZ. Participants highlighted the potential for the ULEZ to positively impact their choice of travel mode to school, experiences of the journey and their health. However, the impact of the ULEZ differed inequitably by journey length, travel mode before implementation and access to reliable and affordable public transport. Conclusions The capacity for the ULEZ to both narrow and exacerbate inequities across different travel contexts suggests when developing such schemes, more emphasis needs to be placed on providing accessible and affordable alternatives to driving.

Taking Global Constitutionalism as an agora, a platform for international interdisciplinary discussions this article asks a question about the state we are in with regard to the international order as an order that is not just a ‘rule-based order’ but also more substantially, a ‘legal order’ based on the rule of law. The topic is illustrated with reference to examples of ‘contested compliance’ i.e. objections to implementing international law and/or international rulings by international actors on behalf of signatories of states parties of a treaty. Three questions guide this discussion. The first is a question of normative change: are we facing a change regarding United Nations member states’ respect for and handling of the rule of law, or is a larger change of international law itself imminent? The second is a question about the effects of the shift from ‘normal’ contestations of norms to ‘deep’ contestations of the international order itself. And the third is a question about pluralism and diversity: are the UN Charter Order’s institutions, conventions and organisations sufficiently equipped to respond to an ever more diverse range of internationally, transnationally, and sub-nationally raised justice-claims? The article elaborates on each of the three themes in light of the current situation of contested compliance with obligations under international law.

Therapeutic cancer vaccines aim to generate a robust immune response against tumour-associated antigens (TAAs) or tumour-specific antigens. While their safety is well established, their efficacy as monotherapy remains limited due to factors such as self-tolerance to TAAs and the immunosuppressive tumour microenvironment. Combining cancer vaccines with systemic anticancer therapies (SACTs) offers a promising strategy to improve efficacy. However, the optimal timing and combination with immune checkpoint inhibitors (ICIs) and chemotherapy to enhance immunogenicity are not yet fully understood. This review aims to assess the evidence regarding the immunogenicity of antiviral and anticancer vaccines when combined with SACTs, including chemotherapy and ICIs, with a particular focus on the timing of vaccine administration relative to SACT. Additionally, we evaluate the impact of steroids on immunogenicity. Our findings suggest that the timing of vaccine administration is critical, with improved immunogenic responses observed when vaccines are administered at nadir (15 days post-chemotherapy). Certain chemotherapies, such as low-dose metronomic cyclophosphamide and paclitaxel, demonstrate potential for immunomodulation, enhancing T-cell responses when combined with vaccines. Conversely, steroids may reduce immunogenicity. The combination of ICIs with cancer vaccines shows evidence of a synergistic effect, with concurrent administration generally yielding better outcomes than sequential approaches. Prospective trials exploring various timings and sequences are essential to optimize the efficacy of anticancer vaccines.

Infection with Plasmodium falciparum carries a significant risk of cerebral malaria (CM). Children are particularly susceptible to human CM (HCM) which manifests as an acute neurovascular encephalopathy leading to high levels of mortality. Occurring in parallel with CM, malarial retinopathy (MR) is readily detected on ophthalmoscopy as one or more of: white-centered retinal hemorrhage, retinal whitening, and vessel discoloration. It leads to several distinct types of blood retinal barrier (BRB) breakdown. The precise molecular mechanisms underpinning CM and MR remain ill-defined, but parasitemia is known to drive progressive neurovascular obstruction and inflammation leading to cerebral and retinal edema and ischemia. Extensive clinical studies in patients with CM have shown that retinal examination is a useful approach for understanding pathology and an indicator for risk of mortality and morbidity. Fully understanding the cellular and molecular mechanisms that underpin CM and MR is important for developing new therapeutic approaches and in this regard the murine model of experimental CM (ECM) has proved to offer considerable value. Much is known about brain pathology in this model although much less is understood about the retina. In this review, we seek to evaluate MR in clinical scenarios and make comparisons with the retina from mice with ECM. Through detailed in vivo and post-mortem studies in the mouse and human retina, this review highlights the links between CM and MR and how this will aid our understanding of the disease progression and pathogenesis.

Background/objectives: Cognitive decline and loss of physical function are common concerns in older adults, with limited effective interventions available. This study aimed to assess the impact of pomegranate extract (PE) supplementation on cognitive and physical function in older adults aged 55–70 years. Methods: A randomised, double-blind placebo-controlled trial was conducted with 86 participants, who were assigned to receive either PE (740 mg) or a placebo (maltodextrin) daily for 12 weeks. Cognitive function was assessed using computerised tests (Corsi, digit span, Wisconsin Card Sorting Test (WCST), Tower of Hanoi, Stroop test and Rey auditory verbal learning test). Physical function was measured through assessments of standing balance, gait speed, chair sit to stand and grip strength. Results: There was a significant effect of treatment and time on WCST performance (F (1,2) = 2.718, p = 0.05), while trends towards better outcomes in the PE group were noted for digit span, Tower of Hanoi and Stroop tests. Physical function did not seem to be affected by the intervention, but results may have been limited by the high baseline physical activity levels and full mobility of the older adults. Conclusions: This was the first study to examine the effect of PE on cognitive and physical function over a duration of 12 weeks. Findings suggest that PE supplementation has potential in improving cognitive function and may offer a promising approach to preventing cognitive decline in ageing adults. Further controlled and well-designed long-term studies are needed to establish the long-term effects of PE on cognitive and physical health, along with the mechanisms of action involved.

Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC) is validated to predict event-free survival (EFS) in breast cancer but has not been studied for invasive lobular carcinoma (ILC). We studied patient-level data from a pooled cohort across 12 institutions. Associations between RCB index, class, and EFS were assessed in ILC and non-ILC with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by RCB components. Of 5106 patients, the diagnosis was ILC in 216 and non-ILC in 4890. Increased RCB index was associated with worse EFS in both ILC and non-ILC ( p = 0.002 and p < 0.001, respectively) and remained prognostic when stratified by receptor subtype and adjusted for age, grade, T category, and nodal status. Recursive partitioning demonstrated residual invasive cancer cellularity as most prognostic in ILC. These results underscore the utility of RCB for evaluating NAC response in those with ILC.

The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendrocytes, is largely unknown. FXS individuals are characterized by white matter changes, which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell-derived oligodendrocytes and an Fmr1 knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro, which persist in the presence of FMRP-expressing axons in chimeric engraftment models. Our findings point to species-conserved, cell-autonomous defects during oligodendrocyte maturation in FXS.

There has been an increase in the availability and utilization of commercially available 3D printers in radiotherapy, with applications in phantoms, brachytherapy applicators, bolus, compensators, and immobilization devices. Additive manufacturing in the form of 3D printing has the advantage of rapid production of personalized patient specific prints or customized phantoms within a short timeframe. One of the barriers to uptake has been the lack of guidance. The aim of this topical review is to present the radiotherapy applications and provide guidance on important areas for establishing a 3D printing service in a radiotherapy department including procurement, commissioning, material selection, establishment of relevant quality assurance, multidisciplinary team creation and training.

We have developed a single-cell assay that combines Cell Painting—a morphological profiling assay—with trajectory inference analysis. We have applied this morphological trajectory inference to the bi-potent HepaRG liver progenitor cell line allowing us to track liver cell fate and map small-molecule-induced changes using a morphological atlas of liver cell differentiation. Our overarching goal is to demonstrate the potential of Cell Painting to study biological processes as continuous trajectories at the single-cell level, enhancing resolution and biological understanding. This work has identified small-molecule Src family kinase inhibitors that promote the differentiation of HepaRG cells toward a hepatocyte-like lineage as well as primary human hepatic progenitor cells toward a hepatocyte-like phenotype in vitro. These findings could significantly advance research on liver cell regeneration mechanisms and facilitate the development of cell-based and small-molecule therapies.

Ozone is a non-thermal food processing method used instead of heat treatment since it is economical and environmentally beneficial. Green technology is another name for it because it has the fewest adverse environmental effects. It is frequently used to increase the seed germination rate and degrade mycotoxin in grains by microbial cleansing. An outline of ozone's effectiveness for microbial cleaning, mycotoxin degradation, insect control, starch modification, functional quality alterations, and germination ability is addressed in this chapter.

Ozone, a potent oxidant, works well against various bacteria in fruits and vegetables. Applying Ozone has shown promising results in addressing issues faced by the food industry, such as mycotoxin and pesticide residues. Ozonation is safe for food applications since it breaks down naturally without leaving dangerous residues in the treatment media. Ozone can negatively affect items when employed incorrectly, including reductions in sensory quality. For Ozone's safe and efficient application, treatment parameters for each product type should be precisely specified.