Biology subjects

Scott, K. J.

Publications and source records attributed to Scott, K. J..

3 recordsLinked to original sources

bioRxiv2026

Multimodal MRI-based neuromarkers trace longitudinal changes in cognitive functioning in ADHD

The National Institute of Mental Healths Research Domain Criteria (RDoC) framework conceptualises cognition as a core functional domain for psychopathology that should be studied across multiple units of analysis and developmental timescales. In ADHD, however, it remains unclear whether neuroimaging-derived markers can not only predict inter-individual differences in cognition but also track longitudinal cognitive development and capture cognition-psychopathology relationships. Using the longitudinal Oregon ADHD-1000 study (n = 594 participants; 1,053 observations), we developed multimodal machine-learning markers of general cognitive functioning (g) from structural and resting-state functional MRI. The multimodal marker achieved an out-of-sample correlation of r = .46 and generalised similarly across children with and without ADHD. The marker explained 25.01% of interindividual variance (r = .48) and 18.82% of intraindividual variance (r = .52) in cognitive functioning. Commonality analyses showed that it captured 60.87% of intraindividual age-related cognitive variation (5.18% of the total variance in g). The marker also accounted for substantial portions of the cognition-hyperactivity association (58.79%; 6.39% of total variance in g) and the cognition-inattention association (25.99%; 4.13% of total variance in g). These findings provide evidence that multimodal structural and functional MRI can generate RDoC-informed markers that predict cognitive functioning, track cognitive development over time, and capture meaningful links between cognition and ADHD symptoms. Although predictive performance remains below levels required for clinical application, the results establish a foundation for longitudinal, RDoC-inspired investigations of cognitive development in ADHD.

neuroscience↗

bioRxiv2025

The immune and genetic heterogeneity of Hepatocellular Carcinoma, with a focus on multifocal disease

Understanding the genetic and immune heterogeneity in hepatocellular carcinoma (HCC) is crucial as treatments advance towards personalisation. This study characterises the genetic and immune heterogeneity within a population of 56 tumours from 28 patients, 10 of whom have multifocal disease, obtained from patients undergoing surgery at the Leeds Teaching Hospital NHS Trust. These samples represent the most common aetiological groups found in the UK: alcohol-related liver disease, non-alcoholic fatty liver disease and hepatitis C. Whole exome sequencing was performed on DNA from these tumour alongside matched background liver samples to determine tumour-specific variants. Tissue sections were stained for both proliferation and immune cell markers. Tumours across aetiological groups showed significant levels of variation, with high inter-individual variation. Analyses of multifocal tumours revealed significant discordance in genetic and immune cell profiles, both between multi-centric primary and metastatic tumours. This work emphasises the genetic and immuneheterogeneity in HCC across HCC subtypes, between and within individuals, highlighting mechansisms for therapeutic resistance and the need for personalised medicine.

cancer biology↗

bioRxiv2024

TKI-conditioned immunotherapy using uv-inactivated reovirus promotes survival in hepatocellular carcinoma, mediated by cytotoxic CD4+ T-cells

Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide. Combination immunotherapy is now standard of care for advanced HCC, improving patient outcomes. However, a considerable number of patients remain unresponsive, or are unable to tolerate therapy. Tyrosine kinase inhibitors (TKIs), such as the former first-line agent sorafenib, remain an option for such patients, yet provide only marginal efficacy. We hypothesised that a clinically advanced immunogenic "oncolytic" virus, namely, human Orthoreovirus, might improve TKI mediated therapy. Surprisingly, uv-inactivated, replication-deficient reovirus, but not live virus, significantly extended survival when combined with sorafenib in preclinical immunocompetent HCC models. Favourable responses were dependent upon adaptive immunity, mediated by IFNB-induced skewing of the infiltrating T-cell ratio in favour of cytotoxic CD4+ T-cells expressing granzyme B and perforin. Interestingly, this subset effectively killed tumours via both contact juxtacrine and paracrine processes, the former being MHCII independent. Moreover, efficacy correlated with more rapid and robust IFN production by inactivated virus due to the absence of innate viral antagonists. Thus, we reveal a means to improve TKI-HCC outcomes through an alternative virus-driven immunotherapy, underpinned by non-classical immunological mechanisms. IMPACT AND IMPLICATIONSImmune checkpoint immunotherapy is revolutionising cancer treatment, yet considerable numbers of patients still fail to respond and must resort to older, more toxic and less effective therapies, including Sorafenib for the management of HCC. We demonstrate that burgeoning virus-driven immunotherapy can be successfully combined with Sorafenib to extend preclinical HCC survival, but only when the virus is uv-inactivated to prevent already attenuated innate immune antagonism, specifically increasing the magnitude of tumour IFNB responses. IFNB was essential to promote tumour infiltration of cytotoxic CD4+ cells during therapy, which was a hallmark of long-term survival mediated by ensuing adaptive responses. We anticipate this work will be of interest to clinicians and cancer immunology researchers, promoting closer inspection of the immune microenvironment and cancer-specific responses to OV therapy, specifically those driven by non-canonical anti-cancer mechanisms involving IFNB and cytotoxic CD4+ T-cells.

immunology↗