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Cognitive symptoms in Primary Biliary Cholangitis (PBC)

2026-06-24T11:28:30Z

Title: Cognitive symptoms in Primary Biliary Cholangitis (PBC) Authors: Phaw, Naw April Abstract: Patients with primary biliary cholangitis (PBC) may suffer from cognitive symptoms in addition to the primary disease burden. These symptoms impact on quality of life but, to date, we have no pharmacological therapies demonstrated to improve these symptoms. It is crucial to understand the nature of cognitive symptoms and underlying neuropathological processes in PBC for the development of effective future clinical trials. In this thesis, neuropsychometric assessments and magnetic resonance Diffusion Tensor Imaging (DTI) measurements were used to determine the nature of cognitive symptoms in PBC, and to explore white matter pathology, as a potential explanation, respectively. In this thesis, cognitive deficits in PBC were found in multiple domains with pronounced impairments in memory, attention, and emotional cognition. Neuropsychometric testing demonstrated cognitive deficits in both patients reporting significant cognitive difficulties and asymptomatic patients, compared to a normative population. Therefore, cognitive symptoms in PBC may be influenced by behavioural variation. Nevertheless, those reporting cognitive symptoms are typically the group with the highest unmet clinical need, and likely to be prioritized for interventional studies. We found that PBC-40 cognitive scores were not closely associated with fractional anisotropy (FA) values from deep white matter tracts, contrary to what we had hypothesised. This suggests that cognitive symptoms do not arise from white matter tract dysfunction, although we acknowledge that we only studied a small number of a priori regions. Only patients with cholestasis demonstrated significant cognitive deficits. Based on these findings, we propose that cognitive symptoms may only become apparent when cholestasis is established, and therefore aggressive treatment for cholestasis at an early stage may be needed. Overall, the characterisation of cognitive symptoms in PBC, together with exploratory brain imaging, are important steps for informing the design of future PBC therapeutic trials by establishing reference endpoints for future studies. Description: MD Thesis

Investigating the systemic immune landscape of thymectomised paediatric transplant patients at risk of EBV-associated post-transplant lymphoproliferative disease

2026-06-24T11:22:48Z

Title: Investigating the systemic immune landscape of thymectomised paediatric transplant patients at risk of EBV-associated post-transplant lymphoproliferative disease Authors: Offor, Ugonna T. Abstract: Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD) are rare but life-threatening lymphoid malignancies that disproportionately affect paediatric heart transplant recipients. Recent discourse has focussed on the role of early removal of the thymus gland, which is critical for normal antiviral immunity, in the aetiology of EBV-PTLD after heart transplantation. This Fellowship aimed to investigate the systemic immune landscape of thymectomised paediatric transplant patients at risk of EBV-PTLD. Fifty-four patients awaiting transplant were recruited to the Immunology of THymectomy And childhood CArdiac transplant (ITHACA) study for immune profiling using full spectrum flow cytometry before transplant and at 3-, 6-, 12-and 24-months post-transplant. Patients were stratified into early (<6 months old) and late (≥6 months old) thymectomy for comparison to age-matched non thymectomy controls. Induction immunosuppression with anti-thymocyte globulin was associated with diminished antiviral CD16+ monocytes compared to Basiliximab induction. Failed expansion of CD16+ monocyte subsets was notable among patients with EBV DNAemia alongside a negative correlation between EBV DNA load and their expression of activation markers. Mycophenolate Mofetil was associated with an overall reduction in NK cells and a phenotypic shift towards immunosenescence. EBV DNAemia was associated with a marked increase in CD16dim CD56dim NK cells but a failure to expand the CD56dim NKG2A+ KIR- subset required for effective EBV control. Early thymectomy was associated with the depletion of regulatory, naïve CD4+ and CD8+ T-lymphocytes and expansion of senescent CD57+ memory T-lymphocytes. Most of these changes persisted after transplant and included the emergence of terminal effector memory subsets with increased expression of immune checkpoint proteins within the memory compartment of early thymectomy patients. Increased immunosenescence and exhaustion of EBV-specific T-lymphocytes were associated with early thymectomy and persistent EBV DNAemia. These data demonstrate that both early thymectomy and choice of immunosuppression are associated with distinct features of immunosenescence, exhaustion and impaired EBV control, all likely contributing to the risk of developing to EBV-PTLD. Description: PhD Thesis

Targeting non-canonical NF-κB signalling in CYLD defective tumours

2026-06-24T11:06:32Z

Title: Targeting non-canonical NF-κB signalling in CYLD defective tumours Authors: Hodgson, Kirsty Abstract: CYLD cutaneous syndrome (CCS) is a rare, autosomal dominant, hair follicle tumour predisposition syndrome where non-surgical therapeutics are needed. In this thesis I delineate non-canonical NF-κB signalling in CYLD defective tumours and evaluate the utility of targeting this pathway with novel small molecule IKKα inhibitors. Such information may underpin the potential development of non-surgical approaches for CCS. First, I sought to establish the genetic landscape of tumours in CCS. Using whole genome sequencing, I showed that biallelic mutation of the cylindromatosis gene (CYLD) was present in almost all tumours studied. In addition, I discovered that a subset of tumours had mutations in epigenetic modifiers that modulate Wnt signalling, a known oncogenic dependency in these tumour cells. CCS has not been successfully modelled in mice, limiting mechanistic insight into how truncating mutations in CYLD result in a skin tumour phenotype. To overcome this, I explored both the canonical and non-canonical NF-κB signalling pathways in CCS whole tumour tissue. I also developed a patient-derived tumour spheroid model that recapitulated in vivo deregulation of both NF-κB signalling pathways. In the non-canonical pathway, I showed processing of the p52 precursor p100 was altered in CCS tumour tissue and spheroids. Given non-canonical NF-κB signalling is targetable by inhibiting IKKα, I inhibited IKKα in CCS spheroids with a novel compound, designated Compound Z, and showed reduction in viability following treatment. To determine the impact of biallelic CYLD truncating mutations on the transcriptome, I used a CD45 depletion method to isolate CD45- CCS tumour keratinocytes by FACS. RNA-sequencing of tumour keratinocytes identified the ectodysplasin a receptor EDAR as highly differentially expressed. Measurement of gene expression after treatment with Compound Z confirmed that EDAR overexpression is IKKα-dependent in CCS spheroids. In summary, I have highlighted the oncogenic dependency of CCS tumour cells on non-canonical NF-κB signalling and demonstrate the effectiveness of targeting IKKα for the treatment of CYLD cutaneous syndrome. Description: Ph. D. Thesis.

Structured cardiac assessment and treatment following exacerbations of Chronic Obstructive Pulmonary Disease

2026-06-16T09:31:51Z

Title: Structured cardiac assessment and treatment following exacerbations of Chronic Obstructive Pulmonary Disease Authors: Kibbler, Joseph Abstract: Introduction: Heart disease is common in COPD, yet is inadequately managed due to systemic deficiencies in both diagnosis and treatment. Through a systematic review and meta-analysis of published studies, it is estimated that 10-20% of patients have undiagnosed left ventricular systolic dysfunction. During exacerbations of COPD (ECOPD), cardiac risk is temporally elevated. In view of these problems, a pilot randomised controlled trial, examining the feasibility and effect of inpatient structured cardiac assessment (SCA) to diagnose and prompt guideline recommended treatment of heart disease, was conducted. Methods: 115 inpatients with ECOPD were randomised 1:1 to receive usual care (UC, n=58) or SCA (n=57), comprising transthoracic echocardiography, CT coronary artery calcium scoring, 24-hour ECG, blood pressure and diabetes assessment. Follow-up was for 12 months. The prevalence of underdiagnosis and undertreatment of heart disease were captured, and potential outcome measures for future trials assessed. An economic analysis was also rehearsed. Results: Among patients undergoing SCA, 42/57 (73.7%) received a new cardiac diagnosis compared with 11/58 (19.0%; p<0.001) in UC. When heart disease was diagnosed, the proportion receiving optimal treatment at discharge was significantly higher in SCA (35/47 (74%) vs 4/11 (34%); p=0.029). There was no difference in days alive outside hospital between the arms. Survival curves for both adverse cardiovascular and cardiopulmonary events separated throughout follow-up, with ACE occurring in 17.2% in usual care vs. 10.5% in SCA in one year. The economic analysis suggested a low probability of cost-effectiveness, but estimates were very broad. Conclusions: A structured cardiac assessment during ECOPD significantly improved diagnosis and treatment of heart disease. Further research is needed in order to establish how to deliver SCA with the greatest clinical and economic effectiveness. Future interventional trials should use time to first adverse cardiovascular or cardiopulmonary event as the primary outcome. Description: PhD Thesis