Nicholas Stafford

Background: Medical schools are under increasing pressure to teach larger cohorts while maintaining an excellent student experience. The University of Manchester replaced Problem-Based Learning (PBL) with Team-Based Learning (TBL) in 2023 to meet growing demand for medical education. While the educational effectiveness of TBL is well established, this study evaluated how the routine data generated within large-scale TBL could be potentially used to support early intervention, monitor curriculum quality, and validate peer assessment processes. Methods: We conducted a prospective mixed-methods evaluation of two consecutive Year-1 medical cohorts at a large UK medical school (2023–24, n = 435; 2024–25, n = 426). Data included TBL individual readiness assurance test (iRAT) scores, student experience surveys, operational measures, and end-of-semester examination results. In the second year, the 50 lowest-performing students after four teaching themes were identified using iRAT data and offered tailored academic and wellbeing support through their academic advisors. Results: TBL maintained high student satisfaction (74% rated sessions “excellent”) whilst simultaneously reducing weekly staff facilitator hours by 63% (160 h vs. 59 h) and room use by 84% (80 h of bookings vs. 13). Student individual weekly performance, as measured by iRAT scores, was strongly predictive of summative performance (R²≈0.38–0.41) and this finding is reproducible over consecutive years. Theme-level variation in iRAT performance also identified differences in content difficulty and alignment, providing a programme-level indicator of curriculum quality and areas of weaker delivery. Early identification and intervention of struggling students increased semester performance by 20% ( p < 0.0001) among the bottom 50 students, improved summative exam marks by 5%, and reduced exam failure rate by 41%, without inflating whole cohort attainment. Conclusions: This study shows how routine TBL data can function as a scalable analytics system to support early intervention, continuous curriculum monitoring, and quality assurance of peer assessment, while also reducing operational demands. These findings provide a transferable model for institutions seeking to expand capacity while maintaining educational quality and equity.

Cardiomyocyte loss following myocardial infarction cannot be addressed with current clinical therapies. Cell therapy with induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a potential approach to replace cardiomyocyte loss. However, engraftment rates in pre-clinical studies have been low, highlighting a need to refine current iPSC-CM technology. In this study, we demonstrated that inducing Yes-associated protein (YAP) by genetic and pharmacological approaches resulted in increased iPSC-CM proliferation and reduced apoptosis in response to oxidative stress. Interestingly, iPSC-CM maturation was differently affected by each strategy, with genetic activation of YAP resulting in a more immature cardiomyocyte-like phenotype not witnessed upon pharmacological YAP activation. Overall, we conclude that YAP activation in iPSC-CMs enhances cell survival and proliferative capacity. Therefore, strategies targeting YAP, or its upstream regulator the Hippo signalling pathway, could potentially be used to improve the efficacy of iPSC-CM technology for use as a future regenerative therapy in myocardial infarction.

Inflammation plays a key role during cardiac hypertrophy and the development of heart failure. Interleukin-10 (IL-10) is a major anti-inflammatory cytokine that is expressed in the heart and may play a crucial role in cardiac remodeling. Based on the evidence that IL-10 potentially reduces pathological hypertrophy, it was hypothesized that signaling via the IL-10 receptor (IL10R) in the heart produces a protective role in reducing cardiac hypertrophy. The aim of this study was to investigate the effects of the ablation of Il-10-r1 gene during pathological cardiac hypertrophy in mice. We found that IL-10R1 gene silencing in cultured cardiomyocytes diminished the anti-hypertrophic effect of Il-10 in TNF-α induced hypertrophy model. We then analyzed mice deficient in the Il-10-r1 gene (IL-10R1^-/- mice) and subjected them to transverse aortic constriction or isoproterenol infusion to induce pathological hypertrophy. In response to transverse aortic constriction for 2 weeks, IL-10R1^-/- mice displayed a significant increase in the hypertrophic response as indicated by heart weight/body weight ratio, which was accompanied by significant increases in cardiomyocyte surface area and interstitial fibrosis. In contrast, there was no difference in hypertrophic response to isoproterenol infusion (10 days) between the knockout and control groups. Analysis of cardiac function using echocardiography and invasive hemodynamic studies did not show any difference between the WT and IL-10R1^-/- groups, most likely due to the short term nature of the models. In conclusion, our data shows that signaling via the IL-10 receptor may produce protective effects against pressure overload-induced hypertrophy but not against β-adrenergic stimuli in the heart. Our data supports previous evidence that signaling modulated by IL-10 and its receptor may become a potential target to control pathological cardiac hypertrophy.

Background and Purpose: The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste‐20 like kinase 1 (Mst1) and mammalian Ste‐20 like kinase 2 (Mst2), modulate cardiac hypertrophy, apoptosis, and fibrosis. Here, we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU‐MP‐1 in controlling the adverse effects of pressure overload‐induced hypertrophy.Experimental Approach: We used cultured neonatal rat cardiomyocytes (NRCM) and C57Bl/6 mice with transverse aortic constriction (TAC) as in vitro and in vivo models, respectively, to test the effects of XMU‐MP‐1 treatment. We used luciferase reporter assays, western blots and immunofluorescence assays in vitro, with echocardiography, qRT‐PCR and immunohistochemical methods in vivo.Key Results: XMU‐MP‐1 treatment significantly increased activity of the Hippo pathway effector yes‐associated protein and inhibited phenylephrine‐induced hypertrophy in NRCM. XMU‐MP‐1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. In vivo, mice 3 weeks after TAC, were treated with XMU‐MP‐1 (1 mg·kg⁻¹) every alternate day for 10 further days. XMU‐MP‐1‐treated mice showed better cardiac contractility than vehicle‐treated mice. Cardiomyocyte cross‐sectional size and expression of the hypertrophic marker, brain natriuretic peptide, were reduced in XMU‐MP‐1‐treated mice. Improved heart function in XMU‐MP‐1‐treated mice with TAC, was accompanied by fewer TUNEL positive cardiomyocytes and lower levels of fibrosis, suggesting inhibition of cardiomyocyte apoptosis and decreased fibrosis.Conclusions and Implications: The Hippo pathway inhibitor, XMU‐MP‐1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload.

Introduction Ischaemic heart disease is a leading cause of death worldwide. Myocardial Infarction (MI) is caused by insufficient or no supply of oxygen to the heart due to narrowing of cardiac blood vessels. This may cause the death of cardiomyocytes, fibroblast and endothelial cells and lead to cardiac hypertrophy, and ultimately heart failure. Although current surgical treatments based on mechanical revascularisation like coronary bypass, grafting, or angioplasty exist, the chances of recurrent heart failure is higher in these patients. Emerging studies show that formation of new capillaries and blood vessels in the ischaemic heart is a promising therapeutical approach to circumvent the occluded blood supply. Unfortunately, the promising results obtained in animal pre-clinical models by delivery of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), into the ischaemic heart, have failed to be translated into clinical practice. Therefore, there is an urgent need to refine current approaches of therapeutic angiogenesis in order to improve neovascularization processes in the ischaemic heart. The recent identification from our laboratory of Plasma Membrane Calcium ATPase 4 (PMCA4) as a negative regulator of VEGF-driven angiogenesis has prompted us to hypothesise that targeting PMCA4-regulated pro-angiogenic signalling pathways can be used to increase cardiac revascularisation and restore blood flow to the myocardium at risk. Methods As a first attempt to elucidate the pro-angiogenic signalling pathways regulated by PMCA4, we have evaluated in this work the expression of genes related to Notch signalling in primary endothelial cells lacking PMCA4. Expression of PMCA4 in HUVEC was silenced by transfection with a siRNA specific for human PMCA4 (or non-target siRNA as control) and stimulated with VEGF. RNA isolated from control or PMCA4-silenced cells was used to screen an array of genes related to Notch signalling. Differences in gene expression were further validated by qPCR using TaqMan gene expression assays. Results Our results demonstrate that siRNA-mediated PMCA4 gene knockdown in primary endothelial cells strongly enhances the VEGF-induced upregulation of DLL1 and Hey1 gene expression. Lack of PMCA4 did not alter the expression of other important Notch ligands involved in angiogenesis regulation such as DLL4, demonstrating the specificity of our data. These data indicate that PMCA4 acts as a negative regulator of the VEGF-induced expression of DLL1 and Hey1. Conclusion These results suggest that PMCA4 negatively regulates Notch signaling activation in endothelial cells stimulated by the pro-angiogenic factor VEGF. Conflict of interest None

The regulation of cell death through apoptosis is essential to a number of physiological processes. Defective apoptosis regulation is associated with many abnormalities including anomalies in organ development, altered immune response and the development of cancer. Several signalling pathways are known to regulate apoptosis including the Tumour Necrosis Factor-α (TNF-α) and Hippo signalling pathways. In this paper we review the cross-talk between the TNF-α pathway and the Hippo signalling pathway. Several molecules that tightly regulate the Hippo pathway, such as members of the Ras-association domain family member (RASSF) family proteins, interact and modulate some key proteins within the TNF-α pathway. Meanwhile, TNF-α stimulation also affects the expression and activation of core components of the Hippo pathway. This implies the crucial role of signal integration between these two major pathways in regulating apoptosis.

Advanced glycation end products (AGE) are central to the development of cardiovascular complications associated with diabetes mellitus. AGE may alter cellular function through cross‐linking of cellular proteins or by activating the AGE receptor (RAGE). However, the signalling molecules involved during AGE stimulation in cardiomyocytes remain unclear. Here, we investigated the effects of AGE treatment on intracellular calcium homeostasis of isolated cardiomyocytes and studied the activation of signalling molecules involved in this process. Treatment of cardiomyocytes with AGE for 24 h resulted in a dose‐dependent reduction in calcium transient amplitude, reaching a maximum 50% reduction at a dose of 1 mg·mL⁻¹. This was accompanied with a 32% reduction in sarcoplasmic reticulum calcium content but without any detectable changes in the expression of major calcium channels. Mechanistically, we observed a significant increase in the production of reactive oxygen species (ROS) in AGE‐treated cardiomyocytes and enhancement of NADPH oxidase activity. This was accompanied with activation of p38 kinase and nuclear translocation of NF‐κB, and subsequently induction of inducible NO synthase (iNOS) expression, leading to excessive nitric oxide production. Overall, our data reveal the molecular signalling that may underlie the alteration of intracellular calcium homeostasis in cardiac myocytes due to AGE stimulation. This may provide new insights into the pathophysiological mechanisms of the development of diabetic cardiomyopathy.