Cancer Research UK Manchester Institute

Experimental evolution has been a useful tool for investigating long-term temporal evolutionary dynamics and molecular mechanisms underlying adaptation. However, extracting fundamental principles and predictive features of evolutionary outcomes from these datasets remains challenging. Here we sought to circumvent these challenges by comparing distant yeast species that share several evolutionary features but differ in evolutionary history and genome architecture, that is Saccharomyces cerevisiae and Schizosaccharomyces pombe. We evolved ten populations of the fission yeast for 10,000 generations in the same conditions as a pre-existing budding yeast dataset, allowing us to observe repeatable evolutionary outcomes within species but diverse molecular targets of adaptation across species. The most frequent route of adaptation was through changes in carbon flux metabolism, which was previously unseen in S. cerevisiae evolved populations, but similar evolutionary paths have been observed in wild populations. This suggests that parallelism is pervasive and that mechanisms of adaptation can be shared among closely related or distant species. Despite similar gene content and identical environments, recurrent adaptation across S. pombe populations involved different genes than in S. cerevisiae and was detectable mostly at the transcriptomic level. This indicates that trans-regulatory effects and contingency may contribute to differences in evolutionary outcomes between these species.

Radiation therapy (RT) is an essential treatment modality for paediatric head and neck (HN) cancer, but irradiation during craniofacial development can cause dentofacial side effects, including facial deformation (FD). This systematic review evaluates the evidence on FD post-RT, including assessment methods, prevalence, and dose-response. A literature search was conducted in PubMed and EMBASE. Studies were included if they reported FD>2 years post-RT on average across the whole cohort in children treated for HN cancer aged 0-18years. Studies were assessed using the Cochrane Childhood Cancer Risk of Bias tool. Of 2766 articles identified, 25 met the inclusion criteria, reporting on 1155 children treated between 1965 and 2022 (median cohort size: 24, range: 6 - 192) participants. Median age at treatment/diagnosis was 4.9years. FD assessment methods were analysed in two categories: objective measures and clinical reporting. Objective measures were further categorised: 1) cephalometric (2D image), 2) external surface (3D), 3) internal anatomy (3D). Clinical reporting included clinician-reported and patient-reported outcomes. Measurement and grading criteria varied considerably. Where it could be calculated, prevalence of FD was between 21% and 97%. In seven of the eight studies which examined dose-response, a range of doses between 24-40Gy was linked to risk of FD, as was age<5-7years at the time of treatment. However, heterogeneity in tumour sites and treatment regimens limited comparability. Additionally, limited data on FD location and severity constrained dose-response study. This review highlights the need for standardised assessment tools and grading criteria that captures both location and severity of FD. Such standardisation would improve clinical reporting and support robust dose-response analysis in future research.

Abstract Mitosis is triggered when the rising activity of CDK1-Cyclin B, amplified by the CDK1/Cdc25/Wee1 feedback loop, overcomes inhibitory signalling from Wee1 and counteracting phosphatases. CDK-opposing phosphatases PP1, PP2A-B55 and PP2A-B56 are regulators of mitosis. A screen for differentially phosphorylated sites in a ΔPP1 dis2 genetic background in Schizosaccharomyces pombe identified phosphorylation of T73 or T75 in the regulatory B56 Par1 subunit. The B56 Par1 .T73T75 phosphorylation is directly mediated by CDK1-Cyclin B, and a phospho-mimetic mutation increased PP2A-B56 Par1 phosphatase activity. Blocking B56 Par1 .T73T75 phosphorylation reduced cell length in unperturbed divisions from 14 to 12 µm, with no other detectable phenotypes. Therefore, blocking phosphorylation at T73T75 alone prematurely unlocked amplification of the CDK1/Cdc25/Wee1 feedback loop, advancing cells into mitosis. Signalling from T73T75 reveals for the first time that timely mitotic commitment in unperturbed cycles is mediated by PP2A-B56.

507 Background: Cholangiocarcinoma (CCA), categorized as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), is often diagnosed at an advanced or metastatic stage. Approximately, 10-15% of iCCA harbor mutations in isocitrate dehydrogenase 1 ( IDH1 ) gene. However, data on real-world clinical outcomes and treatment patterns remain scarce. This study aims to provide a better understanding of the management of patients (pts) with m IDH1 CCA. Methods: This retrospective study utilized Citizen Health data, a real-world dataset harmonized across 3000 healthcare institutions, to evaluate United States CCA pts’ basic characteristics, molecular testing data, and treatment patterns. Pts were followed from the date of initial pathologic diagnosis until death or censored at the last activity in the database. In addition to the descriptive analysis, time-to-event endpoints were estimated using Kaplan-Meier (KM). Results: 602 pts diagnosed with CCA from 2007 to 2025 were included; 59.8% were female, median (range) age was 59.5 (22.3-85.8) years; 157 pts (26.1%) had ECOG performance Status 0 and 236 pts (39.2%) of 1. Most pts had iCCA (61.0%) and advanced or metastatic disease (59.8%) at diagnosis. The majority of pts (n=499, 82.9%) underwent biomarker testing. For 395 pts (79.2%), the testing was tissue-based and, for 106 pts (21.2%), it was performed on liquid biopsy. The main method used was next-generation sequencing (NGS) for 275 pts (55.1%) and immunohistochemistry (IHC) for 194 pts (38.9%). Among pts evaluated for IDH1 alterations, 88 pts (18.6%) had m IDH1 CCA with 60 pts (68.2%) diagnosed with advanced/metastatic disease. 80 pts (90.9%) received first-line (1L) systemic therapy for any stage, including gemcitabine-cisplatin (GemCis) (n=26, 32.5%) or GemCis-durvalumab (n=21, 26.3%) and GemCis-nab-paclitaxel (n=12, 15.0%). In the 1L, median (m) PFS was 8.0 months (mo), mOS was 30.0 mo, and disease control rate (DCR) was 84%. 63 pts (71.6%) received second-line (2L) therapy, including ivosidenib monotherapy (n=22; 34.9%) or in combination (n=7, 11.1%). In the 2L, in pts who received ivo-containing regimens (n=29), mPFS was 6.1 mo, mOS was 25.1 mo, and DCR was 69%; while in pts who received other regimens (n=34), mPFS was 4.1 mo, mOS was 20.1 mo, and DCR was 56%. Conclusions: Most pts with CCA were diagnosed with advanced or metastatic disease and the majority of pts had access to biomarker testing. Pts with m IDH1 CCA received mainly GemCis or GemCis-durvalumab as 1L therapy and ivosidenib as 2L therapy as recommended by current guidelines. mOS was longer than expected in each line of treatment, potentially due to survivorship bias, self-selection bias, and a limited number of pts harboring IDH1 mutations. This real-world study corroborates the efficacy finding from ClarIDHy and supports ivosidenib as a valuable 2L treatment option for patients with m IDH1 CCA.

Cardio-oncology remains a speciality dominated by cardiologists despite the importance of doctors from other specialties, such as oncology and haematology, for managing the cardiovascular health of patients living with cancer. A major reason for this is a distinct lack of cardio-oncology training opportunities for the noncardiology trainee. This is because of several factors, including a lack of awareness of cardio-oncology as a specialty. We propose a cardio-oncology training programme that involves early exposure to cardio-oncology as a specialty and provides the noncardiologist with a good understanding of cardiological investigations and treatment in the context of cancer treatment. Future work should elucidate additional barriers to cardio-oncology training as well as identifying programmes that have integrated cross-disciplinary cardio-oncology content to inform future curriculum development. Future work should also focus on establishing pilot cardio-oncology training programmes for the noncardiologist.

Endometrial cancer is the most common gynaecological cancer, with rising incidence contributing to a growing population at risk of long-term health issues post-treatment. Cardiovascular disease is the leading cause of mortality, yet physical activity engagement is low due to physiological and psychosocial barriers. Although guidelines recommend physical activity after cancer, no reviews have synthesised interventions supporting uptake in women treated for endometrial cancer. This review addresses the gap. A mixed-methods scoping review was conducted. Medline, EMBASE, Cochrane, Web of Science, PEDro, EThOS, and PsycInfo were systematically searched for studies published from January 2011 to October 2024. Eligible studies recruited adults post-treatment for endometrial cancer and reported interventions supporting physical activity. Twenty-two papers describing 12 interventions met inclusion criteria. Six (50%) focused on physical activity only, three (25%) combined diet and physical activity, and three (25%) were multicomponent interventions incorporating diet, physical activity, and additional elements such as mindfulness. Most studies were USA-based (77%). One powered RCT and nine pilot or feasibility trials were included. The RCT reported a significant increase in total physical activity minutes post-intervention. Most studies reported improvements in quality of life, physical function, and self-efficacy. Adherence ranged from 36% to 86%, facilitated by social interaction and hindered by pain, fatigue, and caregiving responsibilities. Early-stage evidence suggests physical activity interventions are feasible in this population. Even modest increases in physical activity may improve quality of life. Future research should integrate co-design, cultural adaptation, and tailoring interventions to baseline mental health, BMI, and activity levels.

Alpha-Synuclein (αSyn) plays a central role in Parkinson's disease (PD), and the p.A53T mutation causes an early-onset familial form of PD with severe manifestations. While its effects on neurons are well studied, its consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated patient-derived p.A53T-αSyn induced pluripotent stem cells (iPSC) to ventral midbrain astrocytes and characterized them via comprehensive molecular, functional, and proteomic analyses. Gene-corrected and healthy iPSC-derived astrocytes served as controls. To assess the effects of p.A53T-αSyn astrocytes on dopamine neurons, we established neuron-astrocyte cocultures of iPSC-derived control and mutant cells at all combinations. Our analyses uncovered cell-intrinsic pathologies in p.A53T-αSyn astrocytes, such as calcium dyshomeostasis, and accumulation of protein aggregates including those of phosphorylated αSyn. Proteomic and mechanistic studies demonstrated perturbed protein catabolic processes, with associated disturbances in lysosomal function and mTOR signaling. These deficits reduced the endocytic clearance capacity of p.A53T-αSyn astrocytes and their ability to process exogenous αSyn cargo. p.A53T-αSyn dopamine neurons cocultured with p.A53T-αSyn astrocytes displayed Lewy-like pathologies, mirroring the histopathological hallmarks identified in postmortem PD brains and exacerbated neurodegeneration, in anatomical and functional aspects. Control astrocytes mitigated these pathologies, highlighting their neuroprotective role. Additionally, p.A53T-αSyn astrocytes induced PD-relevant pathology ιn control neurons. Our findings, validated using an isogenic pair, demonstrate a critical impact of p.A53T-αSyn in disrupting astrocytic protein quality control mechanisms and establish astrocytes as active contributors to PD neuropathology. Our two-dimensional coculture model reflects key aspects of PD pathology, offering a relevant platform for mechanistic and drug discovery studies.